Cancer

New results from a phase 3 clinical trial may shut the door on the addition of progressive death–1 or PD–ligand 1 inhibitors to the combination of BRAF and MEK inhibitors for the treatment of BRAF V600–mutated melanoma.

The approach seemed promising, given the efficacy of PD-1 and PD-L1 inhibitors in metastatic melanoma, and the relatively short response times to BRAF and MEK inhibitors could potentially be supplemented by longer response times associated with PD-1 and PD-L1 inhibitors. The two categories also have different mechanisms of action and nonoverlapping toxicities, which led to an expectation that the combination would be well tolerated.

But the new study joins two previous randomized, controlled trials that also failed to show much clinical benefit. IMspire150 assigned BRAF V600–mutated melanoma patients to vemurafenib and cobimetinib plus the anti–PD-L1 antibody atezolizumab or placebo. The treatment arm had a small benefit in progression-free survival (hazard ratio, 0.78), which led to Food and Drug Administration approval of the combination, though there was no significant difference when the two cohorts were assessed by an independent review committee. The KEYNOTE-022 trial examined dabrafenib plus trametinib with or without the anti–PD-1 antibody pembrolizumab, and found no difference in investigator-assessed progression free survival.

The new study was published in the Journal of Clinical Oncology. In an accompanying editorial, Margaret K. Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Paul B. Chapman, MD, of Weill Cornell Medicine, both in New York, speculated that the toxicity of the triplet combination might explain the latest failure, since patients in the triplet arm had more treatment interruptions and dose reductions than the doublet arm (32% received full-dose dabrafenib vs. 54% in the doublet arm), which may have undermined efficacy.

Citing the fact that there are now three randomized, controlled trials with discouraging results, “we believe that there are sufficient data now to be confident that the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi [RAF inhibitors] plus MEKi [MEK inhibitors] is not associated with a significant clinical benefit and should not be studied further in melanoma.

Moreover, “there is some evidence of harm,” the editorial authors wrote. “As the additional toxicity of triplet combination limited the delivery of combination RAFi plus MEKi therapy in COMBI-I. Focus should turn instead to optimizing doses and schedules of combination RAFi plus MEKi and checkpoint inhibitors, developing treatment strategies to overcome resistance to these therapies, and determining how best to sequence combination RAFi plus MEKi therapy and checkpoint inhibitors. Regarding the latter point, there are several sequential therapy trials currently underway in previously untreated patients with BRAF V600–mutated melanoma.”

In the study, patients were randomized to receive dabrafenib and trametinib plus the anti–PD receptor–1 antibody spartalizumab or placebo. After a median follow-up of 27.2 months, mean progression-free survival was 16.2 months in the spartalizumab arm and 12.0 months in the placebo arm (HR, 0.82; P = .042). The spartalizumab group had a 69% objective response rate versus 64% in the placebo group. 55% of the spartalizumab group experienced grade 3 or higher treatment-related adverse events, compared with 33% in the placebo group.

“These results do not support broad use of first-line immunotherapy plus targeted therapy combination, but they provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600–mutant metastatic melanoma,” the authors of the study wrote.

The study was funded by F Hoffmann–La Roche and Genentech. Dr. Callahan has been employed at Bristol-Myers Squibb, Celgene, and Kleo Pharmaceuticals. Dr. Callahan has consulted for or advised AstraZeneca, Moderna Therapeutics, Merck, and Immunocore. Dr. Chapman has stock or ownership interest in Rgenix; has consulted for or advised Merck, Pfizer, and Black Diamond Therapeutics; and has received research funding from Genentech.

New results from a phase 3 clinical trial may shut the door on the addition of progressive death–1 or PD–ligand 1 inhibitors to the combination of BRAF and MEK inhibitors for the treatment of BRAF V600–mutated melanoma.

The approach seemed promising, given the efficacy of PD-1 and PD-L1 inhibitors in metastatic melanoma, and the relatively short response times to BRAF and MEK inhibitors could potentially be supplemented by longer response times associated with PD-1 and PD-L1 inhibitors. The two categories also have different mechanisms of action and nonoverlapping toxicities, which led to an expectation that the combination would be well tolerated.

But the new study joins two previous randomized, controlled trials that also failed to show much clinical benefit. IMspire150 assigned BRAF V600–mutated melanoma patients to vemurafenib and cobimetinib plus the anti–PD-L1 antibody atezolizumab or placebo. The treatment arm had a small benefit in progression-free survival (hazard ratio, 0.78), which led to Food and Drug Administration approval of the combination, though there was no significant difference when the two cohorts were assessed by an independent review committee. The KEYNOTE-022 trial examined dabrafenib plus trametinib with or without the anti–PD-1 antibody pembrolizumab, and found no difference in investigator-assessed progression free survival.

The new study was published in the Journal of Clinical Oncology. In an accompanying editorial, Margaret K. Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Paul B. Chapman, MD, of Weill Cornell Medicine, both in New York, speculated that the toxicity of the triplet combination might explain the latest failure, since patients in the triplet arm had more treatment interruptions and dose reductions than the doublet arm (32% received full-dose dabrafenib vs. 54% in the doublet arm), which may have undermined efficacy.

Citing the fact that there are now three randomized, controlled trials with discouraging results, “we believe that there are sufficient data now to be confident that the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi [RAF inhibitors] plus MEKi [MEK inhibitors] is not associated with a significant clinical benefit and should not be studied further in melanoma.

Moreover, “there is some evidence of harm,” the editorial authors wrote. “As the additional toxicity of triplet combination limited the delivery of combination RAFi plus MEKi therapy in COMBI-I. Focus should turn instead to optimizing doses and schedules of combination RAFi plus MEKi and checkpoint inhibitors, developing treatment strategies to overcome resistance to these therapies, and determining how best to sequence combination RAFi plus MEKi therapy and checkpoint inhibitors. Regarding the latter point, there are several sequential therapy trials currently underway in previously untreated patients with BRAF V600–mutated melanoma.”

In the study, patients were randomized to receive dabrafenib and trametinib plus the anti–PD receptor–1 antibody spartalizumab or placebo. After a median follow-up of 27.2 months, mean progression-free survival was 16.2 months in the spartalizumab arm and 12.0 months in the placebo arm (HR, 0.82; P = .042). The spartalizumab group had a 69% objective response rate versus 64% in the placebo group. 55% of the spartalizumab group experienced grade 3 or higher treatment-related adverse events, compared with 33% in the placebo group.

“These results do not support broad use of first-line immunotherapy plus targeted therapy combination, but they provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600–mutant metastatic melanoma,” the authors of the study wrote.

The study was funded by F Hoffmann–La Roche and Genentech. Dr. Callahan has been employed at Bristol-Myers Squibb, Celgene, and Kleo Pharmaceuticals. Dr. Callahan has consulted for or advised AstraZeneca, Moderna Therapeutics, Merck, and Immunocore. Dr. Chapman has stock or ownership interest in Rgenix; has consulted for or advised Merck, Pfizer, and Black Diamond Therapeutics; and has received research funding from Genentech.

New results from a phase 3 clinical trial may shut the door on the addition of progressive death–1 or PD–ligand 1 inhibitors to the combination of BRAF and MEK inhibitors for the treatment of BRAF V600–mutated melanoma.

The approach seemed promising, given the efficacy of PD-1 and PD-L1 inhibitors in metastatic melanoma, and the relatively short response times to BRAF and MEK inhibitors could potentially be supplemented by longer response times associated with PD-1 and PD-L1 inhibitors. The two categories also have different mechanisms of action and nonoverlapping toxicities, which led to an expectation that the combination would be well tolerated.

But the new study joins two previous randomized, controlled trials that also failed to show much clinical benefit. IMspire150 assigned BRAF V600–mutated melanoma patients to vemurafenib and cobimetinib plus the anti–PD-L1 antibody atezolizumab or placebo. The treatment arm had a small benefit in progression-free survival (hazard ratio, 0.78), which led to Food and Drug Administration approval of the combination, though there was no significant difference when the two cohorts were assessed by an independent review committee. The KEYNOTE-022 trial examined dabrafenib plus trametinib with or without the anti–PD-1 antibody pembrolizumab, and found no difference in investigator-assessed progression free survival.

The new study was published in the Journal of Clinical Oncology. In an accompanying editorial, Margaret K. Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Paul B. Chapman, MD, of Weill Cornell Medicine, both in New York, speculated that the toxicity of the triplet combination might explain the latest failure, since patients in the triplet arm had more treatment interruptions and dose reductions than the doublet arm (32% received full-dose dabrafenib vs. 54% in the doublet arm), which may have undermined efficacy.

Citing the fact that there are now three randomized, controlled trials with discouraging results, “we believe that there are sufficient data now to be confident that the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi [RAF inhibitors] plus MEKi [MEK inhibitors] is not associated with a significant clinical benefit and should not be studied further in melanoma.

Moreover, “there is some evidence of harm,” the editorial authors wrote. “As the additional toxicity of triplet combination limited the delivery of combination RAFi plus MEKi therapy in COMBI-I. Focus should turn instead to optimizing doses and schedules of combination RAFi plus MEKi and checkpoint inhibitors, developing treatment strategies to overcome resistance to these therapies, and determining how best to sequence combination RAFi plus MEKi therapy and checkpoint inhibitors. Regarding the latter point, there are several sequential therapy trials currently underway in previously untreated patients with BRAF V600–mutated melanoma.”

In the study, patients were randomized to receive dabrafenib and trametinib plus the anti–PD receptor–1 antibody spartalizumab or placebo. After a median follow-up of 27.2 months, mean progression-free survival was 16.2 months in the spartalizumab arm and 12.0 months in the placebo arm (HR, 0.82; P = .042). The spartalizumab group had a 69% objective response rate versus 64% in the placebo group. 55% of the spartalizumab group experienced grade 3 or higher treatment-related adverse events, compared with 33% in the placebo group.

“These results do not support broad use of first-line immunotherapy plus targeted therapy combination, but they provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600–mutant metastatic melanoma,” the authors of the study wrote.

The study was funded by F Hoffmann–La Roche and Genentech. Dr. Callahan has been employed at Bristol-Myers Squibb, Celgene, and Kleo Pharmaceuticals. Dr. Callahan has consulted for or advised AstraZeneca, Moderna Therapeutics, Merck, and Immunocore. Dr. Chapman has stock or ownership interest in Rgenix; has consulted for or advised Merck, Pfizer, and Black Diamond Therapeutics; and has received research funding from Genentech.

Women with ductal carcinoma in situ (DCIS) breast cancer are generally uninformed about their diagnosis and are making uninformed treatment decisions, according to results of a study presented this month at ESMO Breast Cancer 2022, an annual meeting of the European Society for Medical Oncology.

The standard of care for women diagnosed with DCIS includes surgery with or without radiotherapy – even low-risk patients who are increasingly being steered toward active surveillance with annual mammograms. But few patients understand their diagnosis well enough to make informed decisions about treatment, according to a study led by Ellen Engelhardt, PhD, a postdoctoral fellow at The Netherlands Cancer Institute, Amsterdam.

