ESMO Congress 2013

AMSTERDAM – Low-dose aspirin was associated with a survival benefit only in colon cancer patients whose tumors expressed human leukocyte antigen class I in an analysis of 999 colon cancers.

"HLA class I might serve as a predictive biomarker to help identify patients who could benefit from aspirin therapy after diagnosis," Dr. Marlies Reimers reported at the multidisciplinary European cancer congresses.

Several studies, including most recently the Women’s Health Study, have reported that regular low-dose aspirin use can help lower the risk of colorectal cancer, particularly hereditary cases, and reduce polyp formation. Aspirin use after diagnosis has also been associated with better survival. The current findings may explain aspirin’s role in this second pathway, Dr. Reimers said.

In an attempt to elucidate the biologic mechanisms behind aspirin’s benefit, the investigators used tissue microarrays to evaluate the expression of HLA class I and cyclooxygenase (COX)-2 in 999 colon cancers and extracted DNA from 663 tumors to study PIK3CA mutations. The patients were registered with the Eindhoven Cancer Registry between 1998 and 2007, and their aspirin use was obtained from a community pharmacy database.

COX-2 is expressed by about 70% of all colon cancers and is related to tumor genesis, as are PIK3CA mutations. HLA class I is produced by the HLA gene family, which is involved in the immune response.

The investigators hypothesized that aspirin’s role in improved survival could be explained by the interaction of platelets with HLA-positive tumor cells circulating in the bloodstream. Platelets are thought to shield tumor cells in the blood so they can’t be recognized by the immune system, promoting their metastatic potential.

Because aspirin attacks platelet formation, "the protective shield will be lost and the tumor cells could be eliminated by the innate immune system," said Dr. Reimers, who is a PhD student in the department of surgery, Leiden (the Netherlands) University Medical Center.

During the 4-year follow-up, aspirin use after diagnosis was associated with a significantly better overall survival (hazard ratio, 0.64; P = .001).

In patients whose tumors expressed HLA class I, aspirin use cut the risk of death in half, Dr. Reimers said at a press briefing.

No protective effect of aspirin was seen in patients whose tumors did not express HLA class I, expressed COX-2, or contained PIK3CA mutations. A possible explanation for finding no association between COX-2 and PIK3CA with survival could be that pharmacologic data on aspirin indicate that systemic concentrations of aspirin, reached with low-dose aspirin, are inadequate to permanently acetylate COX-2, but are optimal for platelet inhibition, she said in an interview.

Dr. Reimers cautioned reporters that the results are not sufficient to suggest that all colorectal cancer patients should begin taking aspirin and that additional evidence from larger trials is needed to support their findings. Two phase III trials are currently underway: the ASCOLT study of aspirin use in Asian patients with Dukes’ C or high-risk Dukes’ B colorectal cancer and the Add Aspirin trial in the United Kingdom.

Dr. Peter Naredi, president of the European Society of Surgical Oncology, commented in a statement that the results are interesting and that ongoing placebo-controlled randomized trials evaluating the effect of aspirin in colorectal cancer can hopefully strengthen the evidence that aspirin is useful in patients with HLA class I expression."

Dr. Reimers reported having no relevant financial disclosures.

[email protected]

AMSTERDAM – Low-dose aspirin was associated with a survival benefit only in colon cancer patients whose tumors expressed human leukocyte antigen class I in an analysis of 999 colon cancers.

"HLA class I might serve as a predictive biomarker to help identify patients who could benefit from aspirin therapy after diagnosis," Dr. Marlies Reimers reported at the multidisciplinary European cancer congresses.

Several studies, including most recently the Women’s Health Study, have reported that regular low-dose aspirin use can help lower the risk of colorectal cancer, particularly hereditary cases, and reduce polyp formation. Aspirin use after diagnosis has also been associated with better survival. The current findings may explain aspirin’s role in this second pathway, Dr. Reimers said.

In an attempt to elucidate the biologic mechanisms behind aspirin’s benefit, the investigators used tissue microarrays to evaluate the expression of HLA class I and cyclooxygenase (COX)-2 in 999 colon cancers and extracted DNA from 663 tumors to study PIK3CA mutations. The patients were registered with the Eindhoven Cancer Registry between 1998 and 2007, and their aspirin use was obtained from a community pharmacy database.

COX-2 is expressed by about 70% of all colon cancers and is related to tumor genesis, as are PIK3CA mutations. HLA class I is produced by the HLA gene family, which is involved in the immune response.

The investigators hypothesized that aspirin’s role in improved survival could be explained by the interaction of platelets with HLA-positive tumor cells circulating in the bloodstream. Platelets are thought to shield tumor cells in the blood so they can’t be recognized by the immune system, promoting their metastatic potential.

Because aspirin attacks platelet formation, "the protective shield will be lost and the tumor cells could be eliminated by the innate immune system," said Dr. Reimers, who is a PhD student in the department of surgery, Leiden (the Netherlands) University Medical Center.

During the 4-year follow-up, aspirin use after diagnosis was associated with a significantly better overall survival (hazard ratio, 0.64; P = .001).

In patients whose tumors expressed HLA class I, aspirin use cut the risk of death in half, Dr. Reimers said at a press briefing.

No protective effect of aspirin was seen in patients whose tumors did not express HLA class I, expressed COX-2, or contained PIK3CA mutations. A possible explanation for finding no association between COX-2 and PIK3CA with survival could be that pharmacologic data on aspirin indicate that systemic concentrations of aspirin, reached with low-dose aspirin, are inadequate to permanently acetylate COX-2, but are optimal for platelet inhibition, she said in an interview.

Dr. Reimers cautioned reporters that the results are not sufficient to suggest that all colorectal cancer patients should begin taking aspirin and that additional evidence from larger trials is needed to support their findings. Two phase III trials are currently underway: the ASCOLT study of aspirin use in Asian patients with Dukes’ C or high-risk Dukes’ B colorectal cancer and the Add Aspirin trial in the United Kingdom.

Dr. Peter Naredi, president of the European Society of Surgical Oncology, commented in a statement that the results are interesting and that ongoing placebo-controlled randomized trials evaluating the effect of aspirin in colorectal cancer can hopefully strengthen the evidence that aspirin is useful in patients with HLA class I expression."

Dr. Reimers reported having no relevant financial disclosures.

[email protected]

AMSTERDAM – Low-dose aspirin was associated with a survival benefit only in colon cancer patients whose tumors expressed human leukocyte antigen class I in an analysis of 999 colon cancers.

"HLA class I might serve as a predictive biomarker to help identify patients who could benefit from aspirin therapy after diagnosis," Dr. Marlies Reimers reported at the multidisciplinary European cancer congresses.

Several studies, including most recently the Women’s Health Study, have reported that regular low-dose aspirin use can help lower the risk of colorectal cancer, particularly hereditary cases, and reduce polyp formation. Aspirin use after diagnosis has also been associated with better survival. The current findings may explain aspirin’s role in this second pathway, Dr. Reimers said.

In an attempt to elucidate the biologic mechanisms behind aspirin’s benefit, the investigators used tissue microarrays to evaluate the expression of HLA class I and cyclooxygenase (COX)-2 in 999 colon cancers and extracted DNA from 663 tumors to study PIK3CA mutations. The patients were registered with the Eindhoven Cancer Registry between 1998 and 2007, and their aspirin use was obtained from a community pharmacy database.

COX-2 is expressed by about 70% of all colon cancers and is related to tumor genesis, as are PIK3CA mutations. HLA class I is produced by the HLA gene family, which is involved in the immune response.

The investigators hypothesized that aspirin’s role in improved survival could be explained by the interaction of platelets with HLA-positive tumor cells circulating in the bloodstream. Platelets are thought to shield tumor cells in the blood so they can’t be recognized by the immune system, promoting their metastatic potential.

Because aspirin attacks platelet formation, "the protective shield will be lost and the tumor cells could be eliminated by the innate immune system," said Dr. Reimers, who is a PhD student in the department of surgery, Leiden (the Netherlands) University Medical Center.

During the 4-year follow-up, aspirin use after diagnosis was associated with a significantly better overall survival (hazard ratio, 0.64; P = .001).

In patients whose tumors expressed HLA class I, aspirin use cut the risk of death in half, Dr. Reimers said at a press briefing.

No protective effect of aspirin was seen in patients whose tumors did not express HLA class I, expressed COX-2, or contained PIK3CA mutations. A possible explanation for finding no association between COX-2 and PIK3CA with survival could be that pharmacologic data on aspirin indicate that systemic concentrations of aspirin, reached with low-dose aspirin, are inadequate to permanently acetylate COX-2, but are optimal for platelet inhibition, she said in an interview.

Dr. Reimers cautioned reporters that the results are not sufficient to suggest that all colorectal cancer patients should begin taking aspirin and that additional evidence from larger trials is needed to support their findings. Two phase III trials are currently underway: the ASCOLT study of aspirin use in Asian patients with Dukes’ C or high-risk Dukes’ B colorectal cancer and the Add Aspirin trial in the United Kingdom.

Dr. Peter Naredi, president of the European Society of Surgical Oncology, commented in a statement that the results are interesting and that ongoing placebo-controlled randomized trials evaluating the effect of aspirin in colorectal cancer can hopefully strengthen the evidence that aspirin is useful in patients with HLA class I expression."

Dr. Reimers reported having no relevant financial disclosures.

[email protected]

AMSTERDAM – Molecular profiling of cancers with an unknown primary site identified a targetable alteration in 77% of more than 1,400 cases.

Moreover, in a high proportion of cases, profiling directed clinicians to drugs not traditionally considered for cancers of unknown primary site (CUP), Dr. Zoran Gatalica said at the multidisciplinary European cancer congresses.

The study involved 1,459 CUPs, or about 3% of what is expected in the general population, and more than 50,000 patients from 30 countries. This makes it the largest group of patients to date to have their tumor biomarker profiles characterized, said Dr. Gatalica, executive medical director of Caris Life Sciences, Phoenix, Ariz.

Patrice Wendling/IMNG Medical Media

A multiplatform approach was used that included mutational analysis by Sanger sequencing, next-generation sequencing, and polymerase chain reaction (PCR) testing; gene copy number by fluorescent or chromogenic in situ hybridization; O⁶-methylguanine DNA methyltransferase methylation by PCR; and protein expression analysis by immunohistochemistry.

Contrary to expectations, CUP was more prevalent in women (55%, or 822/1,459), and age offered no protection, with patients as young as 11 years and as old as 92 (average, 61 years), Dr. Gatalica said.

The most common site affected by cancer was the liver (24%), followed by other (30%) and lymph nodes (16%).

Not surprisingly, adenocarcinoma was the most common histology (45.3%), but there were also several differences in biomarkers based on histologic subtype, he said. For example, 7% of carcinomas had androgen receptor expression versus 3.3% of undifferentiated and neuroendocrine tumors.

The top "performers" were alterations in TP53 (33%), KRAS (17.5%), PIK3CA (7.4%), APC (3.6%), BRAF (3%), and epidermal growth factor receptor (EGFR) (1.1%), Dr. Gatalica said.

Dr. Gatalica also presented a few illustrative cases including a patient with liver metastases who had significant tumor reduction after being put on irinotecan (Camptostar)/5-fluorouracil on the basis of molecular profiling showing DNA topoisomerase 1 overexpression and thymidylate synthase underexpression.

A second case involved a 64-year-old woman with extensive bone disease who had a near-complete response after being directed to the EGFR-kinase inhibitor erlotinib (Tarceva) because profiling showed she carried an EGFR mutation.

Invited discussant Dr. Lajos Pusztai, codirector of the Yale Cancer Center genetics and genomics program, New Haven, Conn., described the cases as "inspiring" and said the results represent "a treasure trove of data."

Several questions remain, however, including the distribution of anomalies, how the authors defined "targetable," and whether treatment recommendations were actually followed.

"So you give a molecularly targeted treatment recommendation, but how often do physicians follow that?" he asked. "That would be a good way of gauging the test in practicality. What is the benefit rate?"

Audience members also questioned the cost of the test. An unidentified Caris spokesperson rose from the overflow crowd to say the full panel costs about €4,900 Euros (about $6,650 US), but that efforts are underway to bring the price down.

Dr. Gatalica said that in rare instances, molecular profiling "may actually improve the diagnosis of the primary site."

A recent study from the Sarah Cannon Research Institute showed that molecular profiling, using only a 92-gene reverse transcriptase PCR assay, allowed clinicians to predict the site of origin and direct site-specific therapy in 289 CUP patients, resulting in a 3-month gain in overall survival from the historic median of 9 months to 12.5 months (J. Clin. Oncol. 2013;31:217-23).

While molecular profiling represents a "conceptual leap" in the approach to CUP by emphasizing the biology of the tumor and not the primary site, "the problem is we don’t have enough good drugs," Dr. Pusztai observed.

Dr. Gatalica reported ownership and stock options in Caris Life Sciences, which sponsored the study and provided the molecular panel. Dr. Pusztai reported no relevant financial conflicts of interest.

[email protected]

AMSTERDAM – Molecular profiling of cancers with an unknown primary site identified a targetable alteration in 77% of more than 1,400 cases.

Moreover, in a high proportion of cases, profiling directed clinicians to drugs not traditionally considered for cancers of unknown primary site (CUP), Dr. Zoran Gatalica said at the multidisciplinary European cancer congresses.

The study involved 1,459 CUPs, or about 3% of what is expected in the general population, and more than 50,000 patients from 30 countries. This makes it the largest group of patients to date to have their tumor biomarker profiles characterized, said Dr. Gatalica, executive medical director of Caris Life Sciences, Phoenix, Ariz.

