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FDA approves time-saving combo for r/r multiple myeloma
The U.S. Food and Drug Administration who have had one to three prior lines of therapy.
Using the newly approved combination in this setting is a time-saver for patients and clinics, observed an investigator.
“The approval of subcutaneous daratumumab in combination with Kd will help clinicians address unmet patient needs by reducing the administration time from hours to just minutes and reducing the frequency of infusion-related reactions, as compared to the intravenous daratumumab formulation in combination with Kd,” said Ajai Chari, MD, of Mount Sinai Cancer Clinical Trials Office in New York City in a Janssen press statement.
Efficacy data for the new approval come from a single-arm cohort of PLEIADES, a multicohort, open-label trial. The cohort included 66 patients with relapsed or refractory multiple myeloma who had received one or more prior lines of therapy. Patients received daratumumab + hyaluronidase-fihj subcutaneously in combination with carfilzomib and dexamethasone.
The main efficacy outcome measure was overall response rate, which was 84.8%. At a median follow-up of 9.2 months, the median duration of response had not been reached.
The response rate with the new combination, which features a subcutaneous injection, was akin to those with the older combination, which features the more time-consuming IV administration and was FDA approved, according to the company press release.
The most common adverse reactions (≥20%) occurring in patients treated with Darzalex Faspro, Kyprolis, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.
A version of this article first appeared on Medscape.com .
The U.S. Food and Drug Administration who have had one to three prior lines of therapy.
Using the newly approved combination in this setting is a time-saver for patients and clinics, observed an investigator.
“The approval of subcutaneous daratumumab in combination with Kd will help clinicians address unmet patient needs by reducing the administration time from hours to just minutes and reducing the frequency of infusion-related reactions, as compared to the intravenous daratumumab formulation in combination with Kd,” said Ajai Chari, MD, of Mount Sinai Cancer Clinical Trials Office in New York City in a Janssen press statement.
Efficacy data for the new approval come from a single-arm cohort of PLEIADES, a multicohort, open-label trial. The cohort included 66 patients with relapsed or refractory multiple myeloma who had received one or more prior lines of therapy. Patients received daratumumab + hyaluronidase-fihj subcutaneously in combination with carfilzomib and dexamethasone.
The main efficacy outcome measure was overall response rate, which was 84.8%. At a median follow-up of 9.2 months, the median duration of response had not been reached.
The response rate with the new combination, which features a subcutaneous injection, was akin to those with the older combination, which features the more time-consuming IV administration and was FDA approved, according to the company press release.
The most common adverse reactions (≥20%) occurring in patients treated with Darzalex Faspro, Kyprolis, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.
A version of this article first appeared on Medscape.com .
The U.S. Food and Drug Administration who have had one to three prior lines of therapy.
Using the newly approved combination in this setting is a time-saver for patients and clinics, observed an investigator.
“The approval of subcutaneous daratumumab in combination with Kd will help clinicians address unmet patient needs by reducing the administration time from hours to just minutes and reducing the frequency of infusion-related reactions, as compared to the intravenous daratumumab formulation in combination with Kd,” said Ajai Chari, MD, of Mount Sinai Cancer Clinical Trials Office in New York City in a Janssen press statement.
Efficacy data for the new approval come from a single-arm cohort of PLEIADES, a multicohort, open-label trial. The cohort included 66 patients with relapsed or refractory multiple myeloma who had received one or more prior lines of therapy. Patients received daratumumab + hyaluronidase-fihj subcutaneously in combination with carfilzomib and dexamethasone.
The main efficacy outcome measure was overall response rate, which was 84.8%. At a median follow-up of 9.2 months, the median duration of response had not been reached.
The response rate with the new combination, which features a subcutaneous injection, was akin to those with the older combination, which features the more time-consuming IV administration and was FDA approved, according to the company press release.
The most common adverse reactions (≥20%) occurring in patients treated with Darzalex Faspro, Kyprolis, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.
A version of this article first appeared on Medscape.com .
Severe COVID two times higher for cancer patients
A new systematic review and meta-analysis finds that unvaccinated cancer patients who contracted COVID-19 last year, were more than two times more likely – than people without cancer – to develop a case of COVID-19 so severe it required hospitalization in an intensive care unit.
“Our study provides the most precise measure to date of the effect of COVID-19 in cancer patients,” wrote researchers who were led by Paolo Boffetta, MD, MPH, a specialist in population science with the Stony Brook Cancer Center in New York.
Dr. Boffetta and colleagues also found that patients with hematologic neoplasms had a higher mortality rate from COVID-19 comparable to that of all cancers combined.
Cancer patients have long been considered to be among those patients who are at high risk of developing COVID-19, and if they contract the disease, they are at high risk of having poor outcomes. Other high-risk patients include those with hypertension, diabetes, chronic kidney disease, or COPD, or the elderly. But how high the risk of developing severe COVID-19 disease is for cancer patients hasn’t yet been documented on a wide scale.
The study, which was made available as a preprint on medRxiv on Oct. 23, is based on an analysis of COVID-19 cases that were documented in 35 reviews, meta-analyses, case reports, and studies indexed in PubMed from authors in North America, Europe, and Asia.
In this study, the pooled odds ratio for mortality for all patients with any cancer was 2.32 (95% confidence interval, 1.82-2.94; 24 studies). For ICU admission, the odds ratio was 2.39 (95% CI, 1.90-3.02; I2 0.0%; 5 studies). And, for disease severity or hospitalization, it was 2.08 (95% CI, 1.60-2.72; I2 92.1%; 15 studies). The pooled mortality odds ratio for hematologic neoplasms was 2.14 (95% CI, 1.87-2.44; I2 20.8%; 8 studies).
Their findings, which have not yet been peer reviewed, confirmed the results of a similar analysis from China published as a preprint in May 2020. The analysis included 181,323 patients (23,736 cancer patients) from 26 studies reported an odds ratio of 2.54 (95% CI, 1.47-4.42). “Cancer patients with COVID-19 have an increased likelihood of death compared to non-cancer COVID-19 patients,” Venkatesulu et al. wrote. And a systematic review and meta-analysis of five studies of 2,619 patients published in October 2020 in Medicine also found a significantly higher risk of death from COVID-19 among cancer patients (odds ratio, 2.63; 95% confidence interval, 1.14-6.06; P = .023; I2 = 26.4%).
Fakih et al., writing in the journal Hematology/Oncology and Stem Cell Therapy conducted a meta-analysis early last year finding a threefold increase for admission to the intensive care unit, an almost fourfold increase for a severe SARS-CoV-2 infection, and a fivefold increase for being intubated.
The three studies show that mortality rates were higher early in the pandemic “when diagnosis and treatment for SARS-CoV-2 might have been delayed, resulting in higher death rate,” Boffetta et al. wrote, adding that their analysis showed only a twofold increase most likely because it was a year-long analysis.
“Future studies will be able to better analyze this association for the different subtypes of cancer. Furthermore, they will eventually be able to evaluate whether the difference among vaccinated population is reduced,” Boffetta et al. wrote.
The authors noted several limitations for the study, including the fact that many of the studies included in the analysis did not include sex, age, comorbidities, and therapy. Nor were the authors able to analyze specific cancers other than hematologic neoplasms.
The authors declared no conflicts of interest.
A new systematic review and meta-analysis finds that unvaccinated cancer patients who contracted COVID-19 last year, were more than two times more likely – than people without cancer – to develop a case of COVID-19 so severe it required hospitalization in an intensive care unit.
“Our study provides the most precise measure to date of the effect of COVID-19 in cancer patients,” wrote researchers who were led by Paolo Boffetta, MD, MPH, a specialist in population science with the Stony Brook Cancer Center in New York.
Dr. Boffetta and colleagues also found that patients with hematologic neoplasms had a higher mortality rate from COVID-19 comparable to that of all cancers combined.
Cancer patients have long been considered to be among those patients who are at high risk of developing COVID-19, and if they contract the disease, they are at high risk of having poor outcomes. Other high-risk patients include those with hypertension, diabetes, chronic kidney disease, or COPD, or the elderly. But how high the risk of developing severe COVID-19 disease is for cancer patients hasn’t yet been documented on a wide scale.
The study, which was made available as a preprint on medRxiv on Oct. 23, is based on an analysis of COVID-19 cases that were documented in 35 reviews, meta-analyses, case reports, and studies indexed in PubMed from authors in North America, Europe, and Asia.
In this study, the pooled odds ratio for mortality for all patients with any cancer was 2.32 (95% confidence interval, 1.82-2.94; 24 studies). For ICU admission, the odds ratio was 2.39 (95% CI, 1.90-3.02; I2 0.0%; 5 studies). And, for disease severity or hospitalization, it was 2.08 (95% CI, 1.60-2.72; I2 92.1%; 15 studies). The pooled mortality odds ratio for hematologic neoplasms was 2.14 (95% CI, 1.87-2.44; I2 20.8%; 8 studies).
Their findings, which have not yet been peer reviewed, confirmed the results of a similar analysis from China published as a preprint in May 2020. The analysis included 181,323 patients (23,736 cancer patients) from 26 studies reported an odds ratio of 2.54 (95% CI, 1.47-4.42). “Cancer patients with COVID-19 have an increased likelihood of death compared to non-cancer COVID-19 patients,” Venkatesulu et al. wrote. And a systematic review and meta-analysis of five studies of 2,619 patients published in October 2020 in Medicine also found a significantly higher risk of death from COVID-19 among cancer patients (odds ratio, 2.63; 95% confidence interval, 1.14-6.06; P = .023; I2 = 26.4%).
Fakih et al., writing in the journal Hematology/Oncology and Stem Cell Therapy conducted a meta-analysis early last year finding a threefold increase for admission to the intensive care unit, an almost fourfold increase for a severe SARS-CoV-2 infection, and a fivefold increase for being intubated.
The three studies show that mortality rates were higher early in the pandemic “when diagnosis and treatment for SARS-CoV-2 might have been delayed, resulting in higher death rate,” Boffetta et al. wrote, adding that their analysis showed only a twofold increase most likely because it was a year-long analysis.
“Future studies will be able to better analyze this association for the different subtypes of cancer. Furthermore, they will eventually be able to evaluate whether the difference among vaccinated population is reduced,” Boffetta et al. wrote.