“You’re not able to really have an informed preference until you understand the choices,” she said.

Dr. Engelhardt and colleagues surveyed 200 patients (mean age 59 years) from the LORD study, which is currently underway at The Netherlands Cancer Institute. The women were asked to complete a survey before treatment decisions were made. Their objective was to determine how knowledgeable patients were about DCIS. They found that only 34% of women answered four out of seven questions correctly: 19% of patients believed that DCIS could metastasize to organs other than the breast; 31% did not realize DCIS could progress to invasive breast cancer if left untreated; 79% thought DCIS could always be seen on mammograms; and, 93% said that progression could always be detected before it becomes “too extensive.” Knowledge of DCIS was found not to be associated with patient education level.

Susie X. Sun, MD, FACS, a breast surgeon at the University of Texas MD Anderson Cancer Center, Houston, said the findings clearly highlight a disconnect in communication between doctor and patient.

“I was surprised, because this clearly demonstrates there is a disconnect between what patients are being told by their providers and what is being perceived. It really shows us that we need to do a better job of making sure that our patients understand the information they’re given,” she said.

Dr. Sun, who was not involved in the study, said that DCIS needs to be explained well to patients. When they receive a diagnosis, often all they hear is, “I have breast cancer. It is really important for us to stress to patients how DCIS is different from invasive breast cancer,” she said.

The “Management of Low-risk (grade I and II) DCIS (LORD)” study is one of three studies comparing active surveillance to surgery (with or without radiotherapy).

A limitation of the study presented at ESMO Breast Cancer is that it remains unclear why patients answered questions incorrectly. Was information never communicated to them? Or, did they mishear or misunderstand the doctor? In future studies, Dr. Engelhardt and her colleagues plan to record and analyze audio tapes of consultations to determine where the communication disconnect lies.

Dr. Engelhardt did not disclose any conflicts associated with this work.

Women with ductal carcinoma in situ (DCIS) breast cancer are generally uninformed about their diagnosis and are making uninformed treatment decisions, according to results of a study presented this month at ESMO Breast Cancer 2022, an annual meeting of the European Society for Medical Oncology.

The standard of care for women diagnosed with DCIS includes surgery with or without radiotherapy – even low-risk patients who are increasingly being steered toward active surveillance with annual mammograms. But few patients understand their diagnosis well enough to make informed decisions about treatment, according to a study led by Ellen Engelhardt, PhD, a postdoctoral fellow at The Netherlands Cancer Institute, Amsterdam.

“You’re not able to really have an informed preference until you understand the choices,” she said.

Dr. Engelhardt and colleagues surveyed 200 patients (mean age 59 years) from the LORD study, which is currently underway at The Netherlands Cancer Institute. The women were asked to complete a survey before treatment decisions were made. Their objective was to determine how knowledgeable patients were about DCIS. They found that only 34% of women answered four out of seven questions correctly: 19% of patients believed that DCIS could metastasize to organs other than the breast; 31% did not realize DCIS could progress to invasive breast cancer if left untreated; 79% thought DCIS could always be seen on mammograms; and, 93% said that progression could always be detected before it becomes “too extensive.” Knowledge of DCIS was found not to be associated with patient education level.

Susie X. Sun, MD, FACS, a breast surgeon at the University of Texas MD Anderson Cancer Center, Houston, said the findings clearly highlight a disconnect in communication between doctor and patient.

“I was surprised, because this clearly demonstrates there is a disconnect between what patients are being told by their providers and what is being perceived. It really shows us that we need to do a better job of making sure that our patients understand the information they’re given,” she said.

Dr. Sun, who was not involved in the study, said that DCIS needs to be explained well to patients. When they receive a diagnosis, often all they hear is, “I have breast cancer. It is really important for us to stress to patients how DCIS is different from invasive breast cancer,” she said.

The “Management of Low-risk (grade I and II) DCIS (LORD)” study is one of three studies comparing active surveillance to surgery (with or without radiotherapy).

A limitation of the study presented at ESMO Breast Cancer is that it remains unclear why patients answered questions incorrectly. Was information never communicated to them? Or, did they mishear or misunderstand the doctor? In future studies, Dr. Engelhardt and her colleagues plan to record and analyze audio tapes of consultations to determine where the communication disconnect lies.

Dr. Engelhardt did not disclose any conflicts associated with this work.

Women with ductal carcinoma in situ (DCIS) breast cancer are generally uninformed about their diagnosis and are making uninformed treatment decisions, according to results of a study presented this month at ESMO Breast Cancer 2022, an annual meeting of the European Society for Medical Oncology.

The standard of care for women diagnosed with DCIS includes surgery with or without radiotherapy – even low-risk patients who are increasingly being steered toward active surveillance with annual mammograms. But few patients understand their diagnosis well enough to make informed decisions about treatment, according to a study led by Ellen Engelhardt, PhD, a postdoctoral fellow at The Netherlands Cancer Institute, Amsterdam.

“You’re not able to really have an informed preference until you understand the choices,” she said.

Dr. Engelhardt and colleagues surveyed 200 patients (mean age 59 years) from the LORD study, which is currently underway at The Netherlands Cancer Institute. The women were asked to complete a survey before treatment decisions were made. Their objective was to determine how knowledgeable patients were about DCIS. They found that only 34% of women answered four out of seven questions correctly: 19% of patients believed that DCIS could metastasize to organs other than the breast; 31% did not realize DCIS could progress to invasive breast cancer if left untreated; 79% thought DCIS could always be seen on mammograms; and, 93% said that progression could always be detected before it becomes “too extensive.” Knowledge of DCIS was found not to be associated with patient education level.

Susie X. Sun, MD, FACS, a breast surgeon at the University of Texas MD Anderson Cancer Center, Houston, said the findings clearly highlight a disconnect in communication between doctor and patient.

“I was surprised, because this clearly demonstrates there is a disconnect between what patients are being told by their providers and what is being perceived. It really shows us that we need to do a better job of making sure that our patients understand the information they’re given,” she said.

Dr. Sun, who was not involved in the study, said that DCIS needs to be explained well to patients. When they receive a diagnosis, often all they hear is, “I have breast cancer. It is really important for us to stress to patients how DCIS is different from invasive breast cancer,” she said.

The “Management of Low-risk (grade I and II) DCIS (LORD)” study is one of three studies comparing active surveillance to surgery (with or without radiotherapy).

A limitation of the study presented at ESMO Breast Cancer is that it remains unclear why patients answered questions incorrectly. Was information never communicated to them? Or, did they mishear or misunderstand the doctor? In future studies, Dr. Engelhardt and her colleagues plan to record and analyze audio tapes of consultations to determine where the communication disconnect lies.

Dr. Engelhardt did not disclose any conflicts associated with this work.

Early-onset colorectal cancer (CRC) affecting patients younger than 50 years has risen sharply since 1988 from 7.9 to 12.9 cases in 2015 per 100,000 people. The reason for the increase isn’t well understood.

The findings were highlighted in a recent review article published online in the New England Journal of Medicine. “It’s a national phenomenon and it’s also occurring in other parts of the developed world. We’re used to seeing mostly older people who have this diagnosis. Now we’re seeing a lot of younger people with this disease. It’s rather alarming,” said author Frank Sinicrope, MD, a medical oncologist with Mayo Clinic, Rochester, Minn.

The trend contrasts with a decline in later-onset CRC likely attributable to increases in screening. As a result of the two trends, but especially the increased number of early-onset cases, the median age of diagnosis dropped from 72 in the early 2000s to 66 today.

“Although patients with early-onset colorectal cancer are more likely to have a hereditary syndrome than those who have later-onset disease, most cases are sporadic, with no identifiable cause. Furthermore, somatic mutational profiling of early-onset colorectal cancers has not revealed previously unidentified or actionable alterations to inform our understanding of the pathogenesis of these cancers or to guide treatment,” he wrote in the review.

“Early-onset colorectal cancers are most commonly detected in the rectum, followed by the distal colon; more than 70% of early-onset colorectal cancers are in the left colon at presentation,” he wrote in the review. Younger patients tend to be unfamiliar with CRC symptoms, which are often mistaken for benign conditions.

“We’ve moved the screening age down to 45, but that still is not going to capture a lot of these patients,” Dr. Sinicrope said. He estimates that 25% of rectal cancers and 10%-12% of colon cancers diagnosed in the next 10 years will be early onset.

Although the direct cause of the increased incidence isn’t clear, Dr. Sinicrope suggested it may reflect changing dietary habits and rising obesity among adolescents. “The sugar-containing beverages, the processed sugar and a lot of red meat in the diet and refined grains … reflect changes in the diet over the last 50 years. We may now be seeing the end result of many of these dietary changes that have occurred,” he said, calling for a greater emphasis on plant-based diets, which promote a healthier gut microbiome that may reduce CRC risk. Western-style diets can change the gut microbiome leading to inflammation which increases the risk of CRC.

Most patients with early CRC present with advanced disease in the left colon. And, pathogenic germline variants are present in one in six patients – half of which are associated with Lynch syndrome which increases the risk for CRC.

Dr. Sinicrope highlighted the need for more risk-based intervention, which in turn requires a better knowledge of family history.

“We need to do better job to risk stratify, and that will help us figure out who’s best to target our screening efforts toward,” Dr. Sinicrope said. He pointed out guidelines from the U.S. Multi-Society Task Force on Colorectal Cancer and the American Cancer Society that can help physicians identify patients who might benefit from earlier screening. The American Cancer Society recommends that CRC screening be conducted at 45 years for average-risk individuals.

“The best screening test is the one that the patient will do,” Dr. Sinicrope said.

Early-onset colorectal cancer (CRC) affecting patients younger than 50 years has risen sharply since 1988 from 7.9 to 12.9 cases in 2015 per 100,000 people. The reason for the increase isn’t well understood.

The findings were highlighted in a recent review article published online in the New England Journal of Medicine. “It’s a national phenomenon and it’s also occurring in other parts of the developed world. We’re used to seeing mostly older people who have this diagnosis. Now we’re seeing a lot of younger people with this disease. It’s rather alarming,” said author Frank Sinicrope, MD, a medical oncologist with Mayo Clinic, Rochester, Minn.

The trend contrasts with a decline in later-onset CRC likely attributable to increases in screening. As a result of the two trends, but especially the increased number of early-onset cases, the median age of diagnosis dropped from 72 in the early 2000s to 66 today.

“Although patients with early-onset colorectal cancer are more likely to have a hereditary syndrome than those who have later-onset disease, most cases are sporadic, with no identifiable cause. Furthermore, somatic mutational profiling of early-onset colorectal cancers has not revealed previously unidentified or actionable alterations to inform our understanding of the pathogenesis of these cancers or to guide treatment,” he wrote in the review.

“Early-onset colorectal cancers are most commonly detected in the rectum, followed by the distal colon; more than 70% of early-onset colorectal cancers are in the left colon at presentation,” he wrote in the review. Younger patients tend to be unfamiliar with CRC symptoms, which are often mistaken for benign conditions.