Patrice Wendling/IMNG Medical Media

A multiplatform approach was used that included mutational analysis by Sanger sequencing, next-generation sequencing, and polymerase chain reaction (PCR) testing; gene copy number by fluorescent or chromogenic in situ hybridization; O⁶-methylguanine DNA methyltransferase methylation by PCR; and protein expression analysis by immunohistochemistry.

Contrary to expectations, CUP was more prevalent in women (55%, or 822/1,459), and age offered no protection, with patients as young as 11 years and as old as 92 (average, 61 years), Dr. Gatalica said.

The most common site affected by cancer was the liver (24%), followed by other (30%) and lymph nodes (16%).

Not surprisingly, adenocarcinoma was the most common histology (45.3%), but there were also several differences in biomarkers based on histologic subtype, he said. For example, 7% of carcinomas had androgen receptor expression versus 3.3% of undifferentiated and neuroendocrine tumors.

The top "performers" were alterations in TP53 (33%), KRAS (17.5%), PIK3CA (7.4%), APC (3.6%), BRAF (3%), and epidermal growth factor receptor (EGFR) (1.1%), Dr. Gatalica said.

Dr. Gatalica also presented a few illustrative cases including a patient with liver metastases who had significant tumor reduction after being put on irinotecan (Camptostar)/5-fluorouracil on the basis of molecular profiling showing DNA topoisomerase 1 overexpression and thymidylate synthase underexpression.

A second case involved a 64-year-old woman with extensive bone disease who had a near-complete response after being directed to the EGFR-kinase inhibitor erlotinib (Tarceva) because profiling showed she carried an EGFR mutation.

Invited discussant Dr. Lajos Pusztai, codirector of the Yale Cancer Center genetics and genomics program, New Haven, Conn., described the cases as "inspiring" and said the results represent "a treasure trove of data."

Several questions remain, however, including the distribution of anomalies, how the authors defined "targetable," and whether treatment recommendations were actually followed.

"So you give a molecularly targeted treatment recommendation, but how often do physicians follow that?" he asked. "That would be a good way of gauging the test in practicality. What is the benefit rate?"

Audience members also questioned the cost of the test. An unidentified Caris spokesperson rose from the overflow crowd to say the full panel costs about €4,900 Euros (about $6,650 US), but that efforts are underway to bring the price down.

Dr. Gatalica said that in rare instances, molecular profiling "may actually improve the diagnosis of the primary site."

A recent study from the Sarah Cannon Research Institute showed that molecular profiling, using only a 92-gene reverse transcriptase PCR assay, allowed clinicians to predict the site of origin and direct site-specific therapy in 289 CUP patients, resulting in a 3-month gain in overall survival from the historic median of 9 months to 12.5 months (J. Clin. Oncol. 2013;31:217-23).

While molecular profiling represents a "conceptual leap" in the approach to CUP by emphasizing the biology of the tumor and not the primary site, "the problem is we don’t have enough good drugs," Dr. Pusztai observed.

Dr. Gatalica reported ownership and stock options in Caris Life Sciences, which sponsored the study and provided the molecular panel. Dr. Pusztai reported no relevant financial conflicts of interest.

[email protected]

AMSTERDAM – Molecular profiling of cancers with an unknown primary site identified a targetable alteration in 77% of more than 1,400 cases.

Moreover, in a high proportion of cases, profiling directed clinicians to drugs not traditionally considered for cancers of unknown primary site (CUP), Dr. Zoran Gatalica said at the multidisciplinary European cancer congresses.

The study involved 1,459 CUPs, or about 3% of what is expected in the general population, and more than 50,000 patients from 30 countries. This makes it the largest group of patients to date to have their tumor biomarker profiles characterized, said Dr. Gatalica, executive medical director of Caris Life Sciences, Phoenix, Ariz.

Patrice Wendling/IMNG Medical Media

A multiplatform approach was used that included mutational analysis by Sanger sequencing, next-generation sequencing, and polymerase chain reaction (PCR) testing; gene copy number by fluorescent or chromogenic in situ hybridization; O⁶-methylguanine DNA methyltransferase methylation by PCR; and protein expression analysis by immunohistochemistry.

Contrary to expectations, CUP was more prevalent in women (55%, or 822/1,459), and age offered no protection, with patients as young as 11 years and as old as 92 (average, 61 years), Dr. Gatalica said.

The most common site affected by cancer was the liver (24%), followed by other (30%) and lymph nodes (16%).

Not surprisingly, adenocarcinoma was the most common histology (45.3%), but there were also several differences in biomarkers based on histologic subtype, he said. For example, 7% of carcinomas had androgen receptor expression versus 3.3% of undifferentiated and neuroendocrine tumors.

The top "performers" were alterations in TP53 (33%), KRAS (17.5%), PIK3CA (7.4%), APC (3.6%), BRAF (3%), and epidermal growth factor receptor (EGFR) (1.1%), Dr. Gatalica said.

Dr. Gatalica also presented a few illustrative cases including a patient with liver metastases who had significant tumor reduction after being put on irinotecan (Camptostar)/5-fluorouracil on the basis of molecular profiling showing DNA topoisomerase 1 overexpression and thymidylate synthase underexpression.

A second case involved a 64-year-old woman with extensive bone disease who had a near-complete response after being directed to the EGFR-kinase inhibitor erlotinib (Tarceva) because profiling showed she carried an EGFR mutation.

Invited discussant Dr. Lajos Pusztai, codirector of the Yale Cancer Center genetics and genomics program, New Haven, Conn., described the cases as "inspiring" and said the results represent "a treasure trove of data."

Several questions remain, however, including the distribution of anomalies, how the authors defined "targetable," and whether treatment recommendations were actually followed.

"So you give a molecularly targeted treatment recommendation, but how often do physicians follow that?" he asked. "That would be a good way of gauging the test in practicality. What is the benefit rate?"

Audience members also questioned the cost of the test. An unidentified Caris spokesperson rose from the overflow crowd to say the full panel costs about €4,900 Euros (about $6,650 US), but that efforts are underway to bring the price down.

Dr. Gatalica said that in rare instances, molecular profiling "may actually improve the diagnosis of the primary site."

A recent study from the Sarah Cannon Research Institute showed that molecular profiling, using only a 92-gene reverse transcriptase PCR assay, allowed clinicians to predict the site of origin and direct site-specific therapy in 289 CUP patients, resulting in a 3-month gain in overall survival from the historic median of 9 months to 12.5 months (J. Clin. Oncol. 2013;31:217-23).

While molecular profiling represents a "conceptual leap" in the approach to CUP by emphasizing the biology of the tumor and not the primary site, "the problem is we don’t have enough good drugs," Dr. Pusztai observed.

Dr. Gatalica reported ownership and stock options in Caris Life Sciences, which sponsored the study and provided the molecular panel. Dr. Pusztai reported no relevant financial conflicts of interest.

[email protected]

AMSTERDAM – Both progression-free and overall survival were improved by the addition of nintedanib to standard chemotherapy with docetaxel in the second-line treatment of non–small-cell lung cancer in a randomized phase III trial.

Results of the LUME-Lung 1 trial showed progression-free survival of 3.5 months in patients treated with nintedanib plus docetaxel versus 2.7 months for those treated with placebo plus docetaxel (hazard ratio [HR] = 0.85, P = .007) at a data cut-off of February 2013.

Sara Freeman/IMNG Medical Media

"To date, no targeted agent had been shown to prolong overall survival when combined with second-line chemotherapy," said Dr. Anders Mellemgaard of Herlev University Hospital, Copenhagen.

Overall survival was a median of 10.1 months with combination treatment and 9.1 months with docetaxel alone (HR = 0.94; P = .02720). The overall survival results were significantly better in patients with adenocarcinoma (12.6 months vs. 10.3 months, HR = 0.83, P = .0359) and in those adenocarcinoma patients treated within 9 months of the completion of first-line therapy (10.9 vs. 7.9 months, HR = 0.75, P = .0073).

"Patients with advanced non–small-cell lung cancer who have first-line chemotherapy will progress at one point or another," Dr. Mellemgaard said at the multidisciplinary European cancer congresses. Docetaxel is a standard of care for second-line treatment of NSCLC, even though the effects of such treatment are rather modest. Nintedanib is an oral angiokinase inhibitor that blocks the receptors for vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptor.

The LUME-Lung 1 trial comprised 1,314 patients with stage IIIB/IV or recurrent non–small cell lung cancer. Subjects were randomized to treatment with docetaxel at 75 mg/m² on day 1 of a 21-day cycle; 655 patients were randomized to nintedanib 200 mg and 659 patients were given placebo given twice daily on days 2-21. Monotherapy with nintedanib was allowed after four or more cycles of combination therapy.

"Patients with adenocarcinoma histology had significantly improved overall survival with nintedanib," Dr. Mellemgaard said. An exploratory analysis is looking at patients with adenocarcinoma and progressive disease as the best response to first-line treatment showed a 3.5-month survival gain by using the targeted therapy (HR = 0.62, P = .0246).

Diarrhea was the most common adverse effect reported in the combination treatment arm (any grade 43.3% vs. 24.6% in the control group; 6.3% vs. 3.6% for grade 3 or higher). Other common adverse effects were elevated alkaline phosphatase (any grade 37.8% vs. 9.3%; grade 3 or higher 11.6% vs. 0.9%) and fatigue (any grade 30.9% vs. 29.4%; grade 3 or higher 4.7% vs. 4.2%).

"This toxicity was manageable by dose reductions and supportive care," Dr. Mellemgaard observed.

Dr. Mellemgaard is a member of an advisory board for Boehringer Ingelheim, which funded the study.

AMSTERDAM – Both progression-free and overall survival were improved by the addition of nintedanib to standard chemotherapy with docetaxel in the second-line treatment of non–small-cell lung cancer in a randomized phase III trial.

Results of the LUME-Lung 1 trial showed progression-free survival of 3.5 months in patients treated with nintedanib plus docetaxel versus 2.7 months for those treated with placebo plus docetaxel (hazard ratio [HR] = 0.85, P = .007) at a data cut-off of February 2013.

Sara Freeman/IMNG Medical Media

"To date, no targeted agent had been shown to prolong overall survival when combined with second-line chemotherapy," said Dr. Anders Mellemgaard of Herlev University Hospital, Copenhagen.

Overall survival was a median of 10.1 months with combination treatment and 9.1 months with docetaxel alone (HR = 0.94; P = .02720). The overall survival results were significantly better in patients with adenocarcinoma (12.6 months vs. 10.3 months, HR = 0.83, P = .0359) and in those adenocarcinoma patients treated within 9 months of the completion of first-line therapy (10.9 vs. 7.9 months, HR = 0.75, P = .0073).

"Patients with advanced non–small-cell lung cancer who have first-line chemotherapy will progress at one point or another," Dr. Mellemgaard said at the multidisciplinary European cancer congresses. Docetaxel is a standard of care for second-line treatment of NSCLC, even though the effects of such treatment are rather modest. Nintedanib is an oral angiokinase inhibitor that blocks the receptors for vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptor.

The LUME-Lung 1 trial comprised 1,314 patients with stage IIIB/IV or recurrent non–small cell lung cancer. Subjects were randomized to treatment with docetaxel at 75 mg/m² on day 1 of a 21-day cycle; 655 patients were randomized to nintedanib 200 mg and 659 patients were given placebo given twice daily on days 2-21. Monotherapy with nintedanib was allowed after four or more cycles of combination therapy.

"Patients with adenocarcinoma histology had significantly improved overall survival with nintedanib," Dr. Mellemgaard said. An exploratory analysis is looking at patients with adenocarcinoma and progressive disease as the best response to first-line treatment showed a 3.5-month survival gain by using the targeted therapy (HR = 0.62, P = .0246).

Diarrhea was the most common adverse effect reported in the combination treatment arm (any grade 43.3% vs. 24.6% in the control group; 6.3% vs. 3.6% for grade 3 or higher). Other common adverse effects were elevated alkaline phosphatase (any grade 37.8% vs. 9.3%; grade 3 or higher 11.6% vs. 0.9%) and fatigue (any grade 30.9% vs. 29.4%; grade 3 or higher 4.7% vs. 4.2%).

"This toxicity was manageable by dose reductions and supportive care," Dr. Mellemgaard observed.

Dr. Mellemgaard is a member of an advisory board for Boehringer Ingelheim, which funded the study.

AMSTERDAM – Both progression-free and overall survival were improved by the addition of nintedanib to standard chemotherapy with docetaxel in the second-line treatment of non–small-cell lung cancer in a randomized phase III trial.

Results of the LUME-Lung 1 trial showed progression-free survival of 3.5 months in patients treated with nintedanib plus docetaxel versus 2.7 months for those treated with placebo plus docetaxel (hazard ratio [HR] = 0.85, P = .007) at a data cut-off of February 2013.

Sara Freeman/IMNG Medical Media

"To date, no targeted agent had been shown to prolong overall survival when combined with second-line chemotherapy," said Dr. Anders Mellemgaard of Herlev University Hospital, Copenhagen.

Overall survival was a median of 10.1 months with combination treatment and 9.1 months with docetaxel alone (HR = 0.94; P = .02720). The overall survival results were significantly better in patients with adenocarcinoma (12.6 months vs. 10.3 months, HR = 0.83, P = .0359) and in those adenocarcinoma patients treated within 9 months of the completion of first-line therapy (10.9 vs. 7.9 months, HR = 0.75, P = .0073).

"Patients with advanced non–small-cell lung cancer who have first-line chemotherapy will progress at one point or another," Dr. Mellemgaard said at the multidisciplinary European cancer congresses. Docetaxel is a standard of care for second-line treatment of NSCLC, even though the effects of such treatment are rather modest. Nintedanib is an oral angiokinase inhibitor that blocks the receptors for vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptor.