The authors noted several limitations for the study, including the fact that many of the studies included in the analysis did not include sex, age, comorbidities, and therapy. Nor were the authors able to analyze specific cancers other than hematologic neoplasms.
The authors declared no conflicts of interest.
A new systematic review and meta-analysis finds that unvaccinated cancer patients who contracted COVID-19 last year, were more than two times more likely – than people without cancer – to develop a case of COVID-19 so severe it required hospitalization in an intensive care unit.
“Our study provides the most precise measure to date of the effect of COVID-19 in cancer patients,” wrote researchers who were led by Paolo Boffetta, MD, MPH, a specialist in population science with the Stony Brook Cancer Center in New York.
Dr. Boffetta and colleagues also found that patients with hematologic neoplasms had a higher mortality rate from COVID-19 comparable to that of all cancers combined.
Cancer patients have long been considered to be among those patients who are at high risk of developing COVID-19, and if they contract the disease, they are at high risk of having poor outcomes. Other high-risk patients include those with hypertension, diabetes, chronic kidney disease, or COPD, or the elderly. But how high the risk of developing severe COVID-19 disease is for cancer patients hasn’t yet been documented on a wide scale.
The study, which was made available as a preprint on medRxiv on Oct. 23, is based on an analysis of COVID-19 cases that were documented in 35 reviews, meta-analyses, case reports, and studies indexed in PubMed from authors in North America, Europe, and Asia.
In this study, the pooled odds ratio for mortality for all patients with any cancer was 2.32 (95% confidence interval, 1.82-2.94; 24 studies). For ICU admission, the odds ratio was 2.39 (95% CI, 1.90-3.02; I2 0.0%; 5 studies). And, for disease severity or hospitalization, it was 2.08 (95% CI, 1.60-2.72; I2 92.1%; 15 studies). The pooled mortality odds ratio for hematologic neoplasms was 2.14 (95% CI, 1.87-2.44; I2 20.8%; 8 studies).
Their findings, which have not yet been peer reviewed, confirmed the results of a similar analysis from China published as a preprint in May 2020. The analysis included 181,323 patients (23,736 cancer patients) from 26 studies reported an odds ratio of 2.54 (95% CI, 1.47-4.42). “Cancer patients with COVID-19 have an increased likelihood of death compared to non-cancer COVID-19 patients,” Venkatesulu et al. wrote. And a systematic review and meta-analysis of five studies of 2,619 patients published in October 2020 in Medicine also found a significantly higher risk of death from COVID-19 among cancer patients (odds ratio, 2.63; 95% confidence interval, 1.14-6.06; P = .023; I2 = 26.4%).
Fakih et al., writing in the journal Hematology/Oncology and Stem Cell Therapy conducted a meta-analysis early last year finding a threefold increase for admission to the intensive care unit, an almost fourfold increase for a severe SARS-CoV-2 infection, and a fivefold increase for being intubated.
The three studies show that mortality rates were higher early in the pandemic “when diagnosis and treatment for SARS-CoV-2 might have been delayed, resulting in higher death rate,” Boffetta et al. wrote, adding that their analysis showed only a twofold increase most likely because it was a year-long analysis.
“Future studies will be able to better analyze this association for the different subtypes of cancer. Furthermore, they will eventually be able to evaluate whether the difference among vaccinated population is reduced,” Boffetta et al. wrote.
The authors noted several limitations for the study, including the fact that many of the studies included in the analysis did not include sex, age, comorbidities, and therapy. Nor were the authors able to analyze specific cancers other than hematologic neoplasms.
The authors declared no conflicts of interest.
FROM MEDRXIV
FDA warns of higher death risk with Pepaxto in multiple myeloma
participating in the ongoing OCEAN clinical trial.
The drug was granted accelerated approval in February 2021 for use in combination with dexamethasone in the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
As a condition of the accelerated approval, the manufacturer, Oncopeptides, was required to conduct a confirmatory clinical trial and launched the OCEAN trial.
Enrollment in OCEAN as well as other ongoing trials of the drug have now been halted, according to the FDA alert.
The warning comes in the wake of OCEAN trial findings showing worse survival among patients in the experimental group, who were receiving melphalan plus low-dose dexamethasone, compared with patients in the control group, who were receiving pomalidomide plus low-dose dexamethasone (hazard ratio for overall survival, 1.104). Median overall survival in the treatment and control groups was 19.7 and 25.0 months, respectively.
Health care professionals should “review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments,” and patients currently receiving the drug should discuss the risks and benefits with their health care professional, the FDA advises. “Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”
The FDA also hinted at “a future public meeting to discuss the safety findings and explore the continued marketing of Pepaxto,” which has a price tag of $19,000 per treatment course.
Accelerated approval data
Melphalan flufenamide was initially evaluated in combination with low-dose dexamethasone in the multicenter, single-arm HORIZON trial of adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
Patients received melphalan flufenamide at a dose of 40 mg intravenously on day 1 along with oral dexamethasone at a dose of 40 mg (or 20 mg for those over age 75 years) on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.
The most common adverse reactions, occurring in at least 20% of patients, were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities, occurring in at least 50% of patients, were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.
Accelerated approval was granted after the HORIZON trial showed an overall response rate of 23.7% and median duration of response of 4.2 months. The application by Oncopeptides received priority review and orphan drug status.
Confirmatory trial data
The confirmatory OCEAN trial compared melphalan flufenamide plus low-dose dexamethasone to pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2-4 lines of therapy and in patients who were resistant to lenalidomide in the last line of therapy.
The FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cutoff date of February 3, 2021. At a median follow-up of 19.1 months, 117 of 246 patients (48%) in the melphalan flufenamide group had died, compared with 108 of 249 patients (43%) in the pomalidomide control group.
“Patient safety is paramount to Oncopeptides,” the company said in a press statement, which also notes that “dialogue with the FDA” is ongoing and that updated information will be provided as it becomes available.
The company plans to submit complete data from the OCEAN study to the International Myeloma Workshop meeting in Vienna being held September 8-11, 2021.
Health care professionals and patients should report adverse events or quality issues experienced with melphalan flufenamide or any other medication to the FDA MedWatch Adverse Event Reporting program, either online or by downloading and completing a reporting form and submitting via fax at 1-800-FDA-0178.
A version of this article first appeared on Medscape.com.
participating in the ongoing OCEAN clinical trial.
The drug was granted accelerated approval in February 2021 for use in combination with dexamethasone in the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
As a condition of the accelerated approval, the manufacturer, Oncopeptides, was required to conduct a confirmatory clinical trial and launched the OCEAN trial.
Enrollment in OCEAN as well as other ongoing trials of the drug have now been halted, according to the FDA alert.
The warning comes in the wake of OCEAN trial findings showing worse survival among patients in the experimental group, who were receiving melphalan plus low-dose dexamethasone, compared with patients in the control group, who were receiving pomalidomide plus low-dose dexamethasone (hazard ratio for overall survival, 1.104). Median overall survival in the treatment and control groups was 19.7 and 25.0 months, respectively.
Health care professionals should “review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments,” and patients currently receiving the drug should discuss the risks and benefits with their health care professional, the FDA advises. “Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”
The FDA also hinted at “a future public meeting to discuss the safety findings and explore the continued marketing of Pepaxto,” which has a price tag of $19,000 per treatment course.
Accelerated approval data
Melphalan flufenamide was initially evaluated in combination with low-dose dexamethasone in the multicenter, single-arm HORIZON trial of adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
Patients received melphalan flufenamide at a dose of 40 mg intravenously on day 1 along with oral dexamethasone at a dose of 40 mg (or 20 mg for those over age 75 years) on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.
The most common adverse reactions, occurring in at least 20% of patients, were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities, occurring in at least 50% of patients, were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.
Accelerated approval was granted after the HORIZON trial showed an overall response rate of 23.7% and median duration of response of 4.2 months. The application by Oncopeptides received priority review and orphan drug status.
Confirmatory trial data
The confirmatory OCEAN trial compared melphalan flufenamide plus low-dose dexamethasone to pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2-4 lines of therapy and in patients who were resistant to lenalidomide in the last line of therapy.
The FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cutoff date of February 3, 2021. At a median follow-up of 19.1 months, 117 of 246 patients (48%) in the melphalan flufenamide group had died, compared with 108 of 249 patients (43%) in the pomalidomide control group.
“Patient safety is paramount to Oncopeptides,” the company said in a press statement, which also notes that “dialogue with the FDA” is ongoing and that updated information will be provided as it becomes available.
The company plans to submit complete data from the OCEAN study to the International Myeloma Workshop meeting in Vienna being held September 8-11, 2021.
Health care professionals and patients should report adverse events or quality issues experienced with melphalan flufenamide or any other medication to the FDA MedWatch Adverse Event Reporting program, either online or by downloading and completing a reporting form and submitting via fax at 1-800-FDA-0178.
A version of this article first appeared on Medscape.com.
participating in the ongoing OCEAN clinical trial.
The drug was granted accelerated approval in February 2021 for use in combination with dexamethasone in the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
As a condition of the accelerated approval, the manufacturer, Oncopeptides, was required to conduct a confirmatory clinical trial and launched the OCEAN trial.
Enrollment in OCEAN as well as other ongoing trials of the drug have now been halted, according to the FDA alert.
The warning comes in the wake of OCEAN trial findings showing worse survival among patients in the experimental group, who were receiving melphalan plus low-dose dexamethasone, compared with patients in the control group, who were receiving pomalidomide plus low-dose dexamethasone (hazard ratio for overall survival, 1.104). Median overall survival in the treatment and control groups was 19.7 and 25.0 months, respectively.
Health care professionals should “review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments,” and patients currently receiving the drug should discuss the risks and benefits with their health care professional, the FDA advises. “Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”
The FDA also hinted at “a future public meeting to discuss the safety findings and explore the continued marketing of Pepaxto,” which has a price tag of $19,000 per treatment course.
Accelerated approval data
Melphalan flufenamide was initially evaluated in combination with low-dose dexamethasone in the multicenter, single-arm HORIZON trial of adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
Patients received melphalan flufenamide at a dose of 40 mg intravenously on day 1 along with oral dexamethasone at a dose of 40 mg (or 20 mg for those over age 75 years) on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.