“We’ve moved the screening age down to 45, but that still is not going to capture a lot of these patients,” Dr. Sinicrope said. He estimates that 25% of rectal cancers and 10%-12% of colon cancers diagnosed in the next 10 years will be early onset.

Although the direct cause of the increased incidence isn’t clear, Dr. Sinicrope suggested it may reflect changing dietary habits and rising obesity among adolescents. “The sugar-containing beverages, the processed sugar and a lot of red meat in the diet and refined grains … reflect changes in the diet over the last 50 years. We may now be seeing the end result of many of these dietary changes that have occurred,” he said, calling for a greater emphasis on plant-based diets, which promote a healthier gut microbiome that may reduce CRC risk. Western-style diets can change the gut microbiome leading to inflammation which increases the risk of CRC.

Most patients with early CRC present with advanced disease in the left colon. And, pathogenic germline variants are present in one in six patients – half of which are associated with Lynch syndrome which increases the risk for CRC.

Dr. Sinicrope highlighted the need for more risk-based intervention, which in turn requires a better knowledge of family history.

“We need to do better job to risk stratify, and that will help us figure out who’s best to target our screening efforts toward,” Dr. Sinicrope said. He pointed out guidelines from the U.S. Multi-Society Task Force on Colorectal Cancer and the American Cancer Society that can help physicians identify patients who might benefit from earlier screening. The American Cancer Society recommends that CRC screening be conducted at 45 years for average-risk individuals.

“The best screening test is the one that the patient will do,” Dr. Sinicrope said.

Early-onset colorectal cancer (CRC) affecting patients younger than 50 years has risen sharply since 1988 from 7.9 to 12.9 cases in 2015 per 100,000 people. The reason for the increase isn’t well understood.

The findings were highlighted in a recent review article published online in the New England Journal of Medicine. “It’s a national phenomenon and it’s also occurring in other parts of the developed world. We’re used to seeing mostly older people who have this diagnosis. Now we’re seeing a lot of younger people with this disease. It’s rather alarming,” said author Frank Sinicrope, MD, a medical oncologist with Mayo Clinic, Rochester, Minn.

The trend contrasts with a decline in later-onset CRC likely attributable to increases in screening. As a result of the two trends, but especially the increased number of early-onset cases, the median age of diagnosis dropped from 72 in the early 2000s to 66 today.

“Although patients with early-onset colorectal cancer are more likely to have a hereditary syndrome than those who have later-onset disease, most cases are sporadic, with no identifiable cause. Furthermore, somatic mutational profiling of early-onset colorectal cancers has not revealed previously unidentified or actionable alterations to inform our understanding of the pathogenesis of these cancers or to guide treatment,” he wrote in the review.

“Early-onset colorectal cancers are most commonly detected in the rectum, followed by the distal colon; more than 70% of early-onset colorectal cancers are in the left colon at presentation,” he wrote in the review. Younger patients tend to be unfamiliar with CRC symptoms, which are often mistaken for benign conditions.

“We’ve moved the screening age down to 45, but that still is not going to capture a lot of these patients,” Dr. Sinicrope said. He estimates that 25% of rectal cancers and 10%-12% of colon cancers diagnosed in the next 10 years will be early onset.

Although the direct cause of the increased incidence isn’t clear, Dr. Sinicrope suggested it may reflect changing dietary habits and rising obesity among adolescents. “The sugar-containing beverages, the processed sugar and a lot of red meat in the diet and refined grains … reflect changes in the diet over the last 50 years. We may now be seeing the end result of many of these dietary changes that have occurred,” he said, calling for a greater emphasis on plant-based diets, which promote a healthier gut microbiome that may reduce CRC risk. Western-style diets can change the gut microbiome leading to inflammation which increases the risk of CRC.

Most patients with early CRC present with advanced disease in the left colon. And, pathogenic germline variants are present in one in six patients – half of which are associated with Lynch syndrome which increases the risk for CRC.

Dr. Sinicrope highlighted the need for more risk-based intervention, which in turn requires a better knowledge of family history.

“We need to do better job to risk stratify, and that will help us figure out who’s best to target our screening efforts toward,” Dr. Sinicrope said. He pointed out guidelines from the U.S. Multi-Society Task Force on Colorectal Cancer and the American Cancer Society that can help physicians identify patients who might benefit from earlier screening. The American Cancer Society recommends that CRC screening be conducted at 45 years for average-risk individuals.

“The best screening test is the one that the patient will do,” Dr. Sinicrope said.

A qualitative analysis of 20 people with head and neck cancer (HNC) has led to recommendations for improvements in care.

HNC has a high burden of treatment-related adverse events, along with frequent trouble with speech, swallowing, facial disfigurement, and psychological distress.

Among cancer patients, “they have the highest rates of emergency department use and hospitalization during treatment. They also have the highest rates of psychological distress. We have some Ontario data that shows they’ve got the highest rates of suicide and self-harm. So I think this is a really special population that we need to support,” Christopher Noel, MD, PhD, said in an interview. Dr. Noel was the lead author of the study, which was published in JAMA Otolaryngology – Head & Neck Surgery.

These issues can strongly affect quality of life, and even patient outcomes. “Even a 1-day interruption in treatment has been shown to impact oncologic outcomes. This is a very big issue whether you’re a surgeon, a medical oncologist, or a radiation oncologist,” said Dr. Noel, who is a resident physician at the University of Toronto.

He advocates that physicians interview patients and review the results in a structured way and then act on it. “If we just rely on patient [provided] communication, we’re going to miss about 50% of patient symptoms,” he said.

The researchers aimed for the patient’s perspective on treatment. “What is the patient’s perception of going through head neck cancer and their treatment, and managing their symptoms at home? And where do they think that we could do better?” Dr. Noel asked.

The most pressing issue was that patients felt their emotional and informational needs often were not met. That challenge is even harder for patients who have trouble communicating, which in turn makes them more prone to isolation and loneliness. Many felt that they had to get the information on their own. “They wanted it to be a more effortless process,” said Dr. Noel.

He described one patient with oropharynx cancer who was able to talk to people about her grief over her diagnosis, but treatment led to her throat becoming swollen and she lost the ability to communicate. “She felt very isolated and lonely. She really highlighted the emotional and psychosocial barriers in cancer care. Her treatment inherently leaves her feeling very isolated and lonely, and she had such a hard time connecting with a psychotherapist,” Dr. Noel said.

Another common issue revolved around efforts to communicate about symptoms and adverse effects of treatment. Resources often aren’t available on evenings or weekends, and it can take time for a nurse to call them back. Patients wanted to see more modern approaches, such as use of email or apps.

The patients in the study recommended 11 health care improvements.

• 1. Nurse navigator teams should have hours extended to evenings and weekends.
• 2. Patient communication methods should be expanded, using methods like email or apps.
• 3. HNC resources should be more broadly disseminated.
• 4. Education and information approaches should be individualized to the patient.
• 5. All HNC patients should be offered psychological resources.
• 6. Mental health needs should be assessed repeatedly throughout treatment and extended care.
• 7. Physicians should recognize the added symptom burden often faced by patients who travel extensively for treatment.
• 8. Partners and caregivers should be included as part of the treatment team.
• 9. Share symptom data with patients, which can improve engagement.
• 10. Review symptom scores and act on them regularly.
• 11. A member of the care team should be identified to oversee symptom management.

Dr. Noel had no relevant financial disclosures.

A qualitative analysis of 20 people with head and neck cancer (HNC) has led to recommendations for improvements in care.

HNC has a high burden of treatment-related adverse events, along with frequent trouble with speech, swallowing, facial disfigurement, and psychological distress.

Among cancer patients, “they have the highest rates of emergency department use and hospitalization during treatment. They also have the highest rates of psychological distress. We have some Ontario data that shows they’ve got the highest rates of suicide and self-harm. So I think this is a really special population that we need to support,” Christopher Noel, MD, PhD, said in an interview. Dr. Noel was the lead author of the study, which was published in JAMA Otolaryngology – Head & Neck Surgery.

These issues can strongly affect quality of life, and even patient outcomes. “Even a 1-day interruption in treatment has been shown to impact oncologic outcomes. This is a very big issue whether you’re a surgeon, a medical oncologist, or a radiation oncologist,” said Dr. Noel, who is a resident physician at the University of Toronto.

He advocates that physicians interview patients and review the results in a structured way and then act on it. “If we just rely on patient [provided] communication, we’re going to miss about 50% of patient symptoms,” he said.

The researchers aimed for the patient’s perspective on treatment. “What is the patient’s perception of going through head neck cancer and their treatment, and managing their symptoms at home? And where do they think that we could do better?” Dr. Noel asked.

The most pressing issue was that patients felt their emotional and informational needs often were not met. That challenge is even harder for patients who have trouble communicating, which in turn makes them more prone to isolation and loneliness. Many felt that they had to get the information on their own. “They wanted it to be a more effortless process,” said Dr. Noel.

He described one patient with oropharynx cancer who was able to talk to people about her grief over her diagnosis, but treatment led to her throat becoming swollen and she lost the ability to communicate. “She felt very isolated and lonely. She really highlighted the emotional and psychosocial barriers in cancer care. Her treatment inherently leaves her feeling very isolated and lonely, and she had such a hard time connecting with a psychotherapist,” Dr. Noel said.

Another common issue revolved around efforts to communicate about symptoms and adverse effects of treatment. Resources often aren’t available on evenings or weekends, and it can take time for a nurse to call them back. Patients wanted to see more modern approaches, such as use of email or apps.

The patients in the study recommended 11 health care improvements.

• 1. Nurse navigator teams should have hours extended to evenings and weekends.
• 2. Patient communication methods should be expanded, using methods like email or apps.
• 3. HNC resources should be more broadly disseminated.
• 4. Education and information approaches should be individualized to the patient.
• 5. All HNC patients should be offered psychological resources.
• 6. Mental health needs should be assessed repeatedly throughout treatment and extended care.
• 7. Physicians should recognize the added symptom burden often faced by patients who travel extensively for treatment.
• 8. Partners and caregivers should be included as part of the treatment team.
• 9. Share symptom data with patients, which can improve engagement.
• 10. Review symptom scores and act on them regularly.
• 11. A member of the care team should be identified to oversee symptom management.

Dr. Noel had no relevant financial disclosures.

A qualitative analysis of 20 people with head and neck cancer (HNC) has led to recommendations for improvements in care.

HNC has a high burden of treatment-related adverse events, along with frequent trouble with speech, swallowing, facial disfigurement, and psychological distress.

Among cancer patients, “they have the highest rates of emergency department use and hospitalization during treatment. They also have the highest rates of psychological distress. We have some Ontario data that shows they’ve got the highest rates of suicide and self-harm. So I think this is a really special population that we need to support,” Christopher Noel, MD, PhD, said in an interview. Dr. Noel was the lead author of the study, which was published in JAMA Otolaryngology – Head & Neck Surgery.