The LUME-Lung 1 trial comprised 1,314 patients with stage IIIB/IV or recurrent non–small cell lung cancer. Subjects were randomized to treatment with docetaxel at 75 mg/m² on day 1 of a 21-day cycle; 655 patients were randomized to nintedanib 200 mg and 659 patients were given placebo given twice daily on days 2-21. Monotherapy with nintedanib was allowed after four or more cycles of combination therapy.

"Patients with adenocarcinoma histology had significantly improved overall survival with nintedanib," Dr. Mellemgaard said. An exploratory analysis is looking at patients with adenocarcinoma and progressive disease as the best response to first-line treatment showed a 3.5-month survival gain by using the targeted therapy (HR = 0.62, P = .0246).

Diarrhea was the most common adverse effect reported in the combination treatment arm (any grade 43.3% vs. 24.6% in the control group; 6.3% vs. 3.6% for grade 3 or higher). Other common adverse effects were elevated alkaline phosphatase (any grade 37.8% vs. 9.3%; grade 3 or higher 11.6% vs. 0.9%) and fatigue (any grade 30.9% vs. 29.4%; grade 3 or higher 4.7% vs. 4.2%).

"This toxicity was manageable by dose reductions and supportive care," Dr. Mellemgaard observed.

Dr. Mellemgaard is a member of an advisory board for Boehringer Ingelheim, which funded the study.

AMSTERDAM – Ipilimumab may be effective in castration-resistant prostate cancer if patients have a low burden of disease, based on phase III trial results reported at the multidisciplinary European cancer congresses.

In patients whose disease progressed within 6 months of docetaxel therapy, the primary endpoint of overall survival just missed reaching statistical significance in the CA184-043 trial at a median of 11.2 months in patients treated with ipilimumab (Yervoy) and of 10 months for those given placebo (hazard ratio [HR] = 0.85, P = .0053).

Sara Freeman/IMNG Medical Media

Overall survival at 1 year was 47% and 40% in each group, respectively, and 26% and 15% at 2 years.

Patients without visceral metastases were more likely to benefit than were those with visceral metastases, reported Dr. Winald Gerritsen of Radboud University Medical Center in Nijmegen, the Netherlands. The HR for overall survival according to the absence or presence of visceral metastases was 0.73.

Overall survival was better with ipilimumab in patients with an ECOG performance status of 0 rather than 1 (HR = 0.72), alkaline phosphatase levels less than 1.5 times the upper limit of normal rather than higher (HR = 0.78), hemoglobin levels of 11 g/dL rather than lower values (0.79), and normal rather than elevated lactate dehydrogenase levels (HR = 0.82).

Furthermore, an exploratory subgroup analysis showed a greater overall survival benefit for immunotherapy in patients with a better prognostic profile, based on alkaline phosphatase level, hemoglobin level, and the absence of visceral metastases. Overall survival was 22.7 months in these patients and 15.8 months for patients in the placebo group (HR = 0.62).

Progression-free survival was also significantly improved at 4 months for ipilimumab therapy and 3 months for placebo (HR = 0.70; P less than .0001). Further, a higher percentage of patients had a prostate-specific antigen response if they were given the immunotherapy (13.1% vs. 5.3%).

The CA184-043 study comprised 799 men with castration-resistant prostate cancer (CRPC) who had received prior chemotherapy with docetaxel but had signs of progression within 6 months of treatment. Subjects had to have one or more symptomatic bone metastases that could be irradiated with a single dose of radiotherapy (8 Gy). After irradiation, 399 men were randomized to receive ipilimumab at an intravenously infused dose of 10 mg/kg on weeks 1, 4, 7 and 10, and then every 12 weeks until progression or intolerable toxicity, and 400 men were randomized to receive a matching placebo.

Treatment-related adverse events occurred in 75% of those randomized to ipilimumab; 36% of the adverse events were grade 3 or higher. The corresponding percentages for those in the placebo arm were 45.5% and 10%. Grade 3 adverse events in the ipilimumab and placebo arms included gastrointestinal (18% vs. 0.8%), liver-related (4.6% vs. 1.3%), endocrine (2% vs. 0.5%), dermatologic (1% vs. 0%), and neurologic (0.3% vs. 0%).

There were 266 deaths in the active treatment arm and 304 in the placebo arm. Disease progression was the cause of death in 51.9% given active treatment and 61.4% given placebo. Toxicity due to ipilimumab was identified as a cause of death in 1% of patients.

The safety profile of ipilimumab in this study was consistent with that in previously defined adverse event profiles, Dr. Gerritsen maintained, and adverse events could usually be managed with standard management algorithms.

Discussant David Olmos of the Spanish National Cancer Research Centre in Madrid said that 19.8% in the treatment arm and 1.5% in the placebo arm discontinued treatment due to adverse events; 51% actually received four or more doses of the immunotherapy.

Sara Freeman/IMNG Medical Media

The postdocetaxel setting may not be the right one for testing the immunotherapy, he said. Tumor burden is related to the chances a vaccine treatment might work.

"Future trials should consider exploring the activity of a T-cell modulating agent in early settings of castration-resistant prostate cancer," Dr. Olmos proposed.

Ipilimumab 3 mg/kg monotherapy is currently licensed for the treatment of unresectable or metastatic melanoma in more than 40 countries. There are ongoing studies looking at its utility as an adjuvant treatment for melanoma and non–small-cell lung cancer, as well as an ongoing phase III trial in chemotherapy-naive CRPC.

The CA184-043 study was funded by Bristol-Myers Squibb. Dr. Gerritsen has participated in advisory boards for BMS, as well as other pharmaceutical companies, and received speaker’s fees from BMS, Astellas, and Jansen. Dr. Olmos has received speaker fees from Janssen-Cilag and Novartis, and consultant fees for advisory board participation from Janssen Diagnostic.

AMSTERDAM – Ipilimumab may be effective in castration-resistant prostate cancer if patients have a low burden of disease, based on phase III trial results reported at the multidisciplinary European cancer congresses.

In patients whose disease progressed within 6 months of docetaxel therapy, the primary endpoint of overall survival just missed reaching statistical significance in the CA184-043 trial at a median of 11.2 months in patients treated with ipilimumab (Yervoy) and of 10 months for those given placebo (hazard ratio [HR] = 0.85, P = .0053).

Sara Freeman/IMNG Medical Media

Overall survival at 1 year was 47% and 40% in each group, respectively, and 26% and 15% at 2 years.

Patients without visceral metastases were more likely to benefit than were those with visceral metastases, reported Dr. Winald Gerritsen of Radboud University Medical Center in Nijmegen, the Netherlands. The HR for overall survival according to the absence or presence of visceral metastases was 0.73.

Overall survival was better with ipilimumab in patients with an ECOG performance status of 0 rather than 1 (HR = 0.72), alkaline phosphatase levels less than 1.5 times the upper limit of normal rather than higher (HR = 0.78), hemoglobin levels of 11 g/dL rather than lower values (0.79), and normal rather than elevated lactate dehydrogenase levels (HR = 0.82).

Furthermore, an exploratory subgroup analysis showed a greater overall survival benefit for immunotherapy in patients with a better prognostic profile, based on alkaline phosphatase level, hemoglobin level, and the absence of visceral metastases. Overall survival was 22.7 months in these patients and 15.8 months for patients in the placebo group (HR = 0.62).

Progression-free survival was also significantly improved at 4 months for ipilimumab therapy and 3 months for placebo (HR = 0.70; P less than .0001). Further, a higher percentage of patients had a prostate-specific antigen response if they were given the immunotherapy (13.1% vs. 5.3%).

The CA184-043 study comprised 799 men with castration-resistant prostate cancer (CRPC) who had received prior chemotherapy with docetaxel but had signs of progression within 6 months of treatment. Subjects had to have one or more symptomatic bone metastases that could be irradiated with a single dose of radiotherapy (8 Gy). After irradiation, 399 men were randomized to receive ipilimumab at an intravenously infused dose of 10 mg/kg on weeks 1, 4, 7 and 10, and then every 12 weeks until progression or intolerable toxicity, and 400 men were randomized to receive a matching placebo.

Treatment-related adverse events occurred in 75% of those randomized to ipilimumab; 36% of the adverse events were grade 3 or higher. The corresponding percentages for those in the placebo arm were 45.5% and 10%. Grade 3 adverse events in the ipilimumab and placebo arms included gastrointestinal (18% vs. 0.8%), liver-related (4.6% vs. 1.3%), endocrine (2% vs. 0.5%), dermatologic (1% vs. 0%), and neurologic (0.3% vs. 0%).

There were 266 deaths in the active treatment arm and 304 in the placebo arm. Disease progression was the cause of death in 51.9% given active treatment and 61.4% given placebo. Toxicity due to ipilimumab was identified as a cause of death in 1% of patients.

The safety profile of ipilimumab in this study was consistent with that in previously defined adverse event profiles, Dr. Gerritsen maintained, and adverse events could usually be managed with standard management algorithms.

Discussant David Olmos of the Spanish National Cancer Research Centre in Madrid said that 19.8% in the treatment arm and 1.5% in the placebo arm discontinued treatment due to adverse events; 51% actually received four or more doses of the immunotherapy.

Sara Freeman/IMNG Medical Media

The postdocetaxel setting may not be the right one for testing the immunotherapy, he said. Tumor burden is related to the chances a vaccine treatment might work.

"Future trials should consider exploring the activity of a T-cell modulating agent in early settings of castration-resistant prostate cancer," Dr. Olmos proposed.

Ipilimumab 3 mg/kg monotherapy is currently licensed for the treatment of unresectable or metastatic melanoma in more than 40 countries. There are ongoing studies looking at its utility as an adjuvant treatment for melanoma and non–small-cell lung cancer, as well as an ongoing phase III trial in chemotherapy-naive CRPC.

The CA184-043 study was funded by Bristol-Myers Squibb. Dr. Gerritsen has participated in advisory boards for BMS, as well as other pharmaceutical companies, and received speaker’s fees from BMS, Astellas, and Jansen. Dr. Olmos has received speaker fees from Janssen-Cilag and Novartis, and consultant fees for advisory board participation from Janssen Diagnostic.

AMSTERDAM – Ipilimumab may be effective in castration-resistant prostate cancer if patients have a low burden of disease, based on phase III trial results reported at the multidisciplinary European cancer congresses.

In patients whose disease progressed within 6 months of docetaxel therapy, the primary endpoint of overall survival just missed reaching statistical significance in the CA184-043 trial at a median of 11.2 months in patients treated with ipilimumab (Yervoy) and of 10 months for those given placebo (hazard ratio [HR] = 0.85, P = .0053).

Sara Freeman/IMNG Medical Media

Overall survival at 1 year was 47% and 40% in each group, respectively, and 26% and 15% at 2 years.

Patients without visceral metastases were more likely to benefit than were those with visceral metastases, reported Dr. Winald Gerritsen of Radboud University Medical Center in Nijmegen, the Netherlands. The HR for overall survival according to the absence or presence of visceral metastases was 0.73.

Overall survival was better with ipilimumab in patients with an ECOG performance status of 0 rather than 1 (HR = 0.72), alkaline phosphatase levels less than 1.5 times the upper limit of normal rather than higher (HR = 0.78), hemoglobin levels of 11 g/dL rather than lower values (0.79), and normal rather than elevated lactate dehydrogenase levels (HR = 0.82).

Furthermore, an exploratory subgroup analysis showed a greater overall survival benefit for immunotherapy in patients with a better prognostic profile, based on alkaline phosphatase level, hemoglobin level, and the absence of visceral metastases. Overall survival was 22.7 months in these patients and 15.8 months for patients in the placebo group (HR = 0.62).

Progression-free survival was also significantly improved at 4 months for ipilimumab therapy and 3 months for placebo (HR = 0.70; P less than .0001). Further, a higher percentage of patients had a prostate-specific antigen response if they were given the immunotherapy (13.1% vs. 5.3%).

The CA184-043 study comprised 799 men with castration-resistant prostate cancer (CRPC) who had received prior chemotherapy with docetaxel but had signs of progression within 6 months of treatment. Subjects had to have one or more symptomatic bone metastases that could be irradiated with a single dose of radiotherapy (8 Gy). After irradiation, 399 men were randomized to receive ipilimumab at an intravenously infused dose of 10 mg/kg on weeks 1, 4, 7 and 10, and then every 12 weeks until progression or intolerable toxicity, and 400 men were randomized to receive a matching placebo.

Treatment-related adverse events occurred in 75% of those randomized to ipilimumab; 36% of the adverse events were grade 3 or higher. The corresponding percentages for those in the placebo arm were 45.5% and 10%. Grade 3 adverse events in the ipilimumab and placebo arms included gastrointestinal (18% vs. 0.8%), liver-related (4.6% vs. 1.3%), endocrine (2% vs. 0.5%), dermatologic (1% vs. 0%), and neurologic (0.3% vs. 0%).

There were 266 deaths in the active treatment arm and 304 in the placebo arm. Disease progression was the cause of death in 51.9% given active treatment and 61.4% given placebo. Toxicity due to ipilimumab was identified as a cause of death in 1% of patients.

The safety profile of ipilimumab in this study was consistent with that in previously defined adverse event profiles, Dr. Gerritsen maintained, and adverse events could usually be managed with standard management algorithms.

Discussant David Olmos of the Spanish National Cancer Research Centre in Madrid said that 19.8% in the treatment arm and 1.5% in the placebo arm discontinued treatment due to adverse events; 51% actually received four or more doses of the immunotherapy.

Sara Freeman/IMNG Medical Media

The postdocetaxel setting may not be the right one for testing the immunotherapy, he said. Tumor burden is related to the chances a vaccine treatment might work.