The most common adverse reactions, occurring in at least 20% of patients, were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities, occurring in at least 50% of patients, were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.
Accelerated approval was granted after the HORIZON trial showed an overall response rate of 23.7% and median duration of response of 4.2 months. The application by Oncopeptides received priority review and orphan drug status.
Confirmatory trial data
The confirmatory OCEAN trial compared melphalan flufenamide plus low-dose dexamethasone to pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2-4 lines of therapy and in patients who were resistant to lenalidomide in the last line of therapy.
The FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cutoff date of February 3, 2021. At a median follow-up of 19.1 months, 117 of 246 patients (48%) in the melphalan flufenamide group had died, compared with 108 of 249 patients (43%) in the pomalidomide control group.
“Patient safety is paramount to Oncopeptides,” the company said in a press statement, which also notes that “dialogue with the FDA” is ongoing and that updated information will be provided as it becomes available.
The company plans to submit complete data from the OCEAN study to the International Myeloma Workshop meeting in Vienna being held September 8-11, 2021.
Health care professionals and patients should report adverse events or quality issues experienced with melphalan flufenamide or any other medication to the FDA MedWatch Adverse Event Reporting program, either online or by downloading and completing a reporting form and submitting via fax at 1-800-FDA-0178.
A version of this article first appeared on Medscape.com.
Personalized cancer vaccine shows early promise across tumor types
The vaccine, PGV-001, was given to 13 patients with solid tumors or multiple myeloma who had a high risk of recurrence after surgery or autologous stem cell transplant.
At last follow-up, four patients were still alive without evidence of disease and had not received subsequent therapy, four were alive and receiving therapy, three had died, and two were lost to follow-up.
Thomas Marron, MD, PhD , of Mount Sinai in New York presented these results in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 ( Abstract LB048 ). Data in the abstract differ from the data presented.
“While cancer immunotherapy has revolutionized the treatment of cancer, we know that the majority of patients fail to achieve significant clinical response,” Dr. Marron said during his presentation. “One reason for this may be due to lack of preexisting primed T-cell response needed for PD-1 blockade to have a significant effect. To address this, personalized neoantigen vaccines may help prime an improved immune response against tumor cells.”
With this in mind, Dr. Marron and colleagues developed PGV-001, a vaccine consisting of patient-specific synthetic neoantigen peptides given to patients in the adjuvant setting.
Creating a personalized vaccine
The researchers synthesized PGV-001 for 15 patients with advanced malignancies. The patients first underwent tumor and germline DNA sequencing as well as HLA typing. Bulk RNA sequencing was performed on patients’ tumors as well.
Then, the researchers used a computational pipeline called OpenVax to identify candidate neoantigens. This pipeline, developed at Mount Sinai, identified and prioritized candidate neoantigens using predicted MHC class I binding affinity and neoantigen abundance.
OpenVax identified an average of 71.5 neoantigens per patient (range, 7-193). The goal was to synthesize a maximum of 10 peptides per patient, but two patients did not have an adequate number of neoantigens.
Vaccine administration
The peptides were administered over the course of 27 weeks along with poly-ICLC and a tetanus helper peptide. Before receiving their vaccine doses, patients with solid tumors had undergone curative-intent surgery, and those with multiple myeloma had undergone autologous stem cell transplant.
“Most experimental personalized cancer vaccines are administered in the metastatic setting, but prior research indicates that immunotherapies tend to be more effective in patients who have less cancer spread,” principal investigator Nina Bhardwaj, MD, PhD , of Mount Sinai, explained in a press release .
“We have, therefore, developed a neoantigen vaccine that is administered after standard-of-care adjuvant therapy, such as surgery in solid tumors and bone marrow transplant in multiple myeloma, when patients have minimal, typically microscopic, residual disease.”
Feasibility, safety, and immunogenicity
PGV-001 was synthesized for 15 patients and administered to 13 of them. Six of the 13 patients had head and neck squamous cell carcinoma, three had multiple myeloma, two had non–small cell lung cancer, one had breast cancer, and one had urothelial carcinoma.
Eleven patients received all 10 intended doses, and two patients received at least 8 doses.
“The vaccine was well tolerated, with only half of patients experiencing mild, grade 1 adverse events,” Dr. Marron said.
Transient injection site reactions occurred in four patients, and grade 1 fever was reported in one patient.
Immune monitoring is ongoing, but an initial analysis in one patient showed “robust responses” in CD4 and CD8 T cells by intracellular cytokine staining for interferon-gamma, tumor necrosis factor–alpha, and interleukin-2 after in vitro expansion in the presence of vaccine antigens, according to the researchers.
Dr. Marron noted that robust T-cell reactivity was seen at the completion of all 10 doses but was not seen after the 6th dose, and this supports the need for a prolonged dosing schedule.
Survival and subsequent therapy
At a mean follow-up of 880 days, four patients had no evidence of disease and had not received subsequent therapy. This includes one patient with stage IIIA non–small cell lung cancer, one with stage IVA HER-2 positive breast cancer, one with stage II urothelial carcinoma, and one with multiple myeloma.
Four patients were alive and receiving subsequent lines of therapy. Two of these patients had significant responses to anti–PD-1 therapy.
Three patients have died, two of whom had documented recurrence of their malignancy. The last two patients were lost to follow-up without documented recurrence.
“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” Dr. Bhardwaj said.
Trials combining neoantigens identified with the OpenVax platform are ongoing in patients with urothelial carcinoma and glioblastoma multiforme, Dr. Marron said.
The current study ( NCT02721043 ) is sponsored by Dr. Bhardwaj. Dr. Marron and Dr. Bhardwaj reported having no disclosures. Their colleagues disclosed relationships with Bristol Myers Squibb, Sema4, and Related Sciences.
The vaccine, PGV-001, was given to 13 patients with solid tumors or multiple myeloma who had a high risk of recurrence after surgery or autologous stem cell transplant.
At last follow-up, four patients were still alive without evidence of disease and had not received subsequent therapy, four were alive and receiving therapy, three had died, and two were lost to follow-up.
Thomas Marron, MD, PhD , of Mount Sinai in New York presented these results in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 ( Abstract LB048 ). Data in the abstract differ from the data presented.
“While cancer immunotherapy has revolutionized the treatment of cancer, we know that the majority of patients fail to achieve significant clinical response,” Dr. Marron said during his presentation. “One reason for this may be due to lack of preexisting primed T-cell response needed for PD-1 blockade to have a significant effect. To address this, personalized neoantigen vaccines may help prime an improved immune response against tumor cells.”
With this in mind, Dr. Marron and colleagues developed PGV-001, a vaccine consisting of patient-specific synthetic neoantigen peptides given to patients in the adjuvant setting.
Creating a personalized vaccine
The researchers synthesized PGV-001 for 15 patients with advanced malignancies. The patients first underwent tumor and germline DNA sequencing as well as HLA typing. Bulk RNA sequencing was performed on patients’ tumors as well.
Then, the researchers used a computational pipeline called OpenVax to identify candidate neoantigens. This pipeline, developed at Mount Sinai, identified and prioritized candidate neoantigens using predicted MHC class I binding affinity and neoantigen abundance.
OpenVax identified an average of 71.5 neoantigens per patient (range, 7-193). The goal was to synthesize a maximum of 10 peptides per patient, but two patients did not have an adequate number of neoantigens.
Vaccine administration
The peptides were administered over the course of 27 weeks along with poly-ICLC and a tetanus helper peptide. Before receiving their vaccine doses, patients with solid tumors had undergone curative-intent surgery, and those with multiple myeloma had undergone autologous stem cell transplant.
“Most experimental personalized cancer vaccines are administered in the metastatic setting, but prior research indicates that immunotherapies tend to be more effective in patients who have less cancer spread,” principal investigator Nina Bhardwaj, MD, PhD , of Mount Sinai, explained in a press release .
“We have, therefore, developed a neoantigen vaccine that is administered after standard-of-care adjuvant therapy, such as surgery in solid tumors and bone marrow transplant in multiple myeloma, when patients have minimal, typically microscopic, residual disease.”
Feasibility, safety, and immunogenicity
PGV-001 was synthesized for 15 patients and administered to 13 of them. Six of the 13 patients had head and neck squamous cell carcinoma, three had multiple myeloma, two had non–small cell lung cancer, one had breast cancer, and one had urothelial carcinoma.
Eleven patients received all 10 intended doses, and two patients received at least 8 doses.
“The vaccine was well tolerated, with only half of patients experiencing mild, grade 1 adverse events,” Dr. Marron said.
Transient injection site reactions occurred in four patients, and grade 1 fever was reported in one patient.
Immune monitoring is ongoing, but an initial analysis in one patient showed “robust responses” in CD4 and CD8 T cells by intracellular cytokine staining for interferon-gamma, tumor necrosis factor–alpha, and interleukin-2 after in vitro expansion in the presence of vaccine antigens, according to the researchers.
Dr. Marron noted that robust T-cell reactivity was seen at the completion of all 10 doses but was not seen after the 6th dose, and this supports the need for a prolonged dosing schedule.
Survival and subsequent therapy
At a mean follow-up of 880 days, four patients had no evidence of disease and had not received subsequent therapy. This includes one patient with stage IIIA non–small cell lung cancer, one with stage IVA HER-2 positive breast cancer, one with stage II urothelial carcinoma, and one with multiple myeloma.
Four patients were alive and receiving subsequent lines of therapy. Two of these patients had significant responses to anti–PD-1 therapy.
Three patients have died, two of whom had documented recurrence of their malignancy. The last two patients were lost to follow-up without documented recurrence.
“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” Dr. Bhardwaj said.
Trials combining neoantigens identified with the OpenVax platform are ongoing in patients with urothelial carcinoma and glioblastoma multiforme, Dr. Marron said.
The current study ( NCT02721043 ) is sponsored by Dr. Bhardwaj. Dr. Marron and Dr. Bhardwaj reported having no disclosures. Their colleagues disclosed relationships with Bristol Myers Squibb, Sema4, and Related Sciences.
The vaccine, PGV-001, was given to 13 patients with solid tumors or multiple myeloma who had a high risk of recurrence after surgery or autologous stem cell transplant.
At last follow-up, four patients were still alive without evidence of disease and had not received subsequent therapy, four were alive and receiving therapy, three had died, and two were lost to follow-up.