These issues can strongly affect quality of life, and even patient outcomes. “Even a 1-day interruption in treatment has been shown to impact oncologic outcomes. This is a very big issue whether you’re a surgeon, a medical oncologist, or a radiation oncologist,” said Dr. Noel, who is a resident physician at the University of Toronto.

He advocates that physicians interview patients and review the results in a structured way and then act on it. “If we just rely on patient [provided] communication, we’re going to miss about 50% of patient symptoms,” he said.

The researchers aimed for the patient’s perspective on treatment. “What is the patient’s perception of going through head neck cancer and their treatment, and managing their symptoms at home? And where do they think that we could do better?” Dr. Noel asked.

The most pressing issue was that patients felt their emotional and informational needs often were not met. That challenge is even harder for patients who have trouble communicating, which in turn makes them more prone to isolation and loneliness. Many felt that they had to get the information on their own. “They wanted it to be a more effortless process,” said Dr. Noel.

He described one patient with oropharynx cancer who was able to talk to people about her grief over her diagnosis, but treatment led to her throat becoming swollen and she lost the ability to communicate. “She felt very isolated and lonely. She really highlighted the emotional and psychosocial barriers in cancer care. Her treatment inherently leaves her feeling very isolated and lonely, and she had such a hard time connecting with a psychotherapist,” Dr. Noel said.

Another common issue revolved around efforts to communicate about symptoms and adverse effects of treatment. Resources often aren’t available on evenings or weekends, and it can take time for a nurse to call them back. Patients wanted to see more modern approaches, such as use of email or apps.

The patients in the study recommended 11 health care improvements.

• 1. Nurse navigator teams should have hours extended to evenings and weekends.
• 2. Patient communication methods should be expanded, using methods like email or apps.
• 3. HNC resources should be more broadly disseminated.
• 4. Education and information approaches should be individualized to the patient.
• 5. All HNC patients should be offered psychological resources.
• 6. Mental health needs should be assessed repeatedly throughout treatment and extended care.
• 7. Physicians should recognize the added symptom burden often faced by patients who travel extensively for treatment.
• 8. Partners and caregivers should be included as part of the treatment team.
• 9. Share symptom data with patients, which can improve engagement.
• 10. Review symptom scores and act on them regularly.
• 11. A member of the care team should be identified to oversee symptom management.

Dr. Noel had no relevant financial disclosures.

A team of experts is recommending that doctors forgo describing early, low-grade prostate tumors as “cancers” as a way to ease anxiety among patients and their families and reduce unnecessary treatment.

Physicians often advise that men with low-risk prostate tumors wait to see if the disease worsens – an approach called “active surveillance” – rather than rushing to treat the condition. After all, low-grade tumors rarely cause harm, and therapies such as radiation and surgery can carry serious side effects, including impotence and urinary leakage.

Yet doctors still label these lesions “cancer,” and as a result, some experts say, many men in the United States opt for treatment they don’t need.

In a new paper likely to stoke debate, experts from a range of disciplines, as well as one patient, argue that overtreatment could be reduced by removing the word “cancer” from low-risk disease. Tumors that rate 6 on the Gleason score (GS) cannot invade other organs but nonetheless scare patients into undergoing risky treatments, they argue. Fewer than 1% of men with GS6 prostate tumors experience metastatic disease or die from cancer within 15 years of the initial diagnosis, they report.

“No matter how much time a physician may spend downplaying the significance of a GS6 diagnosis or emphasizing the phrase low-risk, the words ‘you have cancer’ have a potent psychological effect on most men and their families,” they wrote in a paper published in the Journal of Clinical Oncology.

Dropping the C word for low-risk tumors, which make up about half of 268,000 prostate cancer diagnoses annually in the United States, is not a new idea. An independent panel convened by the National Institutes of Health proposed just that in 2011.

However, clinician support for the shift appears to be growing, said Scott Eggener, MD, a urologic oncologist and professor of surgery at the University of Chicago, and a coauthor of the new article.

Dr. Eggener said active surveillance has been increasing dramatically in the United States, to about 60% of patients with GS6. “We feel like the landscape is right now to be talking about this issue,” Dr. Eggener told this news organization.

Reducing unnecessary treatment, he and his coauthors argue, could reduce the cost of health care — and boost the benefit of prostate-specific antigen testing for prostate cancer, which the U.S. Preventive Services Task Force at the moment deems small.

In addition, patients with prostate cancer diagnoses encounter increased risk of depression and suicide, disqualification or higher rates for life insurance, and questions from family and friends if they choose active surveillance over treatment – all of which might be ameliorated by a change in terminology.

The word “cancer” has been dropped from bladder, cervical, and thyroid conditions and prostate abnormalities that used to be classified as Gleason 2 through 5, they noted.
 

Keeping the status quo

But some physicians say GS6 doesn’t need a name change.

From a scientific standpoint, GS6 disease has molecular hallmarks of cancer, according to Jonathan Epstein, MD, professor of pathology, urology, and oncology at Johns Hopkins University, Baltimore. More important, Dr. Epstein told Medscape, the classification does not guarantee that more serious cancer is not present, only that it has not been found yet in tissue samples.

Dr. Eggener acknowledged that while GS6 does have molecular markers associated with cancer – a fact that’s “challenging to reconcile with” – giving it another name “would still require surveillance, and since the window of opportunity for curing localized [prostate cancer] is typically measured in years or decades, evidence of histologic progression to a higher-grade cancer would far precede the potential time of future metastasis in the majority of cases.”

Still, Dr. Epstein worries that dropping the cancer designation may lead some patients to forgo active surveillance, which involves repeated imaging and biopsies to check for worse disease. Without such monitoring, he said, “if they do have higher grade cancer that’s unsampled, it will pose a threat to their life.”

Gleason 6 tumors “may progress, some significantly, or be incompletely sampled at the time of diagnosis. Both clinicians and patients need to understand such risk,” Peter Carroll, MD, MPH, a urologist at the University of California, San Francisco, who is critical of the proposed name change, told this news organization.

Regardless of what it’s called, Gleason 6 disease warrants close monitoring, said Joe Gallo, a 77-year-old Pennsylvania man whose high-risk cancer was detected during active surveillance. “If I had taken a laid-back, or less, approach” to monitoring, Mr. Gallo said, “necessary treatment may have been delayed and my condition may have become more serious.”

Some advocates say patients and their families need to be educated that cancer exists on a spectrum of severity.

Mark Lichty, 73, chairman of a support group called Active Surveillance Patients International, received a Gleason 6 diagnosis 17 years ago. He resisted treatment against medical advice, and the cancer never progressed.

Mr. Lichty said active surveillance has been more widely adopted in Sweden, where physicians assure patients that treatment is unnecessary and support systems exist. “Yes, a diagnosis of cancer is frightening,” he said in an interview. But “we can do a lot better in how we communicate the diagnosis.”

Dr. Eggener reported consulting or advisory roles with Sophiris Bio, Francis Medical, Insightec, Profound Medical, and Candel Therapeutics; speakers bureau at Janssen; and fees for travel, accommodations, and expenses from Janssen Biotech and Insightec; as well as an uncompensated relationship with Steba Biotech. The remaining coauthors reported several financial relationships, which are listed in the paper. Dr. Epstein and Dr. Carroll have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A team of experts is recommending that doctors forgo describing early, low-grade prostate tumors as “cancers” as a way to ease anxiety among patients and their families and reduce unnecessary treatment.

Physicians often advise that men with low-risk prostate tumors wait to see if the disease worsens – an approach called “active surveillance” – rather than rushing to treat the condition. After all, low-grade tumors rarely cause harm, and therapies such as radiation and surgery can carry serious side effects, including impotence and urinary leakage.

Yet doctors still label these lesions “cancer,” and as a result, some experts say, many men in the United States opt for treatment they don’t need.

In a new paper likely to stoke debate, experts from a range of disciplines, as well as one patient, argue that overtreatment could be reduced by removing the word “cancer” from low-risk disease. Tumors that rate 6 on the Gleason score (GS) cannot invade other organs but nonetheless scare patients into undergoing risky treatments, they argue. Fewer than 1% of men with GS6 prostate tumors experience metastatic disease or die from cancer within 15 years of the initial diagnosis, they report.

“No matter how much time a physician may spend downplaying the significance of a GS6 diagnosis or emphasizing the phrase low-risk, the words ‘you have cancer’ have a potent psychological effect on most men and their families,” they wrote in a paper published in the Journal of Clinical Oncology.

Dropping the C word for low-risk tumors, which make up about half of 268,000 prostate cancer diagnoses annually in the United States, is not a new idea. An independent panel convened by the National Institutes of Health proposed just that in 2011.

However, clinician support for the shift appears to be growing, said Scott Eggener, MD, a urologic oncologist and professor of surgery at the University of Chicago, and a coauthor of the new article.

Dr. Eggener said active surveillance has been increasing dramatically in the United States, to about 60% of patients with GS6. “We feel like the landscape is right now to be talking about this issue,” Dr. Eggener told this news organization.

Reducing unnecessary treatment, he and his coauthors argue, could reduce the cost of health care — and boost the benefit of prostate-specific antigen testing for prostate cancer, which the U.S. Preventive Services Task Force at the moment deems small.

In addition, patients with prostate cancer diagnoses encounter increased risk of depression and suicide, disqualification or higher rates for life insurance, and questions from family and friends if they choose active surveillance over treatment – all of which might be ameliorated by a change in terminology.

The word “cancer” has been dropped from bladder, cervical, and thyroid conditions and prostate abnormalities that used to be classified as Gleason 2 through 5, they noted.
 

Keeping the status quo

But some physicians say GS6 doesn’t need a name change.

From a scientific standpoint, GS6 disease has molecular hallmarks of cancer, according to Jonathan Epstein, MD, professor of pathology, urology, and oncology at Johns Hopkins University, Baltimore. More important, Dr. Epstein told Medscape, the classification does not guarantee that more serious cancer is not present, only that it has not been found yet in tissue samples.

Dr. Eggener acknowledged that while GS6 does have molecular markers associated with cancer – a fact that’s “challenging to reconcile with” – giving it another name “would still require surveillance, and since the window of opportunity for curing localized [prostate cancer] is typically measured in years or decades, evidence of histologic progression to a higher-grade cancer would far precede the potential time of future metastasis in the majority of cases.”

Still, Dr. Epstein worries that dropping the cancer designation may lead some patients to forgo active surveillance, which involves repeated imaging and biopsies to check for worse disease. Without such monitoring, he said, “if they do have higher grade cancer that’s unsampled, it will pose a threat to their life.”

Gleason 6 tumors “may progress, some significantly, or be incompletely sampled at the time of diagnosis. Both clinicians and patients need to understand such risk,” Peter Carroll, MD, MPH, a urologist at the University of California, San Francisco, who is critical of the proposed name change, told this news organization.