"Future trials should consider exploring the activity of a T-cell modulating agent in early settings of castration-resistant prostate cancer," Dr. Olmos proposed.

Ipilimumab 3 mg/kg monotherapy is currently licensed for the treatment of unresectable or metastatic melanoma in more than 40 countries. There are ongoing studies looking at its utility as an adjuvant treatment for melanoma and non–small-cell lung cancer, as well as an ongoing phase III trial in chemotherapy-naive CRPC.

The CA184-043 study was funded by Bristol-Myers Squibb. Dr. Gerritsen has participated in advisory boards for BMS, as well as other pharmaceutical companies, and received speaker’s fees from BMS, Astellas, and Jansen. Dr. Olmos has received speaker fees from Janssen-Cilag and Novartis, and consultant fees for advisory board participation from Janssen Diagnostic.

AMSTERDAM – Low-grade toxicity resulted in modification of chemotherapy regimens for nearly one in five older cancer patients and discontinuation of treatment in one in ten, judging from findings from a recent study.

"This is a quite clinically meaningful finding in a large, but understudied patient group," Dr. Tania Kalsi said at the multidisciplinary European cancer congresses.

More than half of cancer diagnoses occur in patients older than 65 years, and this heterogeneous group is growing in size with the aging world population.

Dr. Kalsi reported on a subsample of 108 patients treated with chemotherapy who were part of a prospective, cohort of 516 patients, aged 65 years and older, receiving any cancer treatment at the chemotherapy day unit in a tertiary referral hospital in London. All patients completed the Comprehensive Geriatric Assessment screening questionnaire to evaluate their comorbidities, functional status, and quality of life.

Their mean age was 72 years (range 65-86), 51% were male, and 59.3% were receiving chemotherapy with a palliative intent. Cancers were colorectal in 33, gynecologic in 18, upper gastrointestinal in 16, lung in 15, and other in 26. On average, 4.2 cycles of chemotherapy were delivered.

Of the 108 patients studied, 66 (55.5%) required modification of their chemotherapy regimen due to toxicity, and 21 of them (19.4%) had toxicity of grade 2 or lower, said Dr. Kalsi, a geriatric oncology research fellow at Guy’s and St. Thomas’ NHS Foundation Trust, London.

The mean number of grade 2 toxicities resulting in treatment modification was 2.19; seven patients who needed treatment modification had only one grade 2 toxicity.

Dose modifications were most commonly triggered by fatigue and hematologic toxicity (eight patients each), gastrointestinal (six patients), and infections (five patients), she said.

In univariate analysis, no significant association was seen between low- vs. high-grade toxicity treatment modifications and performance status (P = .730), treatment intent (P = .978), and patient age (less than 75 years vs. at least 75 years; P = .47).

"This is really one of the first studies to look at the impact of low-grade toxicity in older people"

Low-grade toxicity, however, triggered treatment modifications significantly more often in patients with multiple comorbidities (four or more) vs. fewer comorbidities (24.4% vs. 58%; P = .011), Dr. Kalsi said.

Although the series involved few patients, this finding is particularly interesting, said Dr. Riccardo Audisio of the University of Liverpool, U.K., who featured the study (Ab. 1555) in a highlights session at the meeting.

Overall, 23 patients (21.2%) stopped chemotherapy early due to toxicity, and nine (8.3%) of these patients had no toxicity above grade 2.

An average of 1.78 grade 2 toxicities prompted treatment discontinuation and 3 patients had only one grade 2 toxicity. The same culprits of fatigue (5 patients) and hematological toxicity (4 patients) caused early discontinuation, Dr. Kalsi said.

Univariate analysis found no significant association between low- vs. high-grade toxicity treatment discontinuation and performance status (P = 1.00), treatment intent (P = .657), patient age (P = .417), or comorbidities (P = .657), although the small sample size may have influenced the analyses, she said.

"This is really one of the first studies to look at the impact of low-grade toxicity in older people" and "highlights some key questions around clinical decision making" Dr. Kalsi said. Future research will need to tease out whether low-grade toxicity truly has a greater clinical impact on older people or whether there are differences in the clinical interaction between doctors and older patients. For example, is there a lower threshold for modifying/discontinuing treatment in older people; do older people report their symptoms differently than younger patients; and would additional support from a geriatrician liaison improve treatment tolerance; she asked.

Dr. Kalsi reported no relevant conflicts of interest.

[email protected]

AMSTERDAM – Low-grade toxicity resulted in modification of chemotherapy regimens for nearly one in five older cancer patients and discontinuation of treatment in one in ten, judging from findings from a recent study.

"This is a quite clinically meaningful finding in a large, but understudied patient group," Dr. Tania Kalsi said at the multidisciplinary European cancer congresses.

More than half of cancer diagnoses occur in patients older than 65 years, and this heterogeneous group is growing in size with the aging world population.

Dr. Kalsi reported on a subsample of 108 patients treated with chemotherapy who were part of a prospective, cohort of 516 patients, aged 65 years and older, receiving any cancer treatment at the chemotherapy day unit in a tertiary referral hospital in London. All patients completed the Comprehensive Geriatric Assessment screening questionnaire to evaluate their comorbidities, functional status, and quality of life.

Their mean age was 72 years (range 65-86), 51% were male, and 59.3% were receiving chemotherapy with a palliative intent. Cancers were colorectal in 33, gynecologic in 18, upper gastrointestinal in 16, lung in 15, and other in 26. On average, 4.2 cycles of chemotherapy were delivered.

Of the 108 patients studied, 66 (55.5%) required modification of their chemotherapy regimen due to toxicity, and 21 of them (19.4%) had toxicity of grade 2 or lower, said Dr. Kalsi, a geriatric oncology research fellow at Guy’s and St. Thomas’ NHS Foundation Trust, London.

The mean number of grade 2 toxicities resulting in treatment modification was 2.19; seven patients who needed treatment modification had only one grade 2 toxicity.

Dose modifications were most commonly triggered by fatigue and hematologic toxicity (eight patients each), gastrointestinal (six patients), and infections (five patients), she said.

In univariate analysis, no significant association was seen between low- vs. high-grade toxicity treatment modifications and performance status (P = .730), treatment intent (P = .978), and patient age (less than 75 years vs. at least 75 years; P = .47).

"This is really one of the first studies to look at the impact of low-grade toxicity in older people"

Low-grade toxicity, however, triggered treatment modifications significantly more often in patients with multiple comorbidities (four or more) vs. fewer comorbidities (24.4% vs. 58%; P = .011), Dr. Kalsi said.

Although the series involved few patients, this finding is particularly interesting, said Dr. Riccardo Audisio of the University of Liverpool, U.K., who featured the study (Ab. 1555) in a highlights session at the meeting.

Overall, 23 patients (21.2%) stopped chemotherapy early due to toxicity, and nine (8.3%) of these patients had no toxicity above grade 2.

An average of 1.78 grade 2 toxicities prompted treatment discontinuation and 3 patients had only one grade 2 toxicity. The same culprits of fatigue (5 patients) and hematological toxicity (4 patients) caused early discontinuation, Dr. Kalsi said.

Univariate analysis found no significant association between low- vs. high-grade toxicity treatment discontinuation and performance status (P = 1.00), treatment intent (P = .657), patient age (P = .417), or comorbidities (P = .657), although the small sample size may have influenced the analyses, she said.

"This is really one of the first studies to look at the impact of low-grade toxicity in older people" and "highlights some key questions around clinical decision making" Dr. Kalsi said. Future research will need to tease out whether low-grade toxicity truly has a greater clinical impact on older people or whether there are differences in the clinical interaction between doctors and older patients. For example, is there a lower threshold for modifying/discontinuing treatment in older people; do older people report their symptoms differently than younger patients; and would additional support from a geriatrician liaison improve treatment tolerance; she asked.

Dr. Kalsi reported no relevant conflicts of interest.

[email protected]

AMSTERDAM – Low-grade toxicity resulted in modification of chemotherapy regimens for nearly one in five older cancer patients and discontinuation of treatment in one in ten, judging from findings from a recent study.

"This is a quite clinically meaningful finding in a large, but understudied patient group," Dr. Tania Kalsi said at the multidisciplinary European cancer congresses.

More than half of cancer diagnoses occur in patients older than 65 years, and this heterogeneous group is growing in size with the aging world population.

Dr. Kalsi reported on a subsample of 108 patients treated with chemotherapy who were part of a prospective, cohort of 516 patients, aged 65 years and older, receiving any cancer treatment at the chemotherapy day unit in a tertiary referral hospital in London. All patients completed the Comprehensive Geriatric Assessment screening questionnaire to evaluate their comorbidities, functional status, and quality of life.

Their mean age was 72 years (range 65-86), 51% were male, and 59.3% were receiving chemotherapy with a palliative intent. Cancers were colorectal in 33, gynecologic in 18, upper gastrointestinal in 16, lung in 15, and other in 26. On average, 4.2 cycles of chemotherapy were delivered.

Of the 108 patients studied, 66 (55.5%) required modification of their chemotherapy regimen due to toxicity, and 21 of them (19.4%) had toxicity of grade 2 or lower, said Dr. Kalsi, a geriatric oncology research fellow at Guy’s and St. Thomas’ NHS Foundation Trust, London.

The mean number of grade 2 toxicities resulting in treatment modification was 2.19; seven patients who needed treatment modification had only one grade 2 toxicity.

Dose modifications were most commonly triggered by fatigue and hematologic toxicity (eight patients each), gastrointestinal (six patients), and infections (five patients), she said.

In univariate analysis, no significant association was seen between low- vs. high-grade toxicity treatment modifications and performance status (P = .730), treatment intent (P = .978), and patient age (less than 75 years vs. at least 75 years; P = .47).

"This is really one of the first studies to look at the impact of low-grade toxicity in older people"

Low-grade toxicity, however, triggered treatment modifications significantly more often in patients with multiple comorbidities (four or more) vs. fewer comorbidities (24.4% vs. 58%; P = .011), Dr. Kalsi said.

Although the series involved few patients, this finding is particularly interesting, said Dr. Riccardo Audisio of the University of Liverpool, U.K., who featured the study (Ab. 1555) in a highlights session at the meeting.

Overall, 23 patients (21.2%) stopped chemotherapy early due to toxicity, and nine (8.3%) of these patients had no toxicity above grade 2.

An average of 1.78 grade 2 toxicities prompted treatment discontinuation and 3 patients had only one grade 2 toxicity. The same culprits of fatigue (5 patients) and hematological toxicity (4 patients) caused early discontinuation, Dr. Kalsi said.

Univariate analysis found no significant association between low- vs. high-grade toxicity treatment discontinuation and performance status (P = 1.00), treatment intent (P = .657), patient age (P = .417), or comorbidities (P = .657), although the small sample size may have influenced the analyses, she said.

"This is really one of the first studies to look at the impact of low-grade toxicity in older people" and "highlights some key questions around clinical decision making" Dr. Kalsi said. Future research will need to tease out whether low-grade toxicity truly has a greater clinical impact on older people or whether there are differences in the clinical interaction between doctors and older patients. For example, is there a lower threshold for modifying/discontinuing treatment in older people; do older people report their symptoms differently than younger patients; and would additional support from a geriatrician liaison improve treatment tolerance; she asked.

Dr. Kalsi reported no relevant conflicts of interest.

[email protected]

AMSTERDAM – Irradiating the internal mammary and medial supraclavicular lymph nodes provides a survival benefit in women with stage I-III breast cancer, independent of the number of lymph nodes involved, a randomized, phase III trial has shown.

At 10 years, internal mammary–medial supraclavicular (IM-MS) irradiation significantly increased overall survival by 1.6%, compared with no IM-MS irradiation (82.3% vs. 80.7%; hazard ratio, 0.87; P = .056), disease-free survival by 3% (72.1% vs. 69.1%; HR, 0.89; P = .044), and metastases-free survival by 3% (78% vs. 75%; HR, 0.86; P = .02).

Importantly, there was "no increased lethal toxicity," Dr. Philip Poortmans reported on behalf of the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups during a presidential session at the European Cancer Congress 2013.

Patrice Wendling/IMNG Medical Media

With irradiation, "we might be able to stop metastasis at their source," he said.

Although metastatic lymph nodes in the axilla are usually treated by surgery and/or radiation therapy, the role of regional IM-MS radiotherapy has remained controversial and is not yet the standard of care, he acknowledged. The internal mammary chain is one of the known draining routes in breast cancer, but the benefits of irradiating such a large area are unclear, and concerns exist over increased late toxicity, particularly cardiac toxicity.

The internal lymph nodes are generally not treated in the United States. Even in the Netherlands, his center is the only one to routinely radiate the internal lymph nodes in high-risk patients, said Dr. Poortmans of the Institute Verbeeten in Tilburg, the Netherlands, and president-elect of the European Society for Radiotherapy and Oncology.

More modern radiation techniques and a trio of recent publications, however, are renewing the conversation. Overall survival and cancer-specific survival were increased with internal mammary node irradiation in a large series of 1,630 node-negative breast cancer patients with inner or centrally located tumors, he observed (Radiother. Oncol. 2013 [doi:10.1016/j.radonc.2013.06.028]).

Dr. Poortmans and EORTC trial 22922/10925 investigators at 46 institutions in 13 countries evenly randomized 4,004 women with stage I, II, and III breast cancer with involved axillary lymph nodes and/or a medially located primary tumor to IM-MS radiation (50 Gy in 25 fractions) or no IM-MS irradiation. Three-fourths of women (76.2%) had breast-conserving surgery, 55.6% had axillary lymph node involvement, and axillary radiation was given to 7.8% of women with IM-MS radiation and 6.8% without.

Radiation therapy was performed with the standard fields in 34%, adapted standard fields in 44%, and individualized in 22%, Dr. Poortmans said.