Thomas Marron, MD, PhD , of Mount Sinai in New York presented these results in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 ( Abstract LB048 ). Data in the abstract differ from the data presented.
“While cancer immunotherapy has revolutionized the treatment of cancer, we know that the majority of patients fail to achieve significant clinical response,” Dr. Marron said during his presentation. “One reason for this may be due to lack of preexisting primed T-cell response needed for PD-1 blockade to have a significant effect. To address this, personalized neoantigen vaccines may help prime an improved immune response against tumor cells.”
With this in mind, Dr. Marron and colleagues developed PGV-001, a vaccine consisting of patient-specific synthetic neoantigen peptides given to patients in the adjuvant setting.
Creating a personalized vaccine
The researchers synthesized PGV-001 for 15 patients with advanced malignancies. The patients first underwent tumor and germline DNA sequencing as well as HLA typing. Bulk RNA sequencing was performed on patients’ tumors as well.
Then, the researchers used a computational pipeline called OpenVax to identify candidate neoantigens. This pipeline, developed at Mount Sinai, identified and prioritized candidate neoantigens using predicted MHC class I binding affinity and neoantigen abundance.
OpenVax identified an average of 71.5 neoantigens per patient (range, 7-193). The goal was to synthesize a maximum of 10 peptides per patient, but two patients did not have an adequate number of neoantigens.
Vaccine administration
The peptides were administered over the course of 27 weeks along with poly-ICLC and a tetanus helper peptide. Before receiving their vaccine doses, patients with solid tumors had undergone curative-intent surgery, and those with multiple myeloma had undergone autologous stem cell transplant.
“Most experimental personalized cancer vaccines are administered in the metastatic setting, but prior research indicates that immunotherapies tend to be more effective in patients who have less cancer spread,” principal investigator Nina Bhardwaj, MD, PhD , of Mount Sinai, explained in a press release .
“We have, therefore, developed a neoantigen vaccine that is administered after standard-of-care adjuvant therapy, such as surgery in solid tumors and bone marrow transplant in multiple myeloma, when patients have minimal, typically microscopic, residual disease.”
Feasibility, safety, and immunogenicity
PGV-001 was synthesized for 15 patients and administered to 13 of them. Six of the 13 patients had head and neck squamous cell carcinoma, three had multiple myeloma, two had non–small cell lung cancer, one had breast cancer, and one had urothelial carcinoma.
Eleven patients received all 10 intended doses, and two patients received at least 8 doses.
“The vaccine was well tolerated, with only half of patients experiencing mild, grade 1 adverse events,” Dr. Marron said.
Transient injection site reactions occurred in four patients, and grade 1 fever was reported in one patient.
Immune monitoring is ongoing, but an initial analysis in one patient showed “robust responses” in CD4 and CD8 T cells by intracellular cytokine staining for interferon-gamma, tumor necrosis factor–alpha, and interleukin-2 after in vitro expansion in the presence of vaccine antigens, according to the researchers.
Dr. Marron noted that robust T-cell reactivity was seen at the completion of all 10 doses but was not seen after the 6th dose, and this supports the need for a prolonged dosing schedule.
Survival and subsequent therapy
At a mean follow-up of 880 days, four patients had no evidence of disease and had not received subsequent therapy. This includes one patient with stage IIIA non–small cell lung cancer, one with stage IVA HER-2 positive breast cancer, one with stage II urothelial carcinoma, and one with multiple myeloma.
Four patients were alive and receiving subsequent lines of therapy. Two of these patients had significant responses to anti–PD-1 therapy.
Three patients have died, two of whom had documented recurrence of their malignancy. The last two patients were lost to follow-up without documented recurrence.
“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” Dr. Bhardwaj said.
Trials combining neoantigens identified with the OpenVax platform are ongoing in patients with urothelial carcinoma and glioblastoma multiforme, Dr. Marron said.
The current study ( NCT02721043 ) is sponsored by Dr. Bhardwaj. Dr. Marron and Dr. Bhardwaj reported having no disclosures. Their colleagues disclosed relationships with Bristol Myers Squibb, Sema4, and Related Sciences.
FROM AACR 2021
Cancer screening stopped by pandemic: Repercussions to come?
Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.
Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.
“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.
She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).
In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.
“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.
A similar picture has emerged elsewhere.
In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.
In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).
Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.
The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.
There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.
“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.
In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.
By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.
Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.
After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.
The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.
The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.
His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.
In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.
Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.
Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.
“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”
He suspects that there is more at play than screening cancellations.
In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.
“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.
She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.
Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.
Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.
“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.
Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.
Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.
“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”
In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.
Public health initiatives to rebalance the messaging are now underway.
Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”
In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”
“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”
Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.
A version of this article first appeared on Medscape.com.
Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.
Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.
“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.
She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).
In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.
“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.
A similar picture has emerged elsewhere.
In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.
In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).
Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.
The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.
There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.
“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.
In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.
By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.
Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.
After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.
The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.
The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.
His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.
In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.
Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.
Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.
“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”
He suspects that there is more at play than screening cancellations.
In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.
“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.
She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.
Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.
Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.
“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.
Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.
Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.
“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”
In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.
Public health initiatives to rebalance the messaging are now underway.
Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”
In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”
“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”
Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.
A version of this article first appeared on Medscape.com.
Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.
Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.
“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.
She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).
In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.
“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.
A similar picture has emerged elsewhere.
In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.
In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).
Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.
The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.
There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.
“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.
In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.
By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.
Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.
After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.
The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.
The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.
His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.
In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.
Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.
Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.
“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”
He suspects that there is more at play than screening cancellations.
In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.
“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.
She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.
Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.
Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.
“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.
Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.
Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.
“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”
In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.
Public health initiatives to rebalance the messaging are now underway.
Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”
In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”
“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”
Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.
A version of this article first appeared on Medscape.com.
Steroids can be stopped in some older multiple myeloma patients
For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.
At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.
The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.
“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.
She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”
This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”
The study was published March 19, 2021, in Blood.
Curtailing steroids
Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.
In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.
The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.
S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”
He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.
“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
Improved event-free survival
In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.
The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.
The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.
With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)
The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).
Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).
Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).
The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.
At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.
The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.
“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.
She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”
This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”
The study was published March 19, 2021, in Blood.
Curtailing steroids
Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.
In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.
The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.
S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”
He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.
“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
Improved event-free survival
In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.
The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.
The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.
With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)
The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).
Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).
Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).
The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.
At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.
The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.
“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.
She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”
This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”
The study was published March 19, 2021, in Blood.
Curtailing steroids
Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.
In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.
The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.
S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”
He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.
“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
Improved event-free survival
In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.
The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.
The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.
With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)
The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).
Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).
Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).
The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
First CAR T-cell therapy for multiple myeloma: Abecma
Chimeric antigen receptor (CAR) T-cell therapy, described as a “living drug,” is now available for patients with relapsed/refractory multiple myeloma who have been treated with four or more prior lines of therapy.
The Food and Drug Administration said these patients represent an “unmet medical need” when it granted approval for the new product – idecabtagene vicleucel (ide-cel; Abecma), developed by bluebird bio and Bristol-Myers Squibb.
Ide-cel is the first CAR T-cell therapy to gain approval for use in multiple myeloma. It is also the first CAR T-cell therapy to target B-cell maturation antigen.
Previously approved CAR T-cell products target CD19 and have been approved for use in certain types of leukemia and lymphoma.
All the CAR T-cell therapies are customized treatments that are created specifically for each individual patient from their own blood. The patient’s own T cells are removed from the blood, are genetically modified and expanded, and are then infused back into the patient. These modified T cells then seek out and destroy blood cancer cells, and they continue to do so long term.
In some patients, this has led to eradication of disease that had previously progressed with every other treatment that had been tried – results that have been described as “absolutely remarkable” and “one-shot therapy that looks to be curative.”
However, this cell therapy comes with serious adverse effects, including neurologic toxicity and cytokine release syndrome (CRS), which can be life threatening. For this reason, all these products have a risk evaluation and mitigation strategy, and the use of CAR T-cell therapies is limited to designated centers.
In addition, these CAR T-cells products are phenomenally expensive; hospitals have reported heavy financial losses with their use, and patients have turned to crowdfunding to pay for these therapies.
‘Phenomenal’ results in MM
The FDA noted that approval of ide-cel for multiple myeloma is based on data from a multicenter study that involved 127 patients with relapsed/refractory disease who had received at least three prior lines of treatment.
The results from this trial were published Feb. 25 in the New England Journal of Medicine.
An expert not involved in the trial described the results as “phenomenal.”
Krina Patel, MD, an associate professor in the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, said that “the response rate of 73% in a patient population with a median of six lines of therapy, and with one-third of those patients achieving a deep response of complete response or better, is phenomenal.
“We are very excited as a myeloma community for this study of idecabtagene vicleucel for relapsed/refractory patients,” Dr. Patel told this news organization at the time.
The lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented:
Both experts highlighted the poor prognosis for patients with relapsed/refractory disease. Recent decades have seen a flurry of new agents for myeloma, and there are now three main classes of agents: immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies.
Nevertheless, in some patients, the disease continues to progress. For patients for whom treatments with all three classes of drugs have failed, the median progression-free survival is 3-4 months, and the median overall survival is 9 months.
In contrast, the results reported in the NEJM article showed that overall median progression-free survival was 8.8 months, but it was more than double that (20.2 months) for patients who achieved a complete or stringent complete response.
Estimated median overall survival was 19.4 months, and the overall survival was 78% at 12 months. The authors note that overall survival data are not yet mature.
The patients who were enrolled in the CAR T-cell trial had undergone many previous treatments. They had undergone a median of six prior drug therapies (range, 3-16), and most of the patients (120, 94%) had also undergone autologous hematopoietic stem cell transplant.
In addition, the majority of patients (84%) had disease that was triple refractory (to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody), 60% had disease that was penta-exposed (to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab), and 26% had disease that was penta-refractory.
In the NEJM article, the authors report that about a third of patients had a complete response to CAR T-cell therapy.
At a median follow-up of 13.3 months, 94 of 128 patients (73%) showed a response to therapy (P < .001); 42 (33%) showed a complete or stringent complete response; and 67 patients (52%) showed a “very good partial response or better,” they write.
In the FDA announcement of the product approval, the figures for complete response were slightly lower. “Of those studied, 28% of patients showed complete response – or disappearance of all signs of multiple myeloma – to Abecma, and 65% of this group remained in complete response to the treatment for at least 12 months,” the agency noted.