Regardless of what it’s called, Gleason 6 disease warrants close monitoring, said Joe Gallo, a 77-year-old Pennsylvania man whose high-risk cancer was detected during active surveillance. “If I had taken a laid-back, or less, approach” to monitoring, Mr. Gallo said, “necessary treatment may have been delayed and my condition may have become more serious.”

Some advocates say patients and their families need to be educated that cancer exists on a spectrum of severity.

Mark Lichty, 73, chairman of a support group called Active Surveillance Patients International, received a Gleason 6 diagnosis 17 years ago. He resisted treatment against medical advice, and the cancer never progressed.

Mr. Lichty said active surveillance has been more widely adopted in Sweden, where physicians assure patients that treatment is unnecessary and support systems exist. “Yes, a diagnosis of cancer is frightening,” he said in an interview. But “we can do a lot better in how we communicate the diagnosis.”

Dr. Eggener reported consulting or advisory roles with Sophiris Bio, Francis Medical, Insightec, Profound Medical, and Candel Therapeutics; speakers bureau at Janssen; and fees for travel, accommodations, and expenses from Janssen Biotech and Insightec; as well as an uncompensated relationship with Steba Biotech. The remaining coauthors reported several financial relationships, which are listed in the paper. Dr. Epstein and Dr. Carroll have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A team of experts is recommending that doctors forgo describing early, low-grade prostate tumors as “cancers” as a way to ease anxiety among patients and their families and reduce unnecessary treatment.

Physicians often advise that men with low-risk prostate tumors wait to see if the disease worsens – an approach called “active surveillance” – rather than rushing to treat the condition. After all, low-grade tumors rarely cause harm, and therapies such as radiation and surgery can carry serious side effects, including impotence and urinary leakage.

Yet doctors still label these lesions “cancer,” and as a result, some experts say, many men in the United States opt for treatment they don’t need.

In a new paper likely to stoke debate, experts from a range of disciplines, as well as one patient, argue that overtreatment could be reduced by removing the word “cancer” from low-risk disease. Tumors that rate 6 on the Gleason score (GS) cannot invade other organs but nonetheless scare patients into undergoing risky treatments, they argue. Fewer than 1% of men with GS6 prostate tumors experience metastatic disease or die from cancer within 15 years of the initial diagnosis, they report.

“No matter how much time a physician may spend downplaying the significance of a GS6 diagnosis or emphasizing the phrase low-risk, the words ‘you have cancer’ have a potent psychological effect on most men and their families,” they wrote in a paper published in the Journal of Clinical Oncology.

Dropping the C word for low-risk tumors, which make up about half of 268,000 prostate cancer diagnoses annually in the United States, is not a new idea. An independent panel convened by the National Institutes of Health proposed just that in 2011.

However, clinician support for the shift appears to be growing, said Scott Eggener, MD, a urologic oncologist and professor of surgery at the University of Chicago, and a coauthor of the new article.

Dr. Eggener said active surveillance has been increasing dramatically in the United States, to about 60% of patients with GS6. “We feel like the landscape is right now to be talking about this issue,” Dr. Eggener told this news organization.

Reducing unnecessary treatment, he and his coauthors argue, could reduce the cost of health care — and boost the benefit of prostate-specific antigen testing for prostate cancer, which the U.S. Preventive Services Task Force at the moment deems small.

In addition, patients with prostate cancer diagnoses encounter increased risk of depression and suicide, disqualification or higher rates for life insurance, and questions from family and friends if they choose active surveillance over treatment – all of which might be ameliorated by a change in terminology.

The word “cancer” has been dropped from bladder, cervical, and thyroid conditions and prostate abnormalities that used to be classified as Gleason 2 through 5, they noted.
 

Keeping the status quo

But some physicians say GS6 doesn’t need a name change.

From a scientific standpoint, GS6 disease has molecular hallmarks of cancer, according to Jonathan Epstein, MD, professor of pathology, urology, and oncology at Johns Hopkins University, Baltimore. More important, Dr. Epstein told Medscape, the classification does not guarantee that more serious cancer is not present, only that it has not been found yet in tissue samples.

Dr. Eggener acknowledged that while GS6 does have molecular markers associated with cancer – a fact that’s “challenging to reconcile with” – giving it another name “would still require surveillance, and since the window of opportunity for curing localized [prostate cancer] is typically measured in years or decades, evidence of histologic progression to a higher-grade cancer would far precede the potential time of future metastasis in the majority of cases.”

Still, Dr. Epstein worries that dropping the cancer designation may lead some patients to forgo active surveillance, which involves repeated imaging and biopsies to check for worse disease. Without such monitoring, he said, “if they do have higher grade cancer that’s unsampled, it will pose a threat to their life.”

Gleason 6 tumors “may progress, some significantly, or be incompletely sampled at the time of diagnosis. Both clinicians and patients need to understand such risk,” Peter Carroll, MD, MPH, a urologist at the University of California, San Francisco, who is critical of the proposed name change, told this news organization.

Regardless of what it’s called, Gleason 6 disease warrants close monitoring, said Joe Gallo, a 77-year-old Pennsylvania man whose high-risk cancer was detected during active surveillance. “If I had taken a laid-back, or less, approach” to monitoring, Mr. Gallo said, “necessary treatment may have been delayed and my condition may have become more serious.”

Some advocates say patients and their families need to be educated that cancer exists on a spectrum of severity.

Mark Lichty, 73, chairman of a support group called Active Surveillance Patients International, received a Gleason 6 diagnosis 17 years ago. He resisted treatment against medical advice, and the cancer never progressed.

Mr. Lichty said active surveillance has been more widely adopted in Sweden, where physicians assure patients that treatment is unnecessary and support systems exist. “Yes, a diagnosis of cancer is frightening,” he said in an interview. But “we can do a lot better in how we communicate the diagnosis.”

Dr. Eggener reported consulting or advisory roles with Sophiris Bio, Francis Medical, Insightec, Profound Medical, and Candel Therapeutics; speakers bureau at Janssen; and fees for travel, accommodations, and expenses from Janssen Biotech and Insightec; as well as an uncompensated relationship with Steba Biotech. The remaining coauthors reported several financial relationships, which are listed in the paper. Dr. Epstein and Dr. Carroll have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The National Comprehensive Cancer Network (NCCN) has recommended a fifth COVID-19 mRNA shot for people who are immunocompromised, including many with cancer or a history of cancer.

A fifth shot of an mRNA vaccine represents a second booster, the group explained, because the primary mRNA immunization series for immunocompromised individuals involves three doses of either the Pfizer or Moderna vaccine.

The update, issued today, comes from the NCCN’s Advisory Committee on COVID-19 Vaccination and Pre-exposure Prophylaxis, which released its first vaccine guidelines for patients with cancer in January 2021. The NCCN has issued numerous updates since then as information about the virus and vaccines has evolved. 

“We know a lot more about COVID-19 and the vaccines now, and we can use that knowledge to minimize the confusion and enhance the protection we can offer to our immunocompromised patients,” said advisory committee co-leader Lindsey Baden, MD, an infectious diseases specialist at the Dana-Farber Cancer Institute, Boston.

The latest iteration of the NCCN’s COVID guidelines includes an update for patients who initially received Johnson & Johnson’s single-shot vaccine, including a recommendation that patients receive an mRNA vaccine for both the first and second booster.

The group also updated dosing recommendations for pre-exposure prevention with tixagevimab plus cilgavimab (Evusheld, AstraZeneca), suggesting 300 mg of each monoclonal antibody instead of 150 mg, based on in vitro activity against Omicron variants.

The group noted that the Moderna and Pfizer shots can be used interchangeably for boosters.

“The NCCN Committee considers both homologous and heterologous boosters to be appropriate options,” the experts wrote.

A version of this article first appeared on Medscape.com.

The National Comprehensive Cancer Network (NCCN) has recommended a fifth COVID-19 mRNA shot for people who are immunocompromised, including many with cancer or a history of cancer.

A fifth shot of an mRNA vaccine represents a second booster, the group explained, because the primary mRNA immunization series for immunocompromised individuals involves three doses of either the Pfizer or Moderna vaccine.

The update, issued today, comes from the NCCN’s Advisory Committee on COVID-19 Vaccination and Pre-exposure Prophylaxis, which released its first vaccine guidelines for patients with cancer in January 2021. The NCCN has issued numerous updates since then as information about the virus and vaccines has evolved. 

“We know a lot more about COVID-19 and the vaccines now, and we can use that knowledge to minimize the confusion and enhance the protection we can offer to our immunocompromised patients,” said advisory committee co-leader Lindsey Baden, MD, an infectious diseases specialist at the Dana-Farber Cancer Institute, Boston.

The latest iteration of the NCCN’s COVID guidelines includes an update for patients who initially received Johnson & Johnson’s single-shot vaccine, including a recommendation that patients receive an mRNA vaccine for both the first and second booster.

The group also updated dosing recommendations for pre-exposure prevention with tixagevimab plus cilgavimab (Evusheld, AstraZeneca), suggesting 300 mg of each monoclonal antibody instead of 150 mg, based on in vitro activity against Omicron variants.

The group noted that the Moderna and Pfizer shots can be used interchangeably for boosters.

“The NCCN Committee considers both homologous and heterologous boosters to be appropriate options,” the experts wrote.

A version of this article first appeared on Medscape.com.

The National Comprehensive Cancer Network (NCCN) has recommended a fifth COVID-19 mRNA shot for people who are immunocompromised, including many with cancer or a history of cancer.

A fifth shot of an mRNA vaccine represents a second booster, the group explained, because the primary mRNA immunization series for immunocompromised individuals involves three doses of either the Pfizer or Moderna vaccine.

The update, issued today, comes from the NCCN’s Advisory Committee on COVID-19 Vaccination and Pre-exposure Prophylaxis, which released its first vaccine guidelines for patients with cancer in January 2021. The NCCN has issued numerous updates since then as information about the virus and vaccines has evolved. 

“We know a lot more about COVID-19 and the vaccines now, and we can use that knowledge to minimize the confusion and enhance the protection we can offer to our immunocompromised patients,” said advisory committee co-leader Lindsey Baden, MD, an infectious diseases specialist at the Dana-Farber Cancer Institute, Boston.

The latest iteration of the NCCN’s COVID guidelines includes an update for patients who initially received Johnson & Johnson’s single-shot vaccine, including a recommendation that patients receive an mRNA vaccine for both the first and second booster.

The group also updated dosing recommendations for pre-exposure prevention with tixagevimab plus cilgavimab (Evusheld, AstraZeneca), suggesting 300 mg of each monoclonal antibody instead of 150 mg, based on in vitro activity against Omicron variants.

The group noted that the Moderna and Pfizer shots can be used interchangeably for boosters.

“The NCCN Committee considers both homologous and heterologous boosters to be appropriate options,” the experts wrote.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – For patients with resectable non–small cell lung cancer (NSCLC), further clinical data continue to show benefit from preoperative treatment with the immune checkpoint inhibitor nivolumab (Opdivo) with chemotherapy.

The combination resulted in significantly longer event-free survival and a 14-fold greater chance of having a pathological complete response compared with chemotherapy alone.