After a median follow-up of 10.9 years (maximum 15.9 years), 382 (9.5% of 4,004) women in the IM-MS arm had died vs. 429 women in the no IM-MS arm (10.7% of 4,004). The causes of death were similar in both groups, including cardiovascular disease (22 deaths vs. 20 deaths) and toxicity (one in each group), although breast cancer deaths were lower with IM-MS therapy (259 vs. 310), he said.

A multivariate analysis showed that the nodal stage did not significantly influence overall survival, although there was a trend favoring IM-MS irradiation with the use of adjuvant systemic therapy, Dr. Poortmans said. Nearly all lymph-node–positive patients (99%) and 66.3% of lymph-node–negative patients received adjuvant systemic therapy.

Commenting on the results, Dr. Roberto Orecchia, director of radiation therapy at the University of Milan, European Institute of Oncology, agreed that irradiation of the internal mammary chain is "quite controversial" and said there is greater consensus about its use in more locally advanced disease with positive nodes.

Part of the problem is inconsistent trial results, he said, pointing to a lack of 10-year overall survival benefit with internal mammary chain irradiation using two-dimensional techniques in one of the three studies highlighted by Dr. Poortmans (Int. J. Radiat. Oncol. Biol. Phys. 2013;86:860-6).

He said that technique may be a problem in the EORTC study, since it started in July 1996 and closed in January 2004 and radiation techniques have evolved, but observed that the lack of toxicity was reassuring.

"In the future, we probably have to consider [improving] our capability to select the patient, not only on the basis of the location of the tumor or the positivity/negativity of the axilla, but also to implement the use of more sophisticated imaging examinations like [positron emission tomography] or scintigraphy" to identify the patients who will benefit most from internal mammary chain irradiation, Dr. Orecchia said.

The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.

[email protected]

AMSTERDAM – Irradiating the internal mammary and medial supraclavicular lymph nodes provides a survival benefit in women with stage I-III breast cancer, independent of the number of lymph nodes involved, a randomized, phase III trial has shown.

At 10 years, internal mammary–medial supraclavicular (IM-MS) irradiation significantly increased overall survival by 1.6%, compared with no IM-MS irradiation (82.3% vs. 80.7%; hazard ratio, 0.87; P = .056), disease-free survival by 3% (72.1% vs. 69.1%; HR, 0.89; P = .044), and metastases-free survival by 3% (78% vs. 75%; HR, 0.86; P = .02).

Importantly, there was "no increased lethal toxicity," Dr. Philip Poortmans reported on behalf of the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups during a presidential session at the European Cancer Congress 2013.

Patrice Wendling/IMNG Medical Media

With irradiation, "we might be able to stop metastasis at their source," he said.

Although metastatic lymph nodes in the axilla are usually treated by surgery and/or radiation therapy, the role of regional IM-MS radiotherapy has remained controversial and is not yet the standard of care, he acknowledged. The internal mammary chain is one of the known draining routes in breast cancer, but the benefits of irradiating such a large area are unclear, and concerns exist over increased late toxicity, particularly cardiac toxicity.

The internal lymph nodes are generally not treated in the United States. Even in the Netherlands, his center is the only one to routinely radiate the internal lymph nodes in high-risk patients, said Dr. Poortmans of the Institute Verbeeten in Tilburg, the Netherlands, and president-elect of the European Society for Radiotherapy and Oncology.

More modern radiation techniques and a trio of recent publications, however, are renewing the conversation. Overall survival and cancer-specific survival were increased with internal mammary node irradiation in a large series of 1,630 node-negative breast cancer patients with inner or centrally located tumors, he observed (Radiother. Oncol. 2013 [doi:10.1016/j.radonc.2013.06.028]).

Dr. Poortmans and EORTC trial 22922/10925 investigators at 46 institutions in 13 countries evenly randomized 4,004 women with stage I, II, and III breast cancer with involved axillary lymph nodes and/or a medially located primary tumor to IM-MS radiation (50 Gy in 25 fractions) or no IM-MS irradiation. Three-fourths of women (76.2%) had breast-conserving surgery, 55.6% had axillary lymph node involvement, and axillary radiation was given to 7.8% of women with IM-MS radiation and 6.8% without.

Radiation therapy was performed with the standard fields in 34%, adapted standard fields in 44%, and individualized in 22%, Dr. Poortmans said.

After a median follow-up of 10.9 years (maximum 15.9 years), 382 (9.5% of 4,004) women in the IM-MS arm had died vs. 429 women in the no IM-MS arm (10.7% of 4,004). The causes of death were similar in both groups, including cardiovascular disease (22 deaths vs. 20 deaths) and toxicity (one in each group), although breast cancer deaths were lower with IM-MS therapy (259 vs. 310), he said.

A multivariate analysis showed that the nodal stage did not significantly influence overall survival, although there was a trend favoring IM-MS irradiation with the use of adjuvant systemic therapy, Dr. Poortmans said. Nearly all lymph-node–positive patients (99%) and 66.3% of lymph-node–negative patients received adjuvant systemic therapy.

Commenting on the results, Dr. Roberto Orecchia, director of radiation therapy at the University of Milan, European Institute of Oncology, agreed that irradiation of the internal mammary chain is "quite controversial" and said there is greater consensus about its use in more locally advanced disease with positive nodes.

Part of the problem is inconsistent trial results, he said, pointing to a lack of 10-year overall survival benefit with internal mammary chain irradiation using two-dimensional techniques in one of the three studies highlighted by Dr. Poortmans (Int. J. Radiat. Oncol. Biol. Phys. 2013;86:860-6).

He said that technique may be a problem in the EORTC study, since it started in July 1996 and closed in January 2004 and radiation techniques have evolved, but observed that the lack of toxicity was reassuring.

"In the future, we probably have to consider [improving] our capability to select the patient, not only on the basis of the location of the tumor or the positivity/negativity of the axilla, but also to implement the use of more sophisticated imaging examinations like [positron emission tomography] or scintigraphy" to identify the patients who will benefit most from internal mammary chain irradiation, Dr. Orecchia said.

The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.

[email protected]

AMSTERDAM – Irradiating the internal mammary and medial supraclavicular lymph nodes provides a survival benefit in women with stage I-III breast cancer, independent of the number of lymph nodes involved, a randomized, phase III trial has shown.

At 10 years, internal mammary–medial supraclavicular (IM-MS) irradiation significantly increased overall survival by 1.6%, compared with no IM-MS irradiation (82.3% vs. 80.7%; hazard ratio, 0.87; P = .056), disease-free survival by 3% (72.1% vs. 69.1%; HR, 0.89; P = .044), and metastases-free survival by 3% (78% vs. 75%; HR, 0.86; P = .02).

Importantly, there was "no increased lethal toxicity," Dr. Philip Poortmans reported on behalf of the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups during a presidential session at the European Cancer Congress 2013.

Patrice Wendling/IMNG Medical Media

With irradiation, "we might be able to stop metastasis at their source," he said.

Although metastatic lymph nodes in the axilla are usually treated by surgery and/or radiation therapy, the role of regional IM-MS radiotherapy has remained controversial and is not yet the standard of care, he acknowledged. The internal mammary chain is one of the known draining routes in breast cancer, but the benefits of irradiating such a large area are unclear, and concerns exist over increased late toxicity, particularly cardiac toxicity.

The internal lymph nodes are generally not treated in the United States. Even in the Netherlands, his center is the only one to routinely radiate the internal lymph nodes in high-risk patients, said Dr. Poortmans of the Institute Verbeeten in Tilburg, the Netherlands, and president-elect of the European Society for Radiotherapy and Oncology.

More modern radiation techniques and a trio of recent publications, however, are renewing the conversation. Overall survival and cancer-specific survival were increased with internal mammary node irradiation in a large series of 1,630 node-negative breast cancer patients with inner or centrally located tumors, he observed (Radiother. Oncol. 2013 [doi:10.1016/j.radonc.2013.06.028]).

Dr. Poortmans and EORTC trial 22922/10925 investigators at 46 institutions in 13 countries evenly randomized 4,004 women with stage I, II, and III breast cancer with involved axillary lymph nodes and/or a medially located primary tumor to IM-MS radiation (50 Gy in 25 fractions) or no IM-MS irradiation. Three-fourths of women (76.2%) had breast-conserving surgery, 55.6% had axillary lymph node involvement, and axillary radiation was given to 7.8% of women with IM-MS radiation and 6.8% without.

Radiation therapy was performed with the standard fields in 34%, adapted standard fields in 44%, and individualized in 22%, Dr. Poortmans said.

After a median follow-up of 10.9 years (maximum 15.9 years), 382 (9.5% of 4,004) women in the IM-MS arm had died vs. 429 women in the no IM-MS arm (10.7% of 4,004). The causes of death were similar in both groups, including cardiovascular disease (22 deaths vs. 20 deaths) and toxicity (one in each group), although breast cancer deaths were lower with IM-MS therapy (259 vs. 310), he said.

A multivariate analysis showed that the nodal stage did not significantly influence overall survival, although there was a trend favoring IM-MS irradiation with the use of adjuvant systemic therapy, Dr. Poortmans said. Nearly all lymph-node–positive patients (99%) and 66.3% of lymph-node–negative patients received adjuvant systemic therapy.

Commenting on the results, Dr. Roberto Orecchia, director of radiation therapy at the University of Milan, European Institute of Oncology, agreed that irradiation of the internal mammary chain is "quite controversial" and said there is greater consensus about its use in more locally advanced disease with positive nodes.

Part of the problem is inconsistent trial results, he said, pointing to a lack of 10-year overall survival benefit with internal mammary chain irradiation using two-dimensional techniques in one of the three studies highlighted by Dr. Poortmans (Int. J. Radiat. Oncol. Biol. Phys. 2013;86:860-6).

He said that technique may be a problem in the EORTC study, since it started in July 1996 and closed in January 2004 and radiation techniques have evolved, but observed that the lack of toxicity was reassuring.

"In the future, we probably have to consider [improving] our capability to select the patient, not only on the basis of the location of the tumor or the positivity/negativity of the axilla, but also to implement the use of more sophisticated imaging examinations like [positron emission tomography] or scintigraphy" to identify the patients who will benefit most from internal mammary chain irradiation, Dr. Orecchia said.

The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.

[email protected]

AMSTERDAM – Almost a quarter of patients with advanced and heavily pretreated lung cancer responded to treatment with the novel immunotherapy MPDL3280A in an ongoing phase I study.

The objective response rate was 23% in 53 patients with non–small cell lung cancer (NSCLC) evaluated for clinical activity, with 17% of patients achieving stable disease for 24 weeks or longer, and a progression-free survival rate of 45%. The best responses were seen in patients with the highest expression of the targeted protein, PD-L1; current or past smokers seemed to gain the greatest benefit from the novel immunotherapy.

Sara Freeman/IMNG Medical Media

MPDL3280A was well tolerated by the 85 patients with NSCLC who were evaluated for safety, which was the main aim of the early clinical study.

"Most adverse events seen in the trial were grade 1 or 2 and did not require intervention," Dr. Jean-Charles Soria said at the multidisciplinary European cancer congresses.

Dr. Soria, director of the Institut Gustave Roussy’s integrated cancer research center in Villejuif, France, noted that were no dose-limiting toxicities with doses of up to 20 mg/kg, and no cases of grade 3-5 pneumonitis. There was, however, a single, severe grade 3-4 adverse event in a patient with large-cell neuroendocrine NSCLC, and one death due to cardiac arrest in a patient with sinus thrombosis and a large tumor mass invading the heart at baseline.

Dr. Soria explained that MPDL3280A inhibits PD-L1 in such a way that it leaves some immune homeostatic functions intact, which could potentially prevent the development of autoimmunity.

The phase I trial he presented included patients with nonsquamous (76%) and squamous (24%) histology who were treated with an intravenous (10, 15, or 20 mg/kg) infusion of MPDL3280A every 3 weeks for up to 1 year. The patients’ median age was 60 years; 56% were male. Most (81%) were current or former smokers, and more than half (55%) of the patients had received three or more systemic regimens. Almost all (95%) patients had metastases involving the central nervous system, and 60% had EGFR wild-type.

Objective response rates (ORRs) were 21% and 27%, respectively, in patients with nonsquamous and squamous histology. Interestingly, the ORR increased with PD-L1 expression, which was determined using immunohistochemistry (IHC), suggesting this might be a potential biomarker for response. The ORR was 83% when 10% or more of the tumor cells were positive for PD-L1 (IHC 3), 46% when 5% or more of the tumor cells were PD-L1 positive (IHC 2 and 3), and 31% when 1% or more of tumor cells were PD-L1 positive (IHC 1/2/3). The respective rates of progressive disease by IHC status were 17%, 23%, and 38%.

Responses to the investigational drug were "outstandingly" durable, and all but one of the 12 patients who had responded to the drug continued to respond at the time of the data cutoff, Dr. Soria said. The longest duration of treatment response seen at this time point was 84 weeks, he added.

As it had been recently suggested that there might be a relationship between the mutational tumor load and the immunogenicity of the tumor (Clin. Cancer Res. 2012;18:6580-7), Dr. Soria and his associates decided to determine if there was any difference in the response to MPDL3280A according to patients’ smoking status. The results were striking: ORRs in smokers versus never-smokers were 26% and 10%, respectively.

"This is extremely important because most advances achieved over the past 10 years with molecularly targeted agents have benefited never-smokers," he said.

"It is very good to now have something for patients who were former smokers," said Dr. Paul Baas of the Netherlands Cancer Institute, Amsterdam. "It works in adenocarcinoma and squamous cell carcinomas, and I think the importance of this [study] is that [MPDL3280A] is already very active in phase I."