The FDA also noted that treatment with Abecma can cause severe side effects. The label carries a boxed warning regarding CRS, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenia, all of which can be fatal or life threatening.
The most common side effects of Abecma are CRS, infections, fatigue, musculoskeletal pain, and a weakened immune system. Side effects from treatment usually appear within the first 1-2 weeks after treatment, but some side effects may occur later.
The agency also noted that, to further evaluate the long-term safety of the drug, it is requiring the manufacturer to conduct a postmarketing observational study.
“The FDA remains committed to advancing novel treatment options for areas of unmet patient need,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.
“While there is no cure for multiple myeloma, the long-term outlook can vary based on the individual’s age and the stage of the condition at the time of diagnosis. Today’s approval provides a new treatment option for patients who have this uncommon type of cancer.”
A version of this article first appeared on Medscape.com.
Chimeric antigen receptor (CAR) T-cell therapy, described as a “living drug,” is now available for patients with relapsed/refractory multiple myeloma who have been treated with four or more prior lines of therapy.
The Food and Drug Administration said these patients represent an “unmet medical need” when it granted approval for the new product – idecabtagene vicleucel (ide-cel; Abecma), developed by bluebird bio and Bristol-Myers Squibb.
Ide-cel is the first CAR T-cell therapy to gain approval for use in multiple myeloma. It is also the first CAR T-cell therapy to target B-cell maturation antigen.
Previously approved CAR T-cell products target CD19 and have been approved for use in certain types of leukemia and lymphoma.
All the CAR T-cell therapies are customized treatments that are created specifically for each individual patient from their own blood. The patient’s own T cells are removed from the blood, are genetically modified and expanded, and are then infused back into the patient. These modified T cells then seek out and destroy blood cancer cells, and they continue to do so long term.
In some patients, this has led to eradication of disease that had previously progressed with every other treatment that had been tried – results that have been described as “absolutely remarkable” and “one-shot therapy that looks to be curative.”
However, this cell therapy comes with serious adverse effects, including neurologic toxicity and cytokine release syndrome (CRS), which can be life threatening. For this reason, all these products have a risk evaluation and mitigation strategy, and the use of CAR T-cell therapies is limited to designated centers.
In addition, these CAR T-cells products are phenomenally expensive; hospitals have reported heavy financial losses with their use, and patients have turned to crowdfunding to pay for these therapies.
‘Phenomenal’ results in MM
The FDA noted that approval of ide-cel for multiple myeloma is based on data from a multicenter study that involved 127 patients with relapsed/refractory disease who had received at least three prior lines of treatment.
The results from this trial were published Feb. 25 in the New England Journal of Medicine.
An expert not involved in the trial described the results as “phenomenal.”
Krina Patel, MD, an associate professor in the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, said that “the response rate of 73% in a patient population with a median of six lines of therapy, and with one-third of those patients achieving a deep response of complete response or better, is phenomenal.
“We are very excited as a myeloma community for this study of idecabtagene vicleucel for relapsed/refractory patients,” Dr. Patel told this news organization at the time.
The lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented:
Both experts highlighted the poor prognosis for patients with relapsed/refractory disease. Recent decades have seen a flurry of new agents for myeloma, and there are now three main classes of agents: immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies.
Nevertheless, in some patients, the disease continues to progress. For patients for whom treatments with all three classes of drugs have failed, the median progression-free survival is 3-4 months, and the median overall survival is 9 months.
In contrast, the results reported in the NEJM article showed that overall median progression-free survival was 8.8 months, but it was more than double that (20.2 months) for patients who achieved a complete or stringent complete response.
Estimated median overall survival was 19.4 months, and the overall survival was 78% at 12 months. The authors note that overall survival data are not yet mature.
The patients who were enrolled in the CAR T-cell trial had undergone many previous treatments. They had undergone a median of six prior drug therapies (range, 3-16), and most of the patients (120, 94%) had also undergone autologous hematopoietic stem cell transplant.
In addition, the majority of patients (84%) had disease that was triple refractory (to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody), 60% had disease that was penta-exposed (to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab), and 26% had disease that was penta-refractory.
In the NEJM article, the authors report that about a third of patients had a complete response to CAR T-cell therapy.
At a median follow-up of 13.3 months, 94 of 128 patients (73%) showed a response to therapy (P < .001); 42 (33%) showed a complete or stringent complete response; and 67 patients (52%) showed a “very good partial response or better,” they write.
In the FDA announcement of the product approval, the figures for complete response were slightly lower. “Of those studied, 28% of patients showed complete response – or disappearance of all signs of multiple myeloma – to Abecma, and 65% of this group remained in complete response to the treatment for at least 12 months,” the agency noted.
The FDA also noted that treatment with Abecma can cause severe side effects. The label carries a boxed warning regarding CRS, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenia, all of which can be fatal or life threatening.
The most common side effects of Abecma are CRS, infections, fatigue, musculoskeletal pain, and a weakened immune system. Side effects from treatment usually appear within the first 1-2 weeks after treatment, but some side effects may occur later.
The agency also noted that, to further evaluate the long-term safety of the drug, it is requiring the manufacturer to conduct a postmarketing observational study.
“The FDA remains committed to advancing novel treatment options for areas of unmet patient need,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.
“While there is no cure for multiple myeloma, the long-term outlook can vary based on the individual’s age and the stage of the condition at the time of diagnosis. Today’s approval provides a new treatment option for patients who have this uncommon type of cancer.”
A version of this article first appeared on Medscape.com.
Chimeric antigen receptor (CAR) T-cell therapy, described as a “living drug,” is now available for patients with relapsed/refractory multiple myeloma who have been treated with four or more prior lines of therapy.
The Food and Drug Administration said these patients represent an “unmet medical need” when it granted approval for the new product – idecabtagene vicleucel (ide-cel; Abecma), developed by bluebird bio and Bristol-Myers Squibb.
Ide-cel is the first CAR T-cell therapy to gain approval for use in multiple myeloma. It is also the first CAR T-cell therapy to target B-cell maturation antigen.
Previously approved CAR T-cell products target CD19 and have been approved for use in certain types of leukemia and lymphoma.
All the CAR T-cell therapies are customized treatments that are created specifically for each individual patient from their own blood. The patient’s own T cells are removed from the blood, are genetically modified and expanded, and are then infused back into the patient. These modified T cells then seek out and destroy blood cancer cells, and they continue to do so long term.
In some patients, this has led to eradication of disease that had previously progressed with every other treatment that had been tried – results that have been described as “absolutely remarkable” and “one-shot therapy that looks to be curative.”
However, this cell therapy comes with serious adverse effects, including neurologic toxicity and cytokine release syndrome (CRS), which can be life threatening. For this reason, all these products have a risk evaluation and mitigation strategy, and the use of CAR T-cell therapies is limited to designated centers.
In addition, these CAR T-cells products are phenomenally expensive; hospitals have reported heavy financial losses with their use, and patients have turned to crowdfunding to pay for these therapies.
‘Phenomenal’ results in MM
The FDA noted that approval of ide-cel for multiple myeloma is based on data from a multicenter study that involved 127 patients with relapsed/refractory disease who had received at least three prior lines of treatment.
The results from this trial were published Feb. 25 in the New England Journal of Medicine.
An expert not involved in the trial described the results as “phenomenal.”
Krina Patel, MD, an associate professor in the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, said that “the response rate of 73% in a patient population with a median of six lines of therapy, and with one-third of those patients achieving a deep response of complete response or better, is phenomenal.
“We are very excited as a myeloma community for this study of idecabtagene vicleucel for relapsed/refractory patients,” Dr. Patel told this news organization at the time.
The lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented:
Both experts highlighted the poor prognosis for patients with relapsed/refractory disease. Recent decades have seen a flurry of new agents for myeloma, and there are now three main classes of agents: immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies.
Nevertheless, in some patients, the disease continues to progress. For patients for whom treatments with all three classes of drugs have failed, the median progression-free survival is 3-4 months, and the median overall survival is 9 months.
In contrast, the results reported in the NEJM article showed that overall median progression-free survival was 8.8 months, but it was more than double that (20.2 months) for patients who achieved a complete or stringent complete response.
Estimated median overall survival was 19.4 months, and the overall survival was 78% at 12 months. The authors note that overall survival data are not yet mature.
The patients who were enrolled in the CAR T-cell trial had undergone many previous treatments. They had undergone a median of six prior drug therapies (range, 3-16), and most of the patients (120, 94%) had also undergone autologous hematopoietic stem cell transplant.
In addition, the majority of patients (84%) had disease that was triple refractory (to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody), 60% had disease that was penta-exposed (to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab), and 26% had disease that was penta-refractory.
In the NEJM article, the authors report that about a third of patients had a complete response to CAR T-cell therapy.
At a median follow-up of 13.3 months, 94 of 128 patients (73%) showed a response to therapy (P < .001); 42 (33%) showed a complete or stringent complete response; and 67 patients (52%) showed a “very good partial response or better,” they write.
In the FDA announcement of the product approval, the figures for complete response were slightly lower. “Of those studied, 28% of patients showed complete response – or disappearance of all signs of multiple myeloma – to Abecma, and 65% of this group remained in complete response to the treatment for at least 12 months,” the agency noted.
The FDA also noted that treatment with Abecma can cause severe side effects. The label carries a boxed warning regarding CRS, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenia, all of which can be fatal or life threatening.
The most common side effects of Abecma are CRS, infections, fatigue, musculoskeletal pain, and a weakened immune system. Side effects from treatment usually appear within the first 1-2 weeks after treatment, but some side effects may occur later.
The agency also noted that, to further evaluate the long-term safety of the drug, it is requiring the manufacturer to conduct a postmarketing observational study.
“The FDA remains committed to advancing novel treatment options for areas of unmet patient need,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.
“While there is no cure for multiple myeloma, the long-term outlook can vary based on the individual’s age and the stage of the condition at the time of diagnosis. Today’s approval provides a new treatment option for patients who have this uncommon type of cancer.”
A version of this article first appeared on Medscape.com.