Adding immunotherapy (IO) to chemotherapy in the neoadjuvant setting represents “a quantum leap in lung cancer therapy,” commented David P. Carbone, MD, PhD, director of the James Thoracic Center at Ohio State University, Columbus.

“Combining IO with surgery I think is a new standard of care and will almost certainly improve overall survival [OS] in early-stage disease, for the first time in decades, in my entire career,” he said while discussing the new data at the annual meeting of the American Association for Cancer Research.

The data come from the phase 3 CheckMate 816 study, an open-label trial involving patients with stage IB-IIIA resectable NSCLC. The study was published in the New England Journal of Medicine to coincide with the presentation.

Results from this trial were the basis of the Food and Drug Administration’s recent approval of neoadjuvant therapy with nivolumab (Opdivo) and platinum-based chemotherapy in this population, which one expert described as “a turning point in how we treat resectable NSCLC.”

“Neoadjuvant IO has multiple theoretical advantages of over adjuvant IO,” commented Dr. Carbone. “CheckMate 816 suggests that practice will prove this theory correct.”

Importance of Neoadjuvant Immunotherapy

New details of the results were presented at the meeting by Nicolas Girard, MD, from Institut Curie in Paris.

Among 358 patients in the trial, the median event-free survival (EFS) was 31.6 months for patients randomly assigned to the combination of the immune checkpoint inhibitor nivolumab and platinum-base chemotherapy, compared with 20.8 months for patients assigned to chemotherapy alone. This translated into a hazard ratio for disease recurrence, progression, or death of 0.63 (P = .005).

In addition, 24% of patients assigned to the nivolumab plus chemotherapy arm had a pathological complete response (pCR) to neoadjuvant therapy, compared with only 2.2% of those assigned to chemotherapy alone (P < .001).

Dr. Girard said the study provided important clues to the importance of neoadjuvant therapy for improving objective responses.

“Event-free survival was improved in patients with a pathological complete response, compared with those without, suggesting pCR is a surrogate endpoint for long-term outcomes in resectable non–small cell lung cancer, and this is the first time [this has been shown] in a randomized, phase 3 study,” he said.
 

Neoadjuvant slow to catch on

About one -fourth of all patients who are diagnosed with NSCLC have resectable disease, Dr. Girard and colleagues noted. However, 30%-55% of patients who undergo surgery with curative intent ultimately experience recurrence and die from their disease.

Neoadjuvant therapy may improve chances for complete resection and prevent or delay recurrence after surgery, but the absolute difference in 5-year recurrence-free survival and OS with neoadjuvant chemotherapy alone is only about 6%, they noted.

The new results suggest that adding neoadjuvant immunotherapy to chemotherapy will improve upon this, although so far, the OS data from this trial are immature.

In an interim analysis, the median OS rate was 83% at 2 years for patients treated with nivolumab plus chemotherapy, compared with 71% for patients treated with chemotherapy alone. The published results show a significant improvement in the two primary endpoints – EFS and pCR.

In an editorial accompanying the study, Christine M. Lovly, MD, PhD, from the Vanderbilt-Ingram Cancer Center at Vanderbilt University in Nashville, Tenn., commented that the results of the trial are expected to change practice.

“However, several issues remain to be addressed,” she wrote. “First, is a pathological complete response predictive of event-free survival? Can event-free survival be used as a surrogate endpoint for overall survival? Second, although not mandated for this trial, approximately 20% of the patients received postoperative therapy. Is adjuvant therapy necessary? What criteria should be used to select patients to receive adjuvant therapy?”

Dr. Lovly also pointed out that patients with tumors harboring mutations in the genes EGFR or ALK were excluded from the trial.

“Therefore, implementation of neoadjuvant therapies requires biomarker testing for patients with early-stage disease at the time of diagnosis, a considerable alteration in the routine practice of lung-cancer medicine,” she wrote.
 

Fears of delaying surgery

In an interview, Upal Basu Roy, PhD, MPH, executive director of research at the LUNGevity Foundation, who was not involved in the study, gave a reason why neoadjuvant therapy is not more widely prescribed for patients with resectable NSCLC.

“Clinicians are always scared, and I think patients are as well, that giving a treatment before surgery would delay surgery,” he said. “When patients are diagnosed with lung cancer and they’re told that surgery offers the potential of cure and then hear that you’re giving them a treatment before surgery and that treatment may potentially delay surgery, that is a huge source of anxiety.”

In addition, clinicians until recently were unsure about which patients were most likely to benefit from neoadjuvant therapy when the only option was chemotherapy, “but that’s changing, obviously, with the recent approval of neoadjuvant nivolumab through CheckMate 816,” he said.
 

CheckMate 816 details

In the CheckMate 816 study, investigators enrolled patients with newly diagnosed resectable NSCLC (stage IB-IIIA) who had good performance status and no known sensitizing EGFR mutations or ALK alterations.

After stratification by stage, programmed death–1 status, and sex, the team randomly assigned patients to receive either nivolumab 360 mg plus platinum-based chemotherapy every 3 weeks for a total of three cycles or chemotherapy alone.

At the end of neoadjuvant therapy, patients underwent radiologic restaging and surgery within 6 weeks. Patients could also receive optional adjuvant chemotherapy with or without radiotherapy.

Of the 179 patients in each arm, 176 received the assigned treatment. In all, 149 (83%) of those assigned to the combination had definitive surgery, as did 135 (75%) of those assigned to chemotherapy alone.

In addition, 35 patients (20%) of those assigned to nivolumab-chemo and 56 (32%) assigned to chemotherapy alone received adjuvant therapy.

The coprimary endpoints of EFS and pCR favored the combination, both in the overall population and across most subgroups, including patients younger than 65, men and women, Asian patients, those with stage IIIA disease, nonsquamous histology, current smokers and never-smokers, and patients with higher levels of PD–ligand 1 expression.

The rates of grade 3 or 4 treatment-related adverse events were similar between the groups, at 33.5% with the combination and 36.9% with chemotherapy alone.

Rates of adverse events leading to study discontinuation, treatment-related adverse events, and surgery-related adverse events were similar between the groups. There were two treatment-related deaths, both in the chemotherapy-alone arm.

CheckMate 816 was funded by Bristol-Myers Squibb (manufacturer of nivolumab). Girard has consulted for and has received grant support from Bristol-Myers Squibb and other companies. Dr. Carbone has consulted for Bristol-Myers Squibb and other companies. Dr. Lovly has consulted for various companies. Dr. Roy has received grants from Bristol-Myers Squibb to the LUNGevity Foundation.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – For patients with resectable non–small cell lung cancer (NSCLC), further clinical data continue to show benefit from preoperative treatment with the immune checkpoint inhibitor nivolumab (Opdivo) with chemotherapy.

The combination resulted in significantly longer event-free survival and a 14-fold greater chance of having a pathological complete response compared with chemotherapy alone.

Adding immunotherapy (IO) to chemotherapy in the neoadjuvant setting represents “a quantum leap in lung cancer therapy,” commented David P. Carbone, MD, PhD, director of the James Thoracic Center at Ohio State University, Columbus.

“Combining IO with surgery I think is a new standard of care and will almost certainly improve overall survival [OS] in early-stage disease, for the first time in decades, in my entire career,” he said while discussing the new data at the annual meeting of the American Association for Cancer Research.

The data come from the phase 3 CheckMate 816 study, an open-label trial involving patients with stage IB-IIIA resectable NSCLC. The study was published in the New England Journal of Medicine to coincide with the presentation.

Results from this trial were the basis of the Food and Drug Administration’s recent approval of neoadjuvant therapy with nivolumab (Opdivo) and platinum-based chemotherapy in this population, which one expert described as “a turning point in how we treat resectable NSCLC.”

“Neoadjuvant IO has multiple theoretical advantages of over adjuvant IO,” commented Dr. Carbone. “CheckMate 816 suggests that practice will prove this theory correct.”

Importance of Neoadjuvant Immunotherapy

New details of the results were presented at the meeting by Nicolas Girard, MD, from Institut Curie in Paris.

Among 358 patients in the trial, the median event-free survival (EFS) was 31.6 months for patients randomly assigned to the combination of the immune checkpoint inhibitor nivolumab and platinum-base chemotherapy, compared with 20.8 months for patients assigned to chemotherapy alone. This translated into a hazard ratio for disease recurrence, progression, or death of 0.63 (P = .005).

In addition, 24% of patients assigned to the nivolumab plus chemotherapy arm had a pathological complete response (pCR) to neoadjuvant therapy, compared with only 2.2% of those assigned to chemotherapy alone (P < .001).

Dr. Girard said the study provided important clues to the importance of neoadjuvant therapy for improving objective responses.

“Event-free survival was improved in patients with a pathological complete response, compared with those without, suggesting pCR is a surrogate endpoint for long-term outcomes in resectable non–small cell lung cancer, and this is the first time [this has been shown] in a randomized, phase 3 study,” he said.
 

Neoadjuvant slow to catch on

About one -fourth of all patients who are diagnosed with NSCLC have resectable disease, Dr. Girard and colleagues noted. However, 30%-55% of patients who undergo surgery with curative intent ultimately experience recurrence and die from their disease.

Neoadjuvant therapy may improve chances for complete resection and prevent or delay recurrence after surgery, but the absolute difference in 5-year recurrence-free survival and OS with neoadjuvant chemotherapy alone is only about 6%, they noted.

The new results suggest that adding neoadjuvant immunotherapy to chemotherapy will improve upon this, although so far, the OS data from this trial are immature.

In an interim analysis, the median OS rate was 83% at 2 years for patients treated with nivolumab plus chemotherapy, compared with 71% for patients treated with chemotherapy alone. The published results show a significant improvement in the two primary endpoints – EFS and pCR.

In an editorial accompanying the study, Christine M. Lovly, MD, PhD, from the Vanderbilt-Ingram Cancer Center at Vanderbilt University in Nashville, Tenn., commented that the results of the trial are expected to change practice.

“However, several issues remain to be addressed,” she wrote. “First, is a pathological complete response predictive of event-free survival? Can event-free survival be used as a surrogate endpoint for overall survival? Second, although not mandated for this trial, approximately 20% of the patients received postoperative therapy. Is adjuvant therapy necessary? What criteria should be used to select patients to receive adjuvant therapy?”

Dr. Lovly also pointed out that patients with tumors harboring mutations in the genes EGFR or ALK were excluded from the trial.

“Therefore, implementation of neoadjuvant therapies requires biomarker testing for patients with early-stage disease at the time of diagnosis, a considerable alteration in the routine practice of lung-cancer medicine,” she wrote.
 

Fears of delaying surgery

In an interview, Upal Basu Roy, PhD, MPH, executive director of research at the LUNGevity Foundation, who was not involved in the study, gave a reason why neoadjuvant therapy is not more widely prescribed for patients with resectable NSCLC.