Roche is now pushing ahead with its clinical development program for MPDL3280A in a larger population of patients with NSCLC to see if the novel immunotherapeutic fulfills this early promise.

"Based on these data, we are moving quickly into late-stage clinical studies that will also include a Roche companion diagnostic to potentially identify those who are more likely to respond to treatment," Dr. Hal Barron, Roche’s chief medical officer and head of global product development, said in a statement.

Phase II studies of MPDL3280A in patients with NSCLC (NCT01846416 and NCT01903993) have already been initiated, and further studies are planned. The investigational drug is also being tested in combination with vemurafenib (Zelboraf) in the treatment of BRAFV600-mutation positive melanoma (NCT01656642), in combination with bevacizumab (Avastin) in patients with advanced solid tumors (NCT01633970), and as a single agent in patients with locally advanced or metastatic solid tumors or hematologic malignancies (NCT01375842).

Genentech, a member of the Roche Group, supported the study. Dr. Soria received research funding and advised the company. Dr. Baas received research grants from Pfizer and Roche and advised MSD and Verastem.

AMSTERDAM – Almost a quarter of patients with advanced and heavily pretreated lung cancer responded to treatment with the novel immunotherapy MPDL3280A in an ongoing phase I study.

The objective response rate was 23% in 53 patients with non–small cell lung cancer (NSCLC) evaluated for clinical activity, with 17% of patients achieving stable disease for 24 weeks or longer, and a progression-free survival rate of 45%. The best responses were seen in patients with the highest expression of the targeted protein, PD-L1; current or past smokers seemed to gain the greatest benefit from the novel immunotherapy.

Sara Freeman/IMNG Medical Media

MPDL3280A was well tolerated by the 85 patients with NSCLC who were evaluated for safety, which was the main aim of the early clinical study.

"Most adverse events seen in the trial were grade 1 or 2 and did not require intervention," Dr. Jean-Charles Soria said at the multidisciplinary European cancer congresses.

Dr. Soria, director of the Institut Gustave Roussy’s integrated cancer research center in Villejuif, France, noted that were no dose-limiting toxicities with doses of up to 20 mg/kg, and no cases of grade 3-5 pneumonitis. There was, however, a single, severe grade 3-4 adverse event in a patient with large-cell neuroendocrine NSCLC, and one death due to cardiac arrest in a patient with sinus thrombosis and a large tumor mass invading the heart at baseline.

Dr. Soria explained that MPDL3280A inhibits PD-L1 in such a way that it leaves some immune homeostatic functions intact, which could potentially prevent the development of autoimmunity.

The phase I trial he presented included patients with nonsquamous (76%) and squamous (24%) histology who were treated with an intravenous (10, 15, or 20 mg/kg) infusion of MPDL3280A every 3 weeks for up to 1 year. The patients’ median age was 60 years; 56% were male. Most (81%) were current or former smokers, and more than half (55%) of the patients had received three or more systemic regimens. Almost all (95%) patients had metastases involving the central nervous system, and 60% had EGFR wild-type.

Objective response rates (ORRs) were 21% and 27%, respectively, in patients with nonsquamous and squamous histology. Interestingly, the ORR increased with PD-L1 expression, which was determined using immunohistochemistry (IHC), suggesting this might be a potential biomarker for response. The ORR was 83% when 10% or more of the tumor cells were positive for PD-L1 (IHC 3), 46% when 5% or more of the tumor cells were PD-L1 positive (IHC 2 and 3), and 31% when 1% or more of tumor cells were PD-L1 positive (IHC 1/2/3). The respective rates of progressive disease by IHC status were 17%, 23%, and 38%.

Responses to the investigational drug were "outstandingly" durable, and all but one of the 12 patients who had responded to the drug continued to respond at the time of the data cutoff, Dr. Soria said. The longest duration of treatment response seen at this time point was 84 weeks, he added.

As it had been recently suggested that there might be a relationship between the mutational tumor load and the immunogenicity of the tumor (Clin. Cancer Res. 2012;18:6580-7), Dr. Soria and his associates decided to determine if there was any difference in the response to MPDL3280A according to patients’ smoking status. The results were striking: ORRs in smokers versus never-smokers were 26% and 10%, respectively.

"This is extremely important because most advances achieved over the past 10 years with molecularly targeted agents have benefited never-smokers," he said.

"It is very good to now have something for patients who were former smokers," said Dr. Paul Baas of the Netherlands Cancer Institute, Amsterdam. "It works in adenocarcinoma and squamous cell carcinomas, and I think the importance of this [study] is that [MPDL3280A] is already very active in phase I."

Roche is now pushing ahead with its clinical development program for MPDL3280A in a larger population of patients with NSCLC to see if the novel immunotherapeutic fulfills this early promise.

"Based on these data, we are moving quickly into late-stage clinical studies that will also include a Roche companion diagnostic to potentially identify those who are more likely to respond to treatment," Dr. Hal Barron, Roche’s chief medical officer and head of global product development, said in a statement.

Phase II studies of MPDL3280A in patients with NSCLC (NCT01846416 and NCT01903993) have already been initiated, and further studies are planned. The investigational drug is also being tested in combination with vemurafenib (Zelboraf) in the treatment of BRAFV600-mutation positive melanoma (NCT01656642), in combination with bevacizumab (Avastin) in patients with advanced solid tumors (NCT01633970), and as a single agent in patients with locally advanced or metastatic solid tumors or hematologic malignancies (NCT01375842).

Genentech, a member of the Roche Group, supported the study. Dr. Soria received research funding and advised the company. Dr. Baas received research grants from Pfizer and Roche and advised MSD and Verastem.

AMSTERDAM – Almost a quarter of patients with advanced and heavily pretreated lung cancer responded to treatment with the novel immunotherapy MPDL3280A in an ongoing phase I study.

The objective response rate was 23% in 53 patients with non–small cell lung cancer (NSCLC) evaluated for clinical activity, with 17% of patients achieving stable disease for 24 weeks or longer, and a progression-free survival rate of 45%. The best responses were seen in patients with the highest expression of the targeted protein, PD-L1; current or past smokers seemed to gain the greatest benefit from the novel immunotherapy.

Sara Freeman/IMNG Medical Media

MPDL3280A was well tolerated by the 85 patients with NSCLC who were evaluated for safety, which was the main aim of the early clinical study.

"Most adverse events seen in the trial were grade 1 or 2 and did not require intervention," Dr. Jean-Charles Soria said at the multidisciplinary European cancer congresses.

Dr. Soria, director of the Institut Gustave Roussy’s integrated cancer research center in Villejuif, France, noted that were no dose-limiting toxicities with doses of up to 20 mg/kg, and no cases of grade 3-5 pneumonitis. There was, however, a single, severe grade 3-4 adverse event in a patient with large-cell neuroendocrine NSCLC, and one death due to cardiac arrest in a patient with sinus thrombosis and a large tumor mass invading the heart at baseline.

Dr. Soria explained that MPDL3280A inhibits PD-L1 in such a way that it leaves some immune homeostatic functions intact, which could potentially prevent the development of autoimmunity.

The phase I trial he presented included patients with nonsquamous (76%) and squamous (24%) histology who were treated with an intravenous (10, 15, or 20 mg/kg) infusion of MPDL3280A every 3 weeks for up to 1 year. The patients’ median age was 60 years; 56% were male. Most (81%) were current or former smokers, and more than half (55%) of the patients had received three or more systemic regimens. Almost all (95%) patients had metastases involving the central nervous system, and 60% had EGFR wild-type.

Objective response rates (ORRs) were 21% and 27%, respectively, in patients with nonsquamous and squamous histology. Interestingly, the ORR increased with PD-L1 expression, which was determined using immunohistochemistry (IHC), suggesting this might be a potential biomarker for response. The ORR was 83% when 10% or more of the tumor cells were positive for PD-L1 (IHC 3), 46% when 5% or more of the tumor cells were PD-L1 positive (IHC 2 and 3), and 31% when 1% or more of tumor cells were PD-L1 positive (IHC 1/2/3). The respective rates of progressive disease by IHC status were 17%, 23%, and 38%.

Responses to the investigational drug were "outstandingly" durable, and all but one of the 12 patients who had responded to the drug continued to respond at the time of the data cutoff, Dr. Soria said. The longest duration of treatment response seen at this time point was 84 weeks, he added.

As it had been recently suggested that there might be a relationship between the mutational tumor load and the immunogenicity of the tumor (Clin. Cancer Res. 2012;18:6580-7), Dr. Soria and his associates decided to determine if there was any difference in the response to MPDL3280A according to patients’ smoking status. The results were striking: ORRs in smokers versus never-smokers were 26% and 10%, respectively.

"This is extremely important because most advances achieved over the past 10 years with molecularly targeted agents have benefited never-smokers," he said.

"It is very good to now have something for patients who were former smokers," said Dr. Paul Baas of the Netherlands Cancer Institute, Amsterdam. "It works in adenocarcinoma and squamous cell carcinomas, and I think the importance of this [study] is that [MPDL3280A] is already very active in phase I."

Roche is now pushing ahead with its clinical development program for MPDL3280A in a larger population of patients with NSCLC to see if the novel immunotherapeutic fulfills this early promise.

"Based on these data, we are moving quickly into late-stage clinical studies that will also include a Roche companion diagnostic to potentially identify those who are more likely to respond to treatment," Dr. Hal Barron, Roche’s chief medical officer and head of global product development, said in a statement.

Phase II studies of MPDL3280A in patients with NSCLC (NCT01846416 and NCT01903993) have already been initiated, and further studies are planned. The investigational drug is also being tested in combination with vemurafenib (Zelboraf) in the treatment of BRAFV600-mutation positive melanoma (NCT01656642), in combination with bevacizumab (Avastin) in patients with advanced solid tumors (NCT01633970), and as a single agent in patients with locally advanced or metastatic solid tumors or hematologic malignancies (NCT01375842).

Genentech, a member of the Roche Group, supported the study. Dr. Soria received research funding and advised the company. Dr. Baas received research grants from Pfizer and Roche and advised MSD and Verastem.

AMSTERDAM – Treatment with the somatostatin analogue lanreotide halves the risk for progression and death in patients with nonfunctioning neuroendocrine gastroenteropancreatic tumors, according to results from a phase III study.

Patients randomized to treatment with lanreotide (Somatuline Autogel) achieved a progression-free survival (PFS) of 66%, compared with 22% for placebo, within 96 weeks of the first injection (hazard ratio, 0.47; P = .0002), Dr. Kjell Öberg reported at the European Cancer Congress 2013. This outcome represents a 53% reduction in the risk for progression and death, he said.

Sara Freeman/IMNG Medical Media

"The previous restrictions on the use of somatostatin analogues in nonfunctioning tumors are no longer justified," said Dr. Öberg, professor of endocrine oncology at University Hospital Uppsala in Sweden.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are those that are not associated with any hormone-related symptoms. It was previously thought that somatostatin analogues were only of benefit to patients with NETs that did produce hormones and had no antiproliferative effects per se. However, this study "has clearly sorted that out," said Dr. Öberg, the invited discussant for the trial, at the multidisciplinary European cancer congresses. "I think that guidelines will be changed within the next year in many countries."

The new findings from CLARINET (Placebo-Controlled Study of Lanreotide Antiproliferative Response in Patients with GEP-NET) build on those of a smaller (n = 85) prospective trial, PROMID. The results of the PROMID study showed that another somatostatin analogue, octreotide (Sandostatin LAR), increased PFS in patients with metastatic midgut NETs – 66.7% vs. 37.2% for placebo – with a median PFS of 14.3 months vs. 6 months (HR, 0.34; P = .00007) (J. Clin. Oncol. 2009;27:4656-63). The most favorable effects seen in that trial were in patients with a low hepatic tumor load and where the primary tumor had been resected.

CLARINET was a much larger, multicenter, randomized, double blind, placebo-controlled trial involving 204 patients with nonfunctioning GEP-NETs. A total of 101 patients were randomized to lanreotide at an intramuscular dose of 120 mg every 28 days, and 102 patients were randomized to a matching placebo.

The mean age of recruited patients was 63 years in the lanreotide arm and 62 years in the placebo arm. Just over half the participants in each group were male. The majority of patients in the lanreotide and placebo groups had tumors involving the pancreas (42% and 48%, respectively) and midgut (33% and 39%), with the hindgut involved in 11% and 3% of cases in each group. Almost all (96%) of those recruited had stable disease (Ki67 less than 10%), and 81% were treatment naive. One-third had a hepatic tumor load of more than 25%.

"Median PFS was not reached with lanreotide; it was 18 months with placebo [P = .0002]," study investigator Dr. Philippe Ruszniewski of the Hôpital Beaujon in Clichy, France, reported.

The effect of active treatment as compared to placebo appeared very pronounced in patients with NETs involving the midgut (HR, 0.35; P = .009), although a significant benefit was seen in patients with pancreatic tumors (HR, 0.58; P = .064). There was also a significant benefit seen regardless of tumor grade (HR, 0.43; P = .0016 for G1; and HR, 0.45; P = .0235 for G2) and hepatic tumor load.

"Patients with a limited hepatic tumor load, below 25%, experienced a significant improvement in PFS [HR, 0.34; P = .0002]," Dr. Ruszniewski noted. Those with higher hepatic tumor loads, above 25%, also showed a significant PFS benefit (HR, 0.45; P = .017). Median PFS was not reached in either subgroup treated with lanreotide, while it was 9 months in the limited tumor load and 24 months in the higher tumor load groups that received placebo.

Sara Freeman/IMNG Medical Media

There was no difference in overall survival, however, with 19 deaths reported in the lanreotide arm and 17 deaths in the placebo arm (P = .879).