FDA scrutinizes cancer therapies granted accelerated approval
U.S. regulators are stepping up scrutiny of therapies that were granted an accelerated approval to treat cancers on the basis of surrogate endpoints but have failed to show clinical or survival benefits upon more extensive testing.
At issue are a number of cancer indications for immunotherapies. Four have already been withdrawn (voluntarily by the manufacturer), and six more will be reviewed at an upcoming meeting.
In recent years, the US Food and Drug Administration has granted accelerated approvals to oncology medicines on the basis of evidence that suggests a benefit for patients. Examples of such evidence relate to response rates and estimates of tumor shrinkage. But these approvals are granted on the condition that the manufacturer conducts larger clinical trials that show clinical benefit, including benefit in overall survival.
Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, has argued that the point of these conditional approvals is to find acceptable surrogate markers to allow people with “desperate illnesses” to have access to potentially helpful drugs while work continues to determine the drug’s actual benefit to patients.
Oncologists are now questioning whether the FDA has become too lenient in its approach, Daniel A. Goldstein, MD, a senior physician in medical oncology and internal medicine at the Rabin Medical Center, Petah Tikva, Israel, told this news organization.
“The main two things you want from a cancer drug is to live longer and live a higher quality of life,” said Goldstein. “But these endpoints that they’ve been using over the past few years are not really giving us confidence that these drugs are actually going to help to live longer or better.”
Dr. Pazdur said the FDA will consider withdrawing its accelerated approvals when results of further studies do not confirm expected benefit for patients.
“This is like the pendulum has swung as far as it was going to swing and now is on the backswing,” said Dr. Goldstein, also of the department of health policy and management at the University of North Carolina at Chapel Hill. “You could call this a watershed moment.”
Although there’s near universal interest in allowing people with advanced cancer access to promising medicines, there’s also rising concern about exposing patients needlessly to costly drugs with potentially tough side effects. That may prompt a shift in the standards U.S. regulators apply to cancer medicines, Dr. Goldstein said.
Indications withdrawn and under review
In a meeting scheduled for April 27-29, the FDA’s Oncologic Drugs Advisory Committee will review indications granted through the accelerated approval process for three immunotherapies: pembrolizumab (Keytruda), atezolizumab (Tecentriq), and nivolumab (Opdivo).
It is part of an industry-wide evaluation of accelerated approvals for cancer indications in which confirmatory trials did not confirm clinical benefit, the FDA noted.
The process has already led to voluntary withdrawals of four cancer indications by the manufacturers, including one indication each for pembrolizumab, atezolizumab, and nivolumab, and one for durvalumab (Imfinzi).
All of these immunotherapies are approved for numerous cancer indications, and they all remain on the market. It is only the U.S. approvals for particular cancer indications that have been withdrawn.
In the past, olaratumab (Lartruvo) was withdrawn from the market altogether. The FDA granted accelerated approval of the drug for soft tissue sarcoma, but clinical benefit was not confirmed in a phase 3 trial.
Issue highlighted by Dr. Prasad and Dr. Gyawali
In recent years, much of the attention on accelerated approvals was spurred by the work of a few researchers, particularly Vinay Prasad, MD, MPH, associate professor in the department of epidemiology and biostatistics, University of California, San Francisco, and Bishal Gyawali, MD, PhD, from Queen’s University Cancer Research Institute, Kingston, Ont. (Both are regular contributors to the oncology section of this news organization.)
Dr. Goldstein made this point in a tweet about the FDA’s announcement of the April ODAC meetings:
“Well done to @oncology_bg and @VPrasadMDMPH among others for highlighting in their papers that the FDA wasn’t properly evaluating accelerated approval drugs.
FDA have listened.
And I thought that the impact of academia was limited!”
Dr. Prasad has made the case for closer scrutiny of accelerated approvals in a number of journal articles and in his 2020 book, “Malignant: How Bad Policy and Bad Evidence Harm People with Cancer,” published by Johns Hopkins University Press.
The book includes highlights of a 2016 article published in Mayo Clinic Proceedings that focused on surrogate endpoints used for FDA approvals. In the article, Dr. Prasad and his coauthor report that they did not find formal analyses of the strength of the surrogate-survival correlation in 14 of 25 cases of accelerated approvals (56%) and in 11 of 30 traditional approvals (37%).
“Our results were concerning. They imply that many surrogates are based on little more than a gut feeling. You might rationalize that and argue a gut feeling is the same as ‘reasonably likely to predict,’ but no reasonable person could think a gut feeling means established,” Dr. Prasad writes in his book. “Our result suggests the FDA is using surrogate endpoints far beyond what may be fair or reasonable.”
Dr. Gyawali has argued that the process by which the FDA assesses cancer drugs for approvals has undergone a profound shift. He has most recently remarked on this in an October 2020 commentary on Medscape.
“Until the recent floodgate of approvals based on response rates from single-arm trials, the majority of cancer therapy decisions were supported by evidence generated from randomized controlled trials (RCTs),” Dr. Gyawali wrote. “The evidence base to support clinical decisions in managing therapeutic side effects has been comparatively sparse.”
Accelerated approval to improve access
The FDA has struggled for about 2 decades with questions of where to set the bar on evidence for promising cancer drugs.
The agency’s accelerated approval program for drugs began in 1992. During the first decade, the focus was largely on medicines related to HIV.
In the early 2000s, oncology drugs began to dominate the program.
Dr. Pazdur has presided over the FDA’s marked changes regarding the use of surrogate markers when weighing whether to allow sales of cancer medicines. Formerly a professor at the University of Texas MD Anderson Cancer Center, Houston, Dr. Pazdur joined the FDA as director of the Division of Oncology Drug Products in 1999.
Soon after his appointment, he had to field inquiries from pharmaceutical companies about how much evidence they needed to receive accelerated approvals.
Early on, he publicly expressed impatience about the drugmakers’ approach. “The purpose of accelerated approval was not accelerated drug company profits,” Dr. Padzur said at a 2004 ODAC meeting.
Rather, the point is to allow access to potentially helpful drugs while work continues to determine their actual benefit to patients, he explained.
“It wasn’t a license to do less, less, less, and less to a point now that we may be getting companies that are coming in” intent on determining the minimum evidence the FDA will take, Dr. Pazdur said. “It shouldn’t be what is the lowest. It is what is a sufficient amount to give patients and physicians a real understanding of what their drug will do.”
In a 2016 interview with The New York Times, Dr. Pazdur said that his views on cancer drug approvals have evolved with time. He described himself as being “on a jihad to streamline the review process and get things out the door faster.”
“I have evolved from regulator to regulator-advocate,” Dr. Pazdur told the newspaper.
His attitude reflected his personal experience in losing his wife to ovarian cancer in 2015, as well as shifts in science and law. In 2012, Congress passed a law that gave the FDA new resources to speed medicines for life-threatening diseases to market. In addition, advances in genetics appeared to be making some medications more effective and easier to test, Dr. Pazdur said in The New York Times interview.
Withdrawals seen as sign of success
Since the program’s inception, only 6% of accelerated approvals for oncology indications have been withdrawn, the FDA said.
It would be a sign that the program is working if the April meetings lead to further withdrawals of indications that have been granted accelerated approval, Julie R. Gralow, MD, chief medical officer of the American Society of Clinical Oncology, said in an interview with this news organization.
“It shouldn’t be seen as a failure,” Dr. Gralow said.
In her own practice at the Fred Hutchinson Cancer Research Center, Seattle, she has seen the value of emerging therapies for patients fighting advanced cancers. During her 25 years of clinical practice in an academic setting, she has gained access to drugs through single-patient investigative new drug applications.
However, this path is not an option for many patients who undergo treatment in facilities other than academic centers, she commented. She noted that the accelerated approval process is a way to expand access to emerging medicines, but she sees a need for caution in the use of drugs that have been given only this conditional approval. She emphasizes that such drugs may be suitable only for certain patients.
“I would say that, for metastatic patients, patients with incurable disease, we are willing to take some risk,” Dr. Gralow said. “We don’t have other options. They can’t wait the years that it would take to get a drug approved.”
One such patient is David Mitchell, who serves as the consumer representative on ODAC. He told this news organization that he is taking three drugs for multiple myeloma that received accelerated approvals: pomalidomide, bortezomib, and daratumumab.
“I want the FDA to have the option to approve drugs in an accelerated pathway, because as a patient taking three drugs granted accelerated approval, I’m benefiting – I’ve lived the benefit,” Mr. Mitchell said, “and I want other patients to have the opportunity to have that benefit.”
He believes that the FDA’s approach regarding accelerated approvals serves to get potentially beneficial medicines to patients who have few options and also fulfills the FDA’s mandate to protect the public from treatments that have little benefit but can cause harm.
Accelerated approval also offers needed flexibility to drugmakers as they develop more specifically targeted drugs for diseases that affect relatively few people, such as multiple myeloma, he said. “As the targeting of your therapies gets tighter and for smaller groups of patients, you have a harder time following the traditional model,” such as conducting large, double-blind, placebo-controlled trials that may indicate increased overall survival, he said.
“To me, this is the way the FDA intended it to work,” he added. “It’s going to offer the accelerated approval based on a surrogate endpoint for a safe drug, but it’s going to require the confirmatory trial, and if the confirmatory trial fails, it will pull the drug off the market.”
Some medicines that have received accelerated approvals may ultimately be found not to benefit patients, Mr. Mitchell acknowledged. But people in his situation, whose disease has progressed despite treatments, may want to take that risk, he added.
Four cancer indications recently withdrawn voluntarily by the manufacturer
- December 2020: Nivolumab for the treatment of patients with metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy (Bristol Myers Squibb).
- February 2021: Durvalumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or following platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy (AstraZeneca).
- March 2021: Pembrolizumab for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy (Merck).
- March 2021: Atezolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing atezolizumab chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy (Genentech).
Six cancer indications under review at the April 2021 ODAC meeting
- Atezolizumab indicated in combination with protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering ≥1% of the tumor area), as determined by an FDA-approved test.
- Atezolizumab indicated for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
- Pembrolizumab indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
- Pembrolizumab indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (Combined Positive Score ≥1), as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
- Pembrolizumab indicated for the treatment of patients with who have been previously treated with .
- Nivolumab indicated as a single agent for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.
A version of this article first appeared on Medscape.com.