“Clinicians are always scared, and I think patients are as well, that giving a treatment before surgery would delay surgery,” he said. “When patients are diagnosed with lung cancer and they’re told that surgery offers the potential of cure and then hear that you’re giving them a treatment before surgery and that treatment may potentially delay surgery, that is a huge source of anxiety.”

In addition, clinicians until recently were unsure about which patients were most likely to benefit from neoadjuvant therapy when the only option was chemotherapy, “but that’s changing, obviously, with the recent approval of neoadjuvant nivolumab through CheckMate 816,” he said.
 

CheckMate 816 details

In the CheckMate 816 study, investigators enrolled patients with newly diagnosed resectable NSCLC (stage IB-IIIA) who had good performance status and no known sensitizing EGFR mutations or ALK alterations.

After stratification by stage, programmed death–1 status, and sex, the team randomly assigned patients to receive either nivolumab 360 mg plus platinum-based chemotherapy every 3 weeks for a total of three cycles or chemotherapy alone.

At the end of neoadjuvant therapy, patients underwent radiologic restaging and surgery within 6 weeks. Patients could also receive optional adjuvant chemotherapy with or without radiotherapy.

Of the 179 patients in each arm, 176 received the assigned treatment. In all, 149 (83%) of those assigned to the combination had definitive surgery, as did 135 (75%) of those assigned to chemotherapy alone.

In addition, 35 patients (20%) of those assigned to nivolumab-chemo and 56 (32%) assigned to chemotherapy alone received adjuvant therapy.

The coprimary endpoints of EFS and pCR favored the combination, both in the overall population and across most subgroups, including patients younger than 65, men and women, Asian patients, those with stage IIIA disease, nonsquamous histology, current smokers and never-smokers, and patients with higher levels of PD–ligand 1 expression.

The rates of grade 3 or 4 treatment-related adverse events were similar between the groups, at 33.5% with the combination and 36.9% with chemotherapy alone.

Rates of adverse events leading to study discontinuation, treatment-related adverse events, and surgery-related adverse events were similar between the groups. There were two treatment-related deaths, both in the chemotherapy-alone arm.

CheckMate 816 was funded by Bristol-Myers Squibb (manufacturer of nivolumab). Girard has consulted for and has received grant support from Bristol-Myers Squibb and other companies. Dr. Carbone has consulted for Bristol-Myers Squibb and other companies. Dr. Lovly has consulted for various companies. Dr. Roy has received grants from Bristol-Myers Squibb to the LUNGevity Foundation.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – For patients with resectable non–small cell lung cancer (NSCLC), further clinical data continue to show benefit from preoperative treatment with the immune checkpoint inhibitor nivolumab (Opdivo) with chemotherapy.

The combination resulted in significantly longer event-free survival and a 14-fold greater chance of having a pathological complete response compared with chemotherapy alone.

Adding immunotherapy (IO) to chemotherapy in the neoadjuvant setting represents “a quantum leap in lung cancer therapy,” commented David P. Carbone, MD, PhD, director of the James Thoracic Center at Ohio State University, Columbus.

“Combining IO with surgery I think is a new standard of care and will almost certainly improve overall survival [OS] in early-stage disease, for the first time in decades, in my entire career,” he said while discussing the new data at the annual meeting of the American Association for Cancer Research.

The data come from the phase 3 CheckMate 816 study, an open-label trial involving patients with stage IB-IIIA resectable NSCLC. The study was published in the New England Journal of Medicine to coincide with the presentation.

Results from this trial were the basis of the Food and Drug Administration’s recent approval of neoadjuvant therapy with nivolumab (Opdivo) and platinum-based chemotherapy in this population, which one expert described as “a turning point in how we treat resectable NSCLC.”

“Neoadjuvant IO has multiple theoretical advantages of over adjuvant IO,” commented Dr. Carbone. “CheckMate 816 suggests that practice will prove this theory correct.”

Importance of Neoadjuvant Immunotherapy

New details of the results were presented at the meeting by Nicolas Girard, MD, from Institut Curie in Paris.

Among 358 patients in the trial, the median event-free survival (EFS) was 31.6 months for patients randomly assigned to the combination of the immune checkpoint inhibitor nivolumab and platinum-base chemotherapy, compared with 20.8 months for patients assigned to chemotherapy alone. This translated into a hazard ratio for disease recurrence, progression, or death of 0.63 (P = .005).

In addition, 24% of patients assigned to the nivolumab plus chemotherapy arm had a pathological complete response (pCR) to neoadjuvant therapy, compared with only 2.2% of those assigned to chemotherapy alone (P < .001).

Dr. Girard said the study provided important clues to the importance of neoadjuvant therapy for improving objective responses.

“Event-free survival was improved in patients with a pathological complete response, compared with those without, suggesting pCR is a surrogate endpoint for long-term outcomes in resectable non–small cell lung cancer, and this is the first time [this has been shown] in a randomized, phase 3 study,” he said.
 

Neoadjuvant slow to catch on

About one -fourth of all patients who are diagnosed with NSCLC have resectable disease, Dr. Girard and colleagues noted. However, 30%-55% of patients who undergo surgery with curative intent ultimately experience recurrence and die from their disease.

Neoadjuvant therapy may improve chances for complete resection and prevent or delay recurrence after surgery, but the absolute difference in 5-year recurrence-free survival and OS with neoadjuvant chemotherapy alone is only about 6%, they noted.

The new results suggest that adding neoadjuvant immunotherapy to chemotherapy will improve upon this, although so far, the OS data from this trial are immature.

In an interim analysis, the median OS rate was 83% at 2 years for patients treated with nivolumab plus chemotherapy, compared with 71% for patients treated with chemotherapy alone. The published results show a significant improvement in the two primary endpoints – EFS and pCR.

In an editorial accompanying the study, Christine M. Lovly, MD, PhD, from the Vanderbilt-Ingram Cancer Center at Vanderbilt University in Nashville, Tenn., commented that the results of the trial are expected to change practice.

“However, several issues remain to be addressed,” she wrote. “First, is a pathological complete response predictive of event-free survival? Can event-free survival be used as a surrogate endpoint for overall survival? Second, although not mandated for this trial, approximately 20% of the patients received postoperative therapy. Is adjuvant therapy necessary? What criteria should be used to select patients to receive adjuvant therapy?”

Dr. Lovly also pointed out that patients with tumors harboring mutations in the genes EGFR or ALK were excluded from the trial.

“Therefore, implementation of neoadjuvant therapies requires biomarker testing for patients with early-stage disease at the time of diagnosis, a considerable alteration in the routine practice of lung-cancer medicine,” she wrote.
 

Fears of delaying surgery

In an interview, Upal Basu Roy, PhD, MPH, executive director of research at the LUNGevity Foundation, who was not involved in the study, gave a reason why neoadjuvant therapy is not more widely prescribed for patients with resectable NSCLC.

“Clinicians are always scared, and I think patients are as well, that giving a treatment before surgery would delay surgery,” he said. “When patients are diagnosed with lung cancer and they’re told that surgery offers the potential of cure and then hear that you’re giving them a treatment before surgery and that treatment may potentially delay surgery, that is a huge source of anxiety.”

In addition, clinicians until recently were unsure about which patients were most likely to benefit from neoadjuvant therapy when the only option was chemotherapy, “but that’s changing, obviously, with the recent approval of neoadjuvant nivolumab through CheckMate 816,” he said.
 

CheckMate 816 details

In the CheckMate 816 study, investigators enrolled patients with newly diagnosed resectable NSCLC (stage IB-IIIA) who had good performance status and no known sensitizing EGFR mutations or ALK alterations.

After stratification by stage, programmed death–1 status, and sex, the team randomly assigned patients to receive either nivolumab 360 mg plus platinum-based chemotherapy every 3 weeks for a total of three cycles or chemotherapy alone.

At the end of neoadjuvant therapy, patients underwent radiologic restaging and surgery within 6 weeks. Patients could also receive optional adjuvant chemotherapy with or without radiotherapy.

Of the 179 patients in each arm, 176 received the assigned treatment. In all, 149 (83%) of those assigned to the combination had definitive surgery, as did 135 (75%) of those assigned to chemotherapy alone.

In addition, 35 patients (20%) of those assigned to nivolumab-chemo and 56 (32%) assigned to chemotherapy alone received adjuvant therapy.

The coprimary endpoints of EFS and pCR favored the combination, both in the overall population and across most subgroups, including patients younger than 65, men and women, Asian patients, those with stage IIIA disease, nonsquamous histology, current smokers and never-smokers, and patients with higher levels of PD–ligand 1 expression.

The rates of grade 3 or 4 treatment-related adverse events were similar between the groups, at 33.5% with the combination and 36.9% with chemotherapy alone.

Rates of adverse events leading to study discontinuation, treatment-related adverse events, and surgery-related adverse events were similar between the groups. There were two treatment-related deaths, both in the chemotherapy-alone arm.

CheckMate 816 was funded by Bristol-Myers Squibb (manufacturer of nivolumab). Girard has consulted for and has received grant support from Bristol-Myers Squibb and other companies. Dr. Carbone has consulted for Bristol-Myers Squibb and other companies. Dr. Lovly has consulted for various companies. Dr. Roy has received grants from Bristol-Myers Squibb to the LUNGevity Foundation.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).

He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.

“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).

He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.

“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).

He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.

“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – One third of patients with non–small cell lung cancers (NSCLC) bearing the KRASG12C mutation were alive 2 years after starting therapy with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).

The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.

That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.

Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.” 

In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.

Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.

He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”

New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”

At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.

“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.

“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
 

Tarnished triumph

As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.

“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
 

Long follow-up

The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.

The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.

Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.

Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.

Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.

At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.

Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.

Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.

In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.

The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.

Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – One third of patients with non–small cell lung cancers (NSCLC) bearing the KRASG12C mutation were alive 2 years after starting therapy with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).

The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.

That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.

Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.” 

In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.

Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.

He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”

New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”

At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.

“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.

“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
 

Tarnished triumph

As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.

“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
 

Long follow-up

The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.

The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.

Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.

Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.

Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.

At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.

Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.

Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.

In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.

The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.

Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – One third of patients with non–small cell lung cancers (NSCLC) bearing the KRASG12C mutation were alive 2 years after starting therapy with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).

The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.

That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.

Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.” 

In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.

Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.

He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”

New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”

At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.

“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.

“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
 

Tarnished triumph

As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.

“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
 

Long follow-up

The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.

The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.

Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.

Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.

Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.

At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.

Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.

Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.

In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.

The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.

Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.

A version of this article first appeared on Medscape.com.

Women diagnosed with early breast cancer facing surgery often have a choice of having all of their breast or only a part of the breast removed.

A new study shows that a patient’s satisfaction with their breasts at 10 years after surgery is similar for both groups of women.

However, superior psychosocial and sexual well-being at 10 years after surgery was reported by women who underwent breast-conserving surgery and adjuvant radiation therapy (RT), compared with those who underwent mastectomy and reconstruction.

“These findings may inform preference-sensitive decision-making for women with early-stage breast cancer,” write the authors, led by Benjamin D. Smith, MD, department of radiation oncology, University of Texas MD Anderson Cancer Center, Houston.