"Safety and tolerability were expected," Dr. Ruszniewski observed. There were 89 and 93 treatment-emergent adverse effects in the lanreotide and placebo groups, respectively. Of these, 50% and 28% were related to the interventions. Three percent of each group withdrew due to treatment-emergent adverse events.

The most common (10% of patients) side effects seen in the lanreotide and placebo arms were diarrhea (26% vs. 9%, respectively), abdominal pain (14% vs. 2%), and cholelithiasis (10% vs. 3%).

The proportion of patients achieving a 50% or greater reduction in chromogranin A levels from baseline – an indicator of an antiproliferative effect – was significantly higher in the lanreotide arm than in the placebo arm (odds ratio, 15.2; P less than .0001).

"The antiproliferative effect of lanreotide may support its place in the treatment algorithm for enteropancreatic NETs," Dr. Ruszniewski said.

In an interview, Dr. Öberg further commented that the CLARINET data show that "somatostatin analogues can be used for patients with all different subtypes of NET with a very low rate of side effects." If more aggressive therapy is needed, he added, then targeted treatment with drugs such as everolimus or chemotherapy may be needed. "The guidelines will change," he reiterated.

The study was sponsored by Ipsen. Dr. Ruszniewski has served as an adviser to Ipsen and received research funding from the company and from Novartis. Dr. Öberg has served as an adviser and speaker for Novartis, Ipsen, and Pfizer.

AMSTERDAM – Treatment with the somatostatin analogue lanreotide halves the risk for progression and death in patients with nonfunctioning neuroendocrine gastroenteropancreatic tumors, according to results from a phase III study.

Patients randomized to treatment with lanreotide (Somatuline Autogel) achieved a progression-free survival (PFS) of 66%, compared with 22% for placebo, within 96 weeks of the first injection (hazard ratio, 0.47; P = .0002), Dr. Kjell Öberg reported at the European Cancer Congress 2013. This outcome represents a 53% reduction in the risk for progression and death, he said.

Sara Freeman/IMNG Medical Media

"The previous restrictions on the use of somatostatin analogues in nonfunctioning tumors are no longer justified," said Dr. Öberg, professor of endocrine oncology at University Hospital Uppsala in Sweden.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are those that are not associated with any hormone-related symptoms. It was previously thought that somatostatin analogues were only of benefit to patients with NETs that did produce hormones and had no antiproliferative effects per se. However, this study "has clearly sorted that out," said Dr. Öberg, the invited discussant for the trial, at the multidisciplinary European cancer congresses. "I think that guidelines will be changed within the next year in many countries."

The new findings from CLARINET (Placebo-Controlled Study of Lanreotide Antiproliferative Response in Patients with GEP-NET) build on those of a smaller (n = 85) prospective trial, PROMID. The results of the PROMID study showed that another somatostatin analogue, octreotide (Sandostatin LAR), increased PFS in patients with metastatic midgut NETs – 66.7% vs. 37.2% for placebo – with a median PFS of 14.3 months vs. 6 months (HR, 0.34; P = .00007) (J. Clin. Oncol. 2009;27:4656-63). The most favorable effects seen in that trial were in patients with a low hepatic tumor load and where the primary tumor had been resected.

CLARINET was a much larger, multicenter, randomized, double blind, placebo-controlled trial involving 204 patients with nonfunctioning GEP-NETs. A total of 101 patients were randomized to lanreotide at an intramuscular dose of 120 mg every 28 days, and 102 patients were randomized to a matching placebo.

The mean age of recruited patients was 63 years in the lanreotide arm and 62 years in the placebo arm. Just over half the participants in each group were male. The majority of patients in the lanreotide and placebo groups had tumors involving the pancreas (42% and 48%, respectively) and midgut (33% and 39%), with the hindgut involved in 11% and 3% of cases in each group. Almost all (96%) of those recruited had stable disease (Ki67 less than 10%), and 81% were treatment naive. One-third had a hepatic tumor load of more than 25%.

"Median PFS was not reached with lanreotide; it was 18 months with placebo [P = .0002]," study investigator Dr. Philippe Ruszniewski of the Hôpital Beaujon in Clichy, France, reported.

The effect of active treatment as compared to placebo appeared very pronounced in patients with NETs involving the midgut (HR, 0.35; P = .009), although a significant benefit was seen in patients with pancreatic tumors (HR, 0.58; P = .064). There was also a significant benefit seen regardless of tumor grade (HR, 0.43; P = .0016 for G1; and HR, 0.45; P = .0235 for G2) and hepatic tumor load.

"Patients with a limited hepatic tumor load, below 25%, experienced a significant improvement in PFS [HR, 0.34; P = .0002]," Dr. Ruszniewski noted. Those with higher hepatic tumor loads, above 25%, also showed a significant PFS benefit (HR, 0.45; P = .017). Median PFS was not reached in either subgroup treated with lanreotide, while it was 9 months in the limited tumor load and 24 months in the higher tumor load groups that received placebo.

Sara Freeman/IMNG Medical Media

There was no difference in overall survival, however, with 19 deaths reported in the lanreotide arm and 17 deaths in the placebo arm (P = .879).

"Safety and tolerability were expected," Dr. Ruszniewski observed. There were 89 and 93 treatment-emergent adverse effects in the lanreotide and placebo groups, respectively. Of these, 50% and 28% were related to the interventions. Three percent of each group withdrew due to treatment-emergent adverse events.

The most common (10% of patients) side effects seen in the lanreotide and placebo arms were diarrhea (26% vs. 9%, respectively), abdominal pain (14% vs. 2%), and cholelithiasis (10% vs. 3%).

The proportion of patients achieving a 50% or greater reduction in chromogranin A levels from baseline – an indicator of an antiproliferative effect – was significantly higher in the lanreotide arm than in the placebo arm (odds ratio, 15.2; P less than .0001).

"The antiproliferative effect of lanreotide may support its place in the treatment algorithm for enteropancreatic NETs," Dr. Ruszniewski said.

In an interview, Dr. Öberg further commented that the CLARINET data show that "somatostatin analogues can be used for patients with all different subtypes of NET with a very low rate of side effects." If more aggressive therapy is needed, he added, then targeted treatment with drugs such as everolimus or chemotherapy may be needed. "The guidelines will change," he reiterated.

The study was sponsored by Ipsen. Dr. Ruszniewski has served as an adviser to Ipsen and received research funding from the company and from Novartis. Dr. Öberg has served as an adviser and speaker for Novartis, Ipsen, and Pfizer.

AMSTERDAM – Treatment with the somatostatin analogue lanreotide halves the risk for progression and death in patients with nonfunctioning neuroendocrine gastroenteropancreatic tumors, according to results from a phase III study.

Patients randomized to treatment with lanreotide (Somatuline Autogel) achieved a progression-free survival (PFS) of 66%, compared with 22% for placebo, within 96 weeks of the first injection (hazard ratio, 0.47; P = .0002), Dr. Kjell Öberg reported at the European Cancer Congress 2013. This outcome represents a 53% reduction in the risk for progression and death, he said.

Sara Freeman/IMNG Medical Media

"The previous restrictions on the use of somatostatin analogues in nonfunctioning tumors are no longer justified," said Dr. Öberg, professor of endocrine oncology at University Hospital Uppsala in Sweden.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are those that are not associated with any hormone-related symptoms. It was previously thought that somatostatin analogues were only of benefit to patients with NETs that did produce hormones and had no antiproliferative effects per se. However, this study "has clearly sorted that out," said Dr. Öberg, the invited discussant for the trial, at the multidisciplinary European cancer congresses. "I think that guidelines will be changed within the next year in many countries."

The new findings from CLARINET (Placebo-Controlled Study of Lanreotide Antiproliferative Response in Patients with GEP-NET) build on those of a smaller (n = 85) prospective trial, PROMID. The results of the PROMID study showed that another somatostatin analogue, octreotide (Sandostatin LAR), increased PFS in patients with metastatic midgut NETs – 66.7% vs. 37.2% for placebo – with a median PFS of 14.3 months vs. 6 months (HR, 0.34; P = .00007) (J. Clin. Oncol. 2009;27:4656-63). The most favorable effects seen in that trial were in patients with a low hepatic tumor load and where the primary tumor had been resected.

CLARINET was a much larger, multicenter, randomized, double blind, placebo-controlled trial involving 204 patients with nonfunctioning GEP-NETs. A total of 101 patients were randomized to lanreotide at an intramuscular dose of 120 mg every 28 days, and 102 patients were randomized to a matching placebo.

The mean age of recruited patients was 63 years in the lanreotide arm and 62 years in the placebo arm. Just over half the participants in each group were male. The majority of patients in the lanreotide and placebo groups had tumors involving the pancreas (42% and 48%, respectively) and midgut (33% and 39%), with the hindgut involved in 11% and 3% of cases in each group. Almost all (96%) of those recruited had stable disease (Ki67 less than 10%), and 81% were treatment naive. One-third had a hepatic tumor load of more than 25%.

"Median PFS was not reached with lanreotide; it was 18 months with placebo [P = .0002]," study investigator Dr. Philippe Ruszniewski of the Hôpital Beaujon in Clichy, France, reported.

The effect of active treatment as compared to placebo appeared very pronounced in patients with NETs involving the midgut (HR, 0.35; P = .009), although a significant benefit was seen in patients with pancreatic tumors (HR, 0.58; P = .064). There was also a significant benefit seen regardless of tumor grade (HR, 0.43; P = .0016 for G1; and HR, 0.45; P = .0235 for G2) and hepatic tumor load.

"Patients with a limited hepatic tumor load, below 25%, experienced a significant improvement in PFS [HR, 0.34; P = .0002]," Dr. Ruszniewski noted. Those with higher hepatic tumor loads, above 25%, also showed a significant PFS benefit (HR, 0.45; P = .017). Median PFS was not reached in either subgroup treated with lanreotide, while it was 9 months in the limited tumor load and 24 months in the higher tumor load groups that received placebo.

Sara Freeman/IMNG Medical Media

There was no difference in overall survival, however, with 19 deaths reported in the lanreotide arm and 17 deaths in the placebo arm (P = .879).

"Safety and tolerability were expected," Dr. Ruszniewski observed. There were 89 and 93 treatment-emergent adverse effects in the lanreotide and placebo groups, respectively. Of these, 50% and 28% were related to the interventions. Three percent of each group withdrew due to treatment-emergent adverse events.

The most common (10% of patients) side effects seen in the lanreotide and placebo arms were diarrhea (26% vs. 9%, respectively), abdominal pain (14% vs. 2%), and cholelithiasis (10% vs. 3%).

The proportion of patients achieving a 50% or greater reduction in chromogranin A levels from baseline – an indicator of an antiproliferative effect – was significantly higher in the lanreotide arm than in the placebo arm (odds ratio, 15.2; P less than .0001).

"The antiproliferative effect of lanreotide may support its place in the treatment algorithm for enteropancreatic NETs," Dr. Ruszniewski said.

In an interview, Dr. Öberg further commented that the CLARINET data show that "somatostatin analogues can be used for patients with all different subtypes of NET with a very low rate of side effects." If more aggressive therapy is needed, he added, then targeted treatment with drugs such as everolimus or chemotherapy may be needed. "The guidelines will change," he reiterated.

The study was sponsored by Ipsen. Dr. Ruszniewski has served as an adviser to Ipsen and received research funding from the company and from Novartis. Dr. Öberg has served as an adviser and speaker for Novartis, Ipsen, and Pfizer.

AMSTERDAM – The investigational second-generation ALK inhibitor alectinib produced objective responses in 54.5% of patients with ALK-positive non–small cell lung cancer refractory to crizotinib in a phase I dose-finding study.

Alectinib had consistent clinical activity in patients with symptomatic brain metastases, including two cases of leptomeningeal carcinomatosis. One of those patients, a 29-year-old woman with a 7-year history of anaplastic lymphoma kinase (ALK)–positive lung cancer, cleared malignant brain cells within 4 weeks after starting oral alectinib, Dr. Sai-Hong Ou said at the multidisciplinary European cancer congresses.

Patrice Wendling/IMNG Medical Media

Alectinib, which is being developed by study sponsor Roche/Chugai Pharmaceutical, has already demonstrated an objective response rate of 93.5% in crizotinib (Xalkori)-naive ALK-positive non–small cell lung cancer. Among those patients, a previously untreated 2.5-cm brain lesion decreased in size by 47% in about 3 weeks and the patient continues to have a confirmed response to alectinib, he said.

Based on the new data, alectinib was granted a breakthrough therapy designation by the Food and Drug Administration to expedite its development and review.

Crizotinib is the only approved ALK-inhibitor for use in ALK-rearranged non–small cell lung cancer; it is available for use in any line therapy in the United States and as second-line therapy only in Europe.

A total of 47 patients were enrolled in the phase I study and treated with twice-daily alectinib at doses ranging from 300 mg to 900 mg. All patients had adenocarcinoma histology, an ECOG performance status of 0-2, and no prior exposure to other ALK inhibitors.

Two dose-limiting toxicities occurred at the 900-mg dose – a grade 3 headache and grade 3 neutropenia requiring dose interruption for 7 days. No patient had to be dose reduced at 600 mg twice daily, which was identified as the recommended phase II dose.

Overall, there were very few grade 3/4 treatment-emergent adverse events, said Dr. Ou of the Chao Family Comprehensive Cancer Center at the University of California Irvine Medical Center, Orange. Most were increased gamma-glutamyl transpeptidase, neutrophil decrease, and hypophosphatemia.

The most common toxicities were fatigue (30%), myalgia and peripheral edema (17%), elevated creatine phosphokinase (15%), and photosensitivity (13%).

Among the 21 patients with brain metastases at baseline, 13 had partial responses to alectinib at varying doses, 6 had stable disease, 1 had progressive disease, and 1 had a pending evaluation.