U.S. regulators are stepping up scrutiny of therapies that were granted an accelerated approval to treat cancers on the basis of surrogate endpoints but have failed to show clinical or survival benefits upon more extensive testing.
At issue are a number of cancer indications for immunotherapies. Four have already been withdrawn (voluntarily by the manufacturer), and six more will be reviewed at an upcoming meeting.
In recent years, the US Food and Drug Administration has granted accelerated approvals to oncology medicines on the basis of evidence that suggests a benefit for patients. Examples of such evidence relate to response rates and estimates of tumor shrinkage. But these approvals are granted on the condition that the manufacturer conducts larger clinical trials that show clinical benefit, including benefit in overall survival.
Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, has argued that the point of these conditional approvals is to find acceptable surrogate markers to allow people with “desperate illnesses” to have access to potentially helpful drugs while work continues to determine the drug’s actual benefit to patients.
Oncologists are now questioning whether the FDA has become too lenient in its approach, Daniel A. Goldstein, MD, a senior physician in medical oncology and internal medicine at the Rabin Medical Center, Petah Tikva, Israel, told this news organization.
“The main two things you want from a cancer drug is to live longer and live a higher quality of life,” said Goldstein. “But these endpoints that they’ve been using over the past few years are not really giving us confidence that these drugs are actually going to help to live longer or better.”
Dr. Pazdur said the FDA will consider withdrawing its accelerated approvals when results of further studies do not confirm expected benefit for patients.
“This is like the pendulum has swung as far as it was going to swing and now is on the backswing,” said Dr. Goldstein, also of the department of health policy and management at the University of North Carolina at Chapel Hill. “You could call this a watershed moment.”
Although there’s near universal interest in allowing people with advanced cancer access to promising medicines, there’s also rising concern about exposing patients needlessly to costly drugs with potentially tough side effects. That may prompt a shift in the standards U.S. regulators apply to cancer medicines, Dr. Goldstein said.
Indications withdrawn and under review
In a meeting scheduled for April 27-29, the FDA’s Oncologic Drugs Advisory Committee will review indications granted through the accelerated approval process for three immunotherapies: pembrolizumab (Keytruda), atezolizumab (Tecentriq), and nivolumab (Opdivo).
It is part of an industry-wide evaluation of accelerated approvals for cancer indications in which confirmatory trials did not confirm clinical benefit, the FDA noted.
The process has already led to voluntary withdrawals of four cancer indications by the manufacturers, including one indication each for pembrolizumab, atezolizumab, and nivolumab, and one for durvalumab (Imfinzi).
All of these immunotherapies are approved for numerous cancer indications, and they all remain on the market. It is only the U.S. approvals for particular cancer indications that have been withdrawn.
In the past, olaratumab (Lartruvo) was withdrawn from the market altogether. The FDA granted accelerated approval of the drug for soft tissue sarcoma, but clinical benefit was not confirmed in a phase 3 trial.
Issue highlighted by Dr. Prasad and Dr. Gyawali
In recent years, much of the attention on accelerated approvals was spurred by the work of a few researchers, particularly Vinay Prasad, MD, MPH, associate professor in the department of epidemiology and biostatistics, University of California, San Francisco, and Bishal Gyawali, MD, PhD, from Queen’s University Cancer Research Institute, Kingston, Ont. (Both are regular contributors to the oncology section of this news organization.)
Dr. Goldstein made this point in a tweet about the FDA’s announcement of the April ODAC meetings:
“Well done to @oncology_bg and @VPrasadMDMPH among others for highlighting in their papers that the FDA wasn’t properly evaluating accelerated approval drugs.
FDA have listened.
And I thought that the impact of academia was limited!”
Dr. Prasad has made the case for closer scrutiny of accelerated approvals in a number of journal articles and in his 2020 book, “Malignant: How Bad Policy and Bad Evidence Harm People with Cancer,” published by Johns Hopkins University Press.
The book includes highlights of a 2016 article published in Mayo Clinic Proceedings that focused on surrogate endpoints used for FDA approvals. In the article, Dr. Prasad and his coauthor report that they did not find formal analyses of the strength of the surrogate-survival correlation in 14 of 25 cases of accelerated approvals (56%) and in 11 of 30 traditional approvals (37%).
“Our results were concerning. They imply that many surrogates are based on little more than a gut feeling. You might rationalize that and argue a gut feeling is the same as ‘reasonably likely to predict,’ but no reasonable person could think a gut feeling means established,” Dr. Prasad writes in his book. “Our result suggests the FDA is using surrogate endpoints far beyond what may be fair or reasonable.”
Dr. Gyawali has argued that the process by which the FDA assesses cancer drugs for approvals has undergone a profound shift. He has most recently remarked on this in an October 2020 commentary on Medscape.
“Until the recent floodgate of approvals based on response rates from single-arm trials, the majority of cancer therapy decisions were supported by evidence generated from randomized controlled trials (RCTs),” Dr. Gyawali wrote. “The evidence base to support clinical decisions in managing therapeutic side effects has been comparatively sparse.”
Accelerated approval to improve access
The FDA has struggled for about 2 decades with questions of where to set the bar on evidence for promising cancer drugs.
The agency’s accelerated approval program for drugs began in 1992. During the first decade, the focus was largely on medicines related to HIV.
In the early 2000s, oncology drugs began to dominate the program.
Dr. Pazdur has presided over the FDA’s marked changes regarding the use of surrogate markers when weighing whether to allow sales of cancer medicines. Formerly a professor at the University of Texas MD Anderson Cancer Center, Houston, Dr. Pazdur joined the FDA as director of the Division of Oncology Drug Products in 1999.
Soon after his appointment, he had to field inquiries from pharmaceutical companies about how much evidence they needed to receive accelerated approvals.
Early on, he publicly expressed impatience about the drugmakers’ approach. “The purpose of accelerated approval was not accelerated drug company profits,” Dr. Padzur said at a 2004 ODAC meeting.
Rather, the point is to allow access to potentially helpful drugs while work continues to determine their actual benefit to patients, he explained.
“It wasn’t a license to do less, less, less, and less to a point now that we may be getting companies that are coming in” intent on determining the minimum evidence the FDA will take, Dr. Pazdur said. “It shouldn’t be what is the lowest. It is what is a sufficient amount to give patients and physicians a real understanding of what their drug will do.”
In a 2016 interview with The New York Times, Dr. Pazdur said that his views on cancer drug approvals have evolved with time. He described himself as being “on a jihad to streamline the review process and get things out the door faster.”
“I have evolved from regulator to regulator-advocate,” Dr. Pazdur told the newspaper.
His attitude reflected his personal experience in losing his wife to ovarian cancer in 2015, as well as shifts in science and law. In 2012, Congress passed a law that gave the FDA new resources to speed medicines for life-threatening diseases to market. In addition, advances in genetics appeared to be making some medications more effective and easier to test, Dr. Pazdur said in The New York Times interview.
Withdrawals seen as sign of success
Since the program’s inception, only 6% of accelerated approvals for oncology indications have been withdrawn, the FDA said.
It would be a sign that the program is working if the April meetings lead to further withdrawals of indications that have been granted accelerated approval, Julie R. Gralow, MD, chief medical officer of the American Society of Clinical Oncology, said in an interview with this news organization.
“It shouldn’t be seen as a failure,” Dr. Gralow said.
In her own practice at the Fred Hutchinson Cancer Research Center, Seattle, she has seen the value of emerging therapies for patients fighting advanced cancers. During her 25 years of clinical practice in an academic setting, she has gained access to drugs through single-patient investigative new drug applications.
However, this path is not an option for many patients who undergo treatment in facilities other than academic centers, she commented. She noted that the accelerated approval process is a way to expand access to emerging medicines, but she sees a need for caution in the use of drugs that have been given only this conditional approval. She emphasizes that such drugs may be suitable only for certain patients.
“I would say that, for metastatic patients, patients with incurable disease, we are willing to take some risk,” Dr. Gralow said. “We don’t have other options. They can’t wait the years that it would take to get a drug approved.”
One such patient is David Mitchell, who serves as the consumer representative on ODAC. He told this news organization that he is taking three drugs for multiple myeloma that received accelerated approvals: pomalidomide, bortezomib, and daratumumab.
“I want the FDA to have the option to approve drugs in an accelerated pathway, because as a patient taking three drugs granted accelerated approval, I’m benefiting – I’ve lived the benefit,” Mr. Mitchell said, “and I want other patients to have the opportunity to have that benefit.”
He believes that the FDA’s approach regarding accelerated approvals serves to get potentially beneficial medicines to patients who have few options and also fulfills the FDA’s mandate to protect the public from treatments that have little benefit but can cause harm.
Accelerated approval also offers needed flexibility to drugmakers as they develop more specifically targeted drugs for diseases that affect relatively few people, such as multiple myeloma, he said. “As the targeting of your therapies gets tighter and for smaller groups of patients, you have a harder time following the traditional model,” such as conducting large, double-blind, placebo-controlled trials that may indicate increased overall survival, he said.
“To me, this is the way the FDA intended it to work,” he added. “It’s going to offer the accelerated approval based on a surrogate endpoint for a safe drug, but it’s going to require the confirmatory trial, and if the confirmatory trial fails, it will pull the drug off the market.”
Some medicines that have received accelerated approvals may ultimately be found not to benefit patients, Mr. Mitchell acknowledged. But people in his situation, whose disease has progressed despite treatments, may want to take that risk, he added.
Four cancer indications recently withdrawn voluntarily by the manufacturer
- December 2020: Nivolumab for the treatment of patients with metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy (Bristol Myers Squibb).
- February 2021: Durvalumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or following platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy (AstraZeneca).
- March 2021: Pembrolizumab for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy (Merck).
- March 2021: Atezolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing atezolizumab chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy (Genentech).
Six cancer indications under review at the April 2021 ODAC meeting
- Atezolizumab indicated in combination with protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering ≥1% of the tumor area), as determined by an FDA-approved test.
- Atezolizumab indicated for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
- Pembrolizumab indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
- Pembrolizumab indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (Combined Positive Score ≥1), as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
- Pembrolizumab indicated for the treatment of patients with who have been previously treated with .
- Nivolumab indicated as a single agent for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.
A version of this article first appeared on Medscape.com.