The study was published online in JAMA Surgery.

These findings have important implications for patient decision-making, given that more women eligible for breast-conserving surgery are opting for a mastectomy, say Sudheer Vemuru, MD, from the University of Colorado at Denver, Aurora, and colleagues, writing in an accompanying editorial.

“Overall, the preponderance of evidence suggests superior short-term and long-term patient-reported outcomes in patients with early-stage breast cancer undergoing breast conserving surgery compared with mastectomy,” they comment.
 

Study details

For their study, Dr. Smith and colleagues conducted a comparative effectiveness research study using data from the Texas Cancer Registry and identified women diagnosed with stage 0-II breast cancer and treated with breast-conserving surgery or mastectomy and reconstruction between 2006 and 2008.

A total of 647 patients were included in their analysis (40%; 356 had undergone breast-conserving surgery; 291 had undergone mastectomy and reconstruction), 551 (85.2%) confirmed treatment with breast-conserving surgery with RT (n = 315) or mastectomy and reconstruction without RT (n = 236).

The median age of the cohort was 53 years and the median time from diagnosis to survey was 10.3 years. Mastectomy and reconstruction were more common among women who were White, younger, node positive, had larger tumors, had bilateral breast cancer, received chemotherapy, and had higher income.

The primary outcome was patient satisfaction with their breasts, as measured with the BREAST-Q patient-reported outcome measure. Secondary outcomes included physical well-being, psychosocial well-being, and sexual well-being. The EuroQol Health-Related Quality of Life 5-Dimension, 3-Level gaged health utility, and local therapy decisional regret was measured via the Decisional Regret Scale.

Using breast-conserving surgery plus RT as the referent, the authors did not find any significant differences in breast satisfaction, physical well-being, health utility, or decisional regret among the study cohorts: breast satisfaction: effect size, 2.71 (P = .30); physical well-being: effect size, –1.80 (P = .36); health utility: effect size, –0.003 (P = .83); and decisional regret: effect size, 1.32 (P = .61).

However, psychosocial well-being (effect size, –8.61; P < .001) and sexual well-being (effect size, –10.68; P < .001) were significantly worse among women who had undergone mastectomy and reconstruction without RT.

They noted that interactions of race and ethnicity and age by treatment group were not significant for reported satisfaction with breast outcomes. But the findings “indicated that the burden of poor long-term QOL outcomes was greater among younger individuals, those with lower educational attainment and income, and certain racial and ethnic minority populations,” they write. “These findings suggest that opportunities exist to enhance equity in the long-term QOL of individuals with breast cancer.”

The editorialists note that previous studies have also found diminished quality of life following mastectomy compared with breast-conserving surgery. However, most of these prior studies included patients undergoing breast-conserving surgery without RT, patients undergoing mastectomy without reconstruction, and patients undergoing mastectomy with RT.

In contrast, this latest study “directly compared breast-conserving surgery with RT vs. mastectomy and reconstruction without RT to avoid those potential confounders,” they point out.

The study was supported by grants from the National Cancer Institute and other bodies. Several of the study authors disclosed relationships with industry and/or with nonprofit organizations. The full list can be found with the original article. Editorialist Clara Lee, MD, reported receiving grants from the Agency for Healthcare Research and Quality during the conduct of the study.

A version of this article first appeared on Medscape.com.

Women diagnosed with early breast cancer facing surgery often have a choice of having all of their breast or only a part of the breast removed.

A new study shows that a patient’s satisfaction with their breasts at 10 years after surgery is similar for both groups of women.

However, superior psychosocial and sexual well-being at 10 years after surgery was reported by women who underwent breast-conserving surgery and adjuvant radiation therapy (RT), compared with those who underwent mastectomy and reconstruction.

“These findings may inform preference-sensitive decision-making for women with early-stage breast cancer,” write the authors, led by Benjamin D. Smith, MD, department of radiation oncology, University of Texas MD Anderson Cancer Center, Houston.

The study was published online in JAMA Surgery.

These findings have important implications for patient decision-making, given that more women eligible for breast-conserving surgery are opting for a mastectomy, say Sudheer Vemuru, MD, from the University of Colorado at Denver, Aurora, and colleagues, writing in an accompanying editorial.

“Overall, the preponderance of evidence suggests superior short-term and long-term patient-reported outcomes in patients with early-stage breast cancer undergoing breast conserving surgery compared with mastectomy,” they comment.
 

Study details

For their study, Dr. Smith and colleagues conducted a comparative effectiveness research study using data from the Texas Cancer Registry and identified women diagnosed with stage 0-II breast cancer and treated with breast-conserving surgery or mastectomy and reconstruction between 2006 and 2008.

A total of 647 patients were included in their analysis (40%; 356 had undergone breast-conserving surgery; 291 had undergone mastectomy and reconstruction), 551 (85.2%) confirmed treatment with breast-conserving surgery with RT (n = 315) or mastectomy and reconstruction without RT (n = 236).

The median age of the cohort was 53 years and the median time from diagnosis to survey was 10.3 years. Mastectomy and reconstruction were more common among women who were White, younger, node positive, had larger tumors, had bilateral breast cancer, received chemotherapy, and had higher income.

The primary outcome was patient satisfaction with their breasts, as measured with the BREAST-Q patient-reported outcome measure. Secondary outcomes included physical well-being, psychosocial well-being, and sexual well-being. The EuroQol Health-Related Quality of Life 5-Dimension, 3-Level gaged health utility, and local therapy decisional regret was measured via the Decisional Regret Scale.

Using breast-conserving surgery plus RT as the referent, the authors did not find any significant differences in breast satisfaction, physical well-being, health utility, or decisional regret among the study cohorts: breast satisfaction: effect size, 2.71 (P = .30); physical well-being: effect size, –1.80 (P = .36); health utility: effect size, –0.003 (P = .83); and decisional regret: effect size, 1.32 (P = .61).

However, psychosocial well-being (effect size, –8.61; P < .001) and sexual well-being (effect size, –10.68; P < .001) were significantly worse among women who had undergone mastectomy and reconstruction without RT.

They noted that interactions of race and ethnicity and age by treatment group were not significant for reported satisfaction with breast outcomes. But the findings “indicated that the burden of poor long-term QOL outcomes was greater among younger individuals, those with lower educational attainment and income, and certain racial and ethnic minority populations,” they write. “These findings suggest that opportunities exist to enhance equity in the long-term QOL of individuals with breast cancer.”

The editorialists note that previous studies have also found diminished quality of life following mastectomy compared with breast-conserving surgery. However, most of these prior studies included patients undergoing breast-conserving surgery without RT, patients undergoing mastectomy without reconstruction, and patients undergoing mastectomy with RT.

In contrast, this latest study “directly compared breast-conserving surgery with RT vs. mastectomy and reconstruction without RT to avoid those potential confounders,” they point out.

The study was supported by grants from the National Cancer Institute and other bodies. Several of the study authors disclosed relationships with industry and/or with nonprofit organizations. The full list can be found with the original article. Editorialist Clara Lee, MD, reported receiving grants from the Agency for Healthcare Research and Quality during the conduct of the study.

A version of this article first appeared on Medscape.com.

Women diagnosed with early breast cancer facing surgery often have a choice of having all of their breast or only a part of the breast removed.

A new study shows that a patient’s satisfaction with their breasts at 10 years after surgery is similar for both groups of women.

However, superior psychosocial and sexual well-being at 10 years after surgery was reported by women who underwent breast-conserving surgery and adjuvant radiation therapy (RT), compared with those who underwent mastectomy and reconstruction.

“These findings may inform preference-sensitive decision-making for women with early-stage breast cancer,” write the authors, led by Benjamin D. Smith, MD, department of radiation oncology, University of Texas MD Anderson Cancer Center, Houston.

The study was published online in JAMA Surgery.

These findings have important implications for patient decision-making, given that more women eligible for breast-conserving surgery are opting for a mastectomy, say Sudheer Vemuru, MD, from the University of Colorado at Denver, Aurora, and colleagues, writing in an accompanying editorial.

“Overall, the preponderance of evidence suggests superior short-term and long-term patient-reported outcomes in patients with early-stage breast cancer undergoing breast conserving surgery compared with mastectomy,” they comment.
 

Study details

For their study, Dr. Smith and colleagues conducted a comparative effectiveness research study using data from the Texas Cancer Registry and identified women diagnosed with stage 0-II breast cancer and treated with breast-conserving surgery or mastectomy and reconstruction between 2006 and 2008.

A total of 647 patients were included in their analysis (40%; 356 had undergone breast-conserving surgery; 291 had undergone mastectomy and reconstruction), 551 (85.2%) confirmed treatment with breast-conserving surgery with RT (n = 315) or mastectomy and reconstruction without RT (n = 236).

The median age of the cohort was 53 years and the median time from diagnosis to survey was 10.3 years. Mastectomy and reconstruction were more common among women who were White, younger, node positive, had larger tumors, had bilateral breast cancer, received chemotherapy, and had higher income.

The primary outcome was patient satisfaction with their breasts, as measured with the BREAST-Q patient-reported outcome measure. Secondary outcomes included physical well-being, psychosocial well-being, and sexual well-being. The EuroQol Health-Related Quality of Life 5-Dimension, 3-Level gaged health utility, and local therapy decisional regret was measured via the Decisional Regret Scale.

Using breast-conserving surgery plus RT as the referent, the authors did not find any significant differences in breast satisfaction, physical well-being, health utility, or decisional regret among the study cohorts: breast satisfaction: effect size, 2.71 (P = .30); physical well-being: effect size, –1.80 (P = .36); health utility: effect size, –0.003 (P = .83); and decisional regret: effect size, 1.32 (P = .61).

However, psychosocial well-being (effect size, –8.61; P < .001) and sexual well-being (effect size, –10.68; P < .001) were significantly worse among women who had undergone mastectomy and reconstruction without RT.

They noted that interactions of race and ethnicity and age by treatment group were not significant for reported satisfaction with breast outcomes. But the findings “indicated that the burden of poor long-term QOL outcomes was greater among younger individuals, those with lower educational attainment and income, and certain racial and ethnic minority populations,” they write. “These findings suggest that opportunities exist to enhance equity in the long-term QOL of individuals with breast cancer.”

The editorialists note that previous studies have also found diminished quality of life following mastectomy compared with breast-conserving surgery. However, most of these prior studies included patients undergoing breast-conserving surgery without RT, patients undergoing mastectomy without reconstruction, and patients undergoing mastectomy with RT.

In contrast, this latest study “directly compared breast-conserving surgery with RT vs. mastectomy and reconstruction without RT to avoid those potential confounders,” they point out.

The study was supported by grants from the National Cancer Institute and other bodies. Several of the study authors disclosed relationships with industry and/or with nonprofit organizations. The full list can be found with the original article. Editorialist Clara Lee, MD, reported receiving grants from the Agency for Healthcare Research and Quality during the conduct of the study.

A version of this article first appeared on Medscape.com.