U.S. regulators are stepping up scrutiny of therapies that were granted an accelerated approval to treat cancers on the basis of surrogate endpoints but have failed to show clinical or survival benefits upon more extensive testing.
At issue are a number of cancer indications for immunotherapies. Four have already been withdrawn (voluntarily by the manufacturer), and six more will be reviewed at an upcoming meeting.
In recent years, the US Food and Drug Administration has granted accelerated approvals to oncology medicines on the basis of evidence that suggests a benefit for patients. Examples of such evidence relate to response rates and estimates of tumor shrinkage. But these approvals are granted on the condition that the manufacturer conducts larger clinical trials that show clinical benefit, including benefit in overall survival.
Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, has argued that the point of these conditional approvals is to find acceptable surrogate markers to allow people with “desperate illnesses” to have access to potentially helpful drugs while work continues to determine the drug’s actual benefit to patients.
Oncologists are now questioning whether the FDA has become too lenient in its approach, Daniel A. Goldstein, MD, a senior physician in medical oncology and internal medicine at the Rabin Medical Center, Petah Tikva, Israel, told this news organization.
“The main two things you want from a cancer drug is to live longer and live a higher quality of life,” said Goldstein. “But these endpoints that they’ve been using over the past few years are not really giving us confidence that these drugs are actually going to help to live longer or better.”
Dr. Pazdur said the FDA will consider withdrawing its accelerated approvals when results of further studies do not confirm expected benefit for patients.
“This is like the pendulum has swung as far as it was going to swing and now is on the backswing,” said Dr. Goldstein, also of the department of health policy and management at the University of North Carolina at Chapel Hill. “You could call this a watershed moment.”
Although there’s near universal interest in allowing people with advanced cancer access to promising medicines, there’s also rising concern about exposing patients needlessly to costly drugs with potentially tough side effects. That may prompt a shift in the standards U.S. regulators apply to cancer medicines, Dr. Goldstein said.
Indications withdrawn and under review
In a meeting scheduled for April 27-29, the FDA’s Oncologic Drugs Advisory Committee will review indications granted through the accelerated approval process for three immunotherapies: pembrolizumab (Keytruda), atezolizumab (Tecentriq), and nivolumab (Opdivo).
It is part of an industry-wide evaluation of accelerated approvals for cancer indications in which confirmatory trials did not confirm clinical benefit, the FDA noted.
The process has already led to voluntary withdrawals of four cancer indications by the manufacturers, including one indication each for pembrolizumab, atezolizumab, and nivolumab, and one for durvalumab (Imfinzi).
All of these immunotherapies are approved for numerous cancer indications, and they all remain on the market. It is only the U.S. approvals for particular cancer indications that have been withdrawn.
In the past, olaratumab (Lartruvo) was withdrawn from the market altogether. The FDA granted accelerated approval of the drug for soft tissue sarcoma, but clinical benefit was not confirmed in a phase 3 trial.
Issue highlighted by Dr. Prasad and Dr. Gyawali
In recent years, much of the attention on accelerated approvals was spurred by the work of a few researchers, particularly Vinay Prasad, MD, MPH, associate professor in the department of epidemiology and biostatistics, University of California, San Francisco, and Bishal Gyawali, MD, PhD, from Queen’s University Cancer Research Institute, Kingston, Ont. (Both are regular contributors to the oncology section of this news organization.)
Dr. Goldstein made this point in a tweet about the FDA’s announcement of the April ODAC meetings:
“Well done to @oncology_bg and @VPrasadMDMPH among others for highlighting in their papers that the FDA wasn’t properly evaluating accelerated approval drugs.
FDA have listened.
And I thought that the impact of academia was limited!”
Dr. Prasad has made the case for closer scrutiny of accelerated approvals in a number of journal articles and in his 2020 book, “Malignant: How Bad Policy and Bad Evidence Harm People with Cancer,” published by Johns Hopkins University Press.
The book includes highlights of a 2016 article published in Mayo Clinic Proceedings that focused on surrogate endpoints used for FDA approvals. In the article, Dr. Prasad and his coauthor report that they did not find formal analyses of the strength of the surrogate-survival correlation in 14 of 25 cases of accelerated approvals (56%) and in 11 of 30 traditional approvals (37%).
“Our results were concerning. They imply that many surrogates are based on little more than a gut feeling. You might rationalize that and argue a gut feeling is the same as ‘reasonably likely to predict,’ but no reasonable person could think a gut feeling means established,” Dr. Prasad writes in his book. “Our result suggests the FDA is using surrogate endpoints far beyond what may be fair or reasonable.”
Dr. Gyawali has argued that the process by which the FDA assesses cancer drugs for approvals has undergone a profound shift. He has most recently remarked on this in an October 2020 commentary on Medscape.
“Until the recent floodgate of approvals based on response rates from single-arm trials, the majority of cancer therapy decisions were supported by evidence generated from randomized controlled trials (RCTs),” Dr. Gyawali wrote. “The evidence base to support clinical decisions in managing therapeutic side effects has been comparatively sparse.”
Accelerated approval to improve access
The FDA has struggled for about 2 decades with questions of where to set the bar on evidence for promising cancer drugs.
The agency’s accelerated approval program for drugs began in 1992. During the first decade, the focus was largely on medicines related to HIV.
In the early 2000s, oncology drugs began to dominate the program.
Dr. Pazdur has presided over the FDA’s marked changes regarding the use of surrogate markers when weighing whether to allow sales of cancer medicines. Formerly a professor at the University of Texas MD Anderson Cancer Center, Houston, Dr. Pazdur joined the FDA as director of the Division of Oncology Drug Products in 1999.
Soon after his appointment, he had to field inquiries from pharmaceutical companies about how much evidence they needed to receive accelerated approvals.
Early on, he publicly expressed impatience about the drugmakers’ approach. “The purpose of accelerated approval was not accelerated drug company profits,” Dr. Padzur said at a 2004 ODAC meeting.
Rather, the point is to allow access to potentially helpful drugs while work continues to determine their actual benefit to patients, he explained.
“It wasn’t a license to do less, less, less, and less to a point now that we may be getting companies that are coming in” intent on determining the minimum evidence the FDA will take, Dr. Pazdur said. “It shouldn’t be what is the lowest. It is what is a sufficient amount to give patients and physicians a real understanding of what their drug will do.”
In a 2016 interview with The New York Times, Dr. Pazdur said that his views on cancer drug approvals have evolved with time. He described himself as being “on a jihad to streamline the review process and get things out the door faster.”
“I have evolved from regulator to regulator-advocate,” Dr. Pazdur told the newspaper.
His attitude reflected his personal experience in losing his wife to ovarian cancer in 2015, as well as shifts in science and law. In 2012, Congress passed a law that gave the FDA new resources to speed medicines for life-threatening diseases to market. In addition, advances in genetics appeared to be making some medications more effective and easier to test, Dr. Pazdur said in The New York Times interview.
Withdrawals seen as sign of success
Since the program’s inception, only 6% of accelerated approvals for oncology indications have been withdrawn, the FDA said.
It would be a sign that the program is working if the April meetings lead to further withdrawals of indications that have been granted accelerated approval, Julie R. Gralow, MD, chief medical officer of the American Society of Clinical Oncology, said in an interview with this news organization.
“It shouldn’t be seen as a failure,” Dr. Gralow said.
In her own practice at the Fred Hutchinson Cancer Research Center, Seattle, she has seen the value of emerging therapies for patients fighting advanced cancers. During her 25 years of clinical practice in an academic setting, she has gained access to drugs through single-patient investigative new drug applications.
However, this path is not an option for many patients who undergo treatment in facilities other than academic centers, she commented. She noted that the accelerated approval process is a way to expand access to emerging medicines, but she sees a need for caution in the use of drugs that have been given only this conditional approval. She emphasizes that such drugs may be suitable only for certain patients.
“I would say that, for metastatic patients, patients with incurable disease, we are willing to take some risk,” Dr. Gralow said. “We don’t have other options. They can’t wait the years that it would take to get a drug approved.”
One such patient is David Mitchell, who serves as the consumer representative on ODAC. He told this news organization that he is taking three drugs for multiple myeloma that received accelerated approvals: pomalidomide, bortezomib, and daratumumab.
“I want the FDA to have the option to approve drugs in an accelerated pathway, because as a patient taking three drugs granted accelerated approval, I’m benefiting – I’ve lived the benefit,” Mr. Mitchell said, “and I want other patients to have the opportunity to have that benefit.”
He believes that the FDA’s approach regarding accelerated approvals serves to get potentially beneficial medicines to patients who have few options and also fulfills the FDA’s mandate to protect the public from treatments that have little benefit but can cause harm.
Accelerated approval also offers needed flexibility to drugmakers as they develop more specifically targeted drugs for diseases that affect relatively few people, such as multiple myeloma, he said. “As the targeting of your therapies gets tighter and for smaller groups of patients, you have a harder time following the traditional model,” such as conducting large, double-blind, placebo-controlled trials that may indicate increased overall survival, he said.
“To me, this is the way the FDA intended it to work,” he added. “It’s going to offer the accelerated approval based on a surrogate endpoint for a safe drug, but it’s going to require the confirmatory trial, and if the confirmatory trial fails, it will pull the drug off the market.”
Some medicines that have received accelerated approvals may ultimately be found not to benefit patients, Mr. Mitchell acknowledged. But people in his situation, whose disease has progressed despite treatments, may want to take that risk, he added.
Four cancer indications recently withdrawn voluntarily by the manufacturer
- December 2020: Nivolumab for the treatment of patients with metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy (Bristol Myers Squibb).
- February 2021: Durvalumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or following platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy (AstraZeneca).
- March 2021: Pembrolizumab for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy (Merck).
- March 2021: Atezolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing atezolizumab chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy (Genentech).
Six cancer indications under review at the April 2021 ODAC meeting
- Atezolizumab indicated in combination with protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering ≥1% of the tumor area), as determined by an FDA-approved test.
- Atezolizumab indicated for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
- Pembrolizumab indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
- Pembrolizumab indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (Combined Positive Score ≥1), as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
- Pembrolizumab indicated for the treatment of patients with who have been previously treated with .
- Nivolumab indicated as a single agent for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.
A version of this article first appeared on Medscape.com.
Don’t delay: Cancer patients need both doses of COVID vaccine
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.