Dr. Ou said that a new 150-mg capsule has been formulated to reduce the number of capsules needed each day and that a phase II study (Accalia G2L) of alectinib is underway in crizotinib-resistant ALK-positive non–small cell lung cancer. A phase III head-to-head comparison between alectinib and crizotinib is also planned, with the protocol to be completed by January 2014, he said.

Roche/Chugai Pharmaceuticals sponsored the trial. Dr. Ou reported consulting for Chugai, Genentech, and Pfizer and serving on speakers bureaus for Boehringer Ingelheim, Genentech, and Pfizer.

[email protected]

AMSTERDAM – The investigational second-generation ALK inhibitor alectinib produced objective responses in 54.5% of patients with ALK-positive non–small cell lung cancer refractory to crizotinib in a phase I dose-finding study.

Alectinib had consistent clinical activity in patients with symptomatic brain metastases, including two cases of leptomeningeal carcinomatosis. One of those patients, a 29-year-old woman with a 7-year history of anaplastic lymphoma kinase (ALK)–positive lung cancer, cleared malignant brain cells within 4 weeks after starting oral alectinib, Dr. Sai-Hong Ou said at the multidisciplinary European cancer congresses.

Patrice Wendling/IMNG Medical Media

Alectinib, which is being developed by study sponsor Roche/Chugai Pharmaceutical, has already demonstrated an objective response rate of 93.5% in crizotinib (Xalkori)-naive ALK-positive non–small cell lung cancer. Among those patients, a previously untreated 2.5-cm brain lesion decreased in size by 47% in about 3 weeks and the patient continues to have a confirmed response to alectinib, he said.

Based on the new data, alectinib was granted a breakthrough therapy designation by the Food and Drug Administration to expedite its development and review.

Crizotinib is the only approved ALK-inhibitor for use in ALK-rearranged non–small cell lung cancer; it is available for use in any line therapy in the United States and as second-line therapy only in Europe.

A total of 47 patients were enrolled in the phase I study and treated with twice-daily alectinib at doses ranging from 300 mg to 900 mg. All patients had adenocarcinoma histology, an ECOG performance status of 0-2, and no prior exposure to other ALK inhibitors.

Two dose-limiting toxicities occurred at the 900-mg dose – a grade 3 headache and grade 3 neutropenia requiring dose interruption for 7 days. No patient had to be dose reduced at 600 mg twice daily, which was identified as the recommended phase II dose.

Overall, there were very few grade 3/4 treatment-emergent adverse events, said Dr. Ou of the Chao Family Comprehensive Cancer Center at the University of California Irvine Medical Center, Orange. Most were increased gamma-glutamyl transpeptidase, neutrophil decrease, and hypophosphatemia.

The most common toxicities were fatigue (30%), myalgia and peripheral edema (17%), elevated creatine phosphokinase (15%), and photosensitivity (13%).

Among the 21 patients with brain metastases at baseline, 13 had partial responses to alectinib at varying doses, 6 had stable disease, 1 had progressive disease, and 1 had a pending evaluation.

Dr. Ou said that a new 150-mg capsule has been formulated to reduce the number of capsules needed each day and that a phase II study (Accalia G2L) of alectinib is underway in crizotinib-resistant ALK-positive non–small cell lung cancer. A phase III head-to-head comparison between alectinib and crizotinib is also planned, with the protocol to be completed by January 2014, he said.

Roche/Chugai Pharmaceuticals sponsored the trial. Dr. Ou reported consulting for Chugai, Genentech, and Pfizer and serving on speakers bureaus for Boehringer Ingelheim, Genentech, and Pfizer.

[email protected]

AMSTERDAM – The investigational second-generation ALK inhibitor alectinib produced objective responses in 54.5% of patients with ALK-positive non–small cell lung cancer refractory to crizotinib in a phase I dose-finding study.

Alectinib had consistent clinical activity in patients with symptomatic brain metastases, including two cases of leptomeningeal carcinomatosis. One of those patients, a 29-year-old woman with a 7-year history of anaplastic lymphoma kinase (ALK)–positive lung cancer, cleared malignant brain cells within 4 weeks after starting oral alectinib, Dr. Sai-Hong Ou said at the multidisciplinary European cancer congresses.

Patrice Wendling/IMNG Medical Media

Alectinib, which is being developed by study sponsor Roche/Chugai Pharmaceutical, has already demonstrated an objective response rate of 93.5% in crizotinib (Xalkori)-naive ALK-positive non–small cell lung cancer. Among those patients, a previously untreated 2.5-cm brain lesion decreased in size by 47% in about 3 weeks and the patient continues to have a confirmed response to alectinib, he said.

Based on the new data, alectinib was granted a breakthrough therapy designation by the Food and Drug Administration to expedite its development and review.

Crizotinib is the only approved ALK-inhibitor for use in ALK-rearranged non–small cell lung cancer; it is available for use in any line therapy in the United States and as second-line therapy only in Europe.

A total of 47 patients were enrolled in the phase I study and treated with twice-daily alectinib at doses ranging from 300 mg to 900 mg. All patients had adenocarcinoma histology, an ECOG performance status of 0-2, and no prior exposure to other ALK inhibitors.

Two dose-limiting toxicities occurred at the 900-mg dose – a grade 3 headache and grade 3 neutropenia requiring dose interruption for 7 days. No patient had to be dose reduced at 600 mg twice daily, which was identified as the recommended phase II dose.

Overall, there were very few grade 3/4 treatment-emergent adverse events, said Dr. Ou of the Chao Family Comprehensive Cancer Center at the University of California Irvine Medical Center, Orange. Most were increased gamma-glutamyl transpeptidase, neutrophil decrease, and hypophosphatemia.

The most common toxicities were fatigue (30%), myalgia and peripheral edema (17%), elevated creatine phosphokinase (15%), and photosensitivity (13%).

Among the 21 patients with brain metastases at baseline, 13 had partial responses to alectinib at varying doses, 6 had stable disease, 1 had progressive disease, and 1 had a pending evaluation.

Dr. Ou said that a new 150-mg capsule has been formulated to reduce the number of capsules needed each day and that a phase II study (Accalia G2L) of alectinib is underway in crizotinib-resistant ALK-positive non–small cell lung cancer. A phase III head-to-head comparison between alectinib and crizotinib is also planned, with the protocol to be completed by January 2014, he said.

Roche/Chugai Pharmaceuticals sponsored the trial. Dr. Ou reported consulting for Chugai, Genentech, and Pfizer and serving on speakers bureaus for Boehringer Ingelheim, Genentech, and Pfizer.

[email protected]

AMSTERDAM – Another investigational lung cancer vaccine did not improve overall survival, although its use might still benefit some patients, according to results of a phase III study presented at the multidisciplinary European cancer congresses.

The therapeutic tumor cell cancer vaccine belagenpumatucel-L (Lucanix) was no better than placebo at improving the primary endpoint of overall survival after frontline, platinum-based chemotherapy in the STOP study. A total of 532 patients with stable stage III or IV non–small cell lung cancer (NSCLC) participated in the study.

Sara Freeman/IMNG Medical Media

Median overall survival was 20.3 months in the vaccinated patients and 17.8 months in those who had received placebo over a 2-year period (hazard ratio, 0.54; P = .0595).

There was an indication that overall survival might be improved, however, if patients were given the vaccine within 12 weeks of stopping their frontline chemotherapy. Indeed, overall survival was 20.7 months in 169 patients who were vaccinated within 12 weeks of stopping chemotherapy versus 13.3 months in 149 patients who did not receive the vaccine until after that time (HR, 0.77; P = .0092).

"Prospective subset data support further development of belagenpumatucel-L in NSCLC," said Dr. Giuseppe Giaccone, the presenting investigator and associate director of clinical research at the Lombardi Comprehensive Cancer Center at Georgetown University, Washington.

Dr. Giaccone said that the trial was not appropriately powered to meet its primary endpoint. The trial design presumed that the placebo-treated patients would achieve a median survival of around 10.5 months, which was the norm at the time the trial was conceived.

The somewhat disappointing findings in the STOP trial follow those of the phase III START trial, which found no overall survival benefit with a different investigational lung cancer vaccine, tecemotide (Stimuvax). Development of tecemotide also continues, however, as there was an indication that the vaccine might work if given concurrently with chemoradiation rather than after it. The START2 trial will be investigating that hypothesis.

The STOP trial was a randomized, double blind, placebo-controlled investigation performed in eight countries that ran for 46 months and involved patients with late-stage NSCLC; 490 patients had stage IIIB/IV cancer and 42 had stage IIIA cancers. Patients could be enrolled in the trial if they had stable disease after up to six cycles of platinum-based chemotherapy. The aim of the study was to determine if vaccination with belagenpumatucel-L could prevent progression after successful first-line chemotherapy.

Belagenpumatucel-L consists of four allogeneic NSCLC cell lines that have been modified to express an antisense DNA molecule that binds to the gene responsible for producing transforming growth factor beta (TGF-beta), thus blocking production of the protein. TGF-beta has immunosuppressive properties and helps tumor cells evade immune defenses. During the study, the vaccine was given as 18-month intradermal injections followed by a further two injections given 3 months apart. Each dose contained 2.5 × 10⁷ cells.

"Overall, the response rate to the vaccination was low, at 2.6%," Dr. Giaccone reported. There were only one (0.4%) complete and six (2.2%) partial responses. "Progression-free survival did not correlate with overall survival, and there was a trend in some of the subgroups toward an improved PFS, but this was not statistically significant."

The most common side effects were injection-site reactions (grade 1-2), occurring in 260 of the vaccinated and 62 of the placebo-treated patients. Unexpected effects included abdominal pain, constipation, decreased appetite, nasopharyngitis, and noncardiac chest pain, all affecting more patients who received belagenpumatucel-L than those who received placebo. Five serious adverse events occurred, three of which were in patients treated with the vaccine, and only one of these, an allergic reaction, was probably due to the vaccine itself.

NovaRx sponsored the study. Dr. Giaccone said he had no conflicts of interest but noted his coinvestigators included employees of NovaRx.

AMSTERDAM – Another investigational lung cancer vaccine did not improve overall survival, although its use might still benefit some patients, according to results of a phase III study presented at the multidisciplinary European cancer congresses.

The therapeutic tumor cell cancer vaccine belagenpumatucel-L (Lucanix) was no better than placebo at improving the primary endpoint of overall survival after frontline, platinum-based chemotherapy in the STOP study. A total of 532 patients with stable stage III or IV non–small cell lung cancer (NSCLC) participated in the study.

Sara Freeman/IMNG Medical Media

Median overall survival was 20.3 months in the vaccinated patients and 17.8 months in those who had received placebo over a 2-year period (hazard ratio, 0.54; P = .0595).

There was an indication that overall survival might be improved, however, if patients were given the vaccine within 12 weeks of stopping their frontline chemotherapy. Indeed, overall survival was 20.7 months in 169 patients who were vaccinated within 12 weeks of stopping chemotherapy versus 13.3 months in 149 patients who did not receive the vaccine until after that time (HR, 0.77; P = .0092).

"Prospective subset data support further development of belagenpumatucel-L in NSCLC," said Dr. Giuseppe Giaccone, the presenting investigator and associate director of clinical research at the Lombardi Comprehensive Cancer Center at Georgetown University, Washington.

Dr. Giaccone said that the trial was not appropriately powered to meet its primary endpoint. The trial design presumed that the placebo-treated patients would achieve a median survival of around 10.5 months, which was the norm at the time the trial was conceived.

The somewhat disappointing findings in the STOP trial follow those of the phase III START trial, which found no overall survival benefit with a different investigational lung cancer vaccine, tecemotide (Stimuvax). Development of tecemotide also continues, however, as there was an indication that the vaccine might work if given concurrently with chemoradiation rather than after it. The START2 trial will be investigating that hypothesis.

The STOP trial was a randomized, double blind, placebo-controlled investigation performed in eight countries that ran for 46 months and involved patients with late-stage NSCLC; 490 patients had stage IIIB/IV cancer and 42 had stage IIIA cancers. Patients could be enrolled in the trial if they had stable disease after up to six cycles of platinum-based chemotherapy. The aim of the study was to determine if vaccination with belagenpumatucel-L could prevent progression after successful first-line chemotherapy.

Belagenpumatucel-L consists of four allogeneic NSCLC cell lines that have been modified to express an antisense DNA molecule that binds to the gene responsible for producing transforming growth factor beta (TGF-beta), thus blocking production of the protein. TGF-beta has immunosuppressive properties and helps tumor cells evade immune defenses. During the study, the vaccine was given as 18-month intradermal injections followed by a further two injections given 3 months apart. Each dose contained 2.5 × 10⁷ cells.

"Overall, the response rate to the vaccination was low, at 2.6%," Dr. Giaccone reported. There were only one (0.4%) complete and six (2.2%) partial responses. "Progression-free survival did not correlate with overall survival, and there was a trend in some of the subgroups toward an improved PFS, but this was not statistically significant."

The most common side effects were injection-site reactions (grade 1-2), occurring in 260 of the vaccinated and 62 of the placebo-treated patients. Unexpected effects included abdominal pain, constipation, decreased appetite, nasopharyngitis, and noncardiac chest pain, all affecting more patients who received belagenpumatucel-L than those who received placebo. Five serious adverse events occurred, three of which were in patients treated with the vaccine, and only one of these, an allergic reaction, was probably due to the vaccine itself.

NovaRx sponsored the study. Dr. Giaccone said he had no conflicts of interest but noted his coinvestigators included employees of NovaRx.

AMSTERDAM – Another investigational lung cancer vaccine did not improve overall survival, although its use might still benefit some patients, according to results of a phase III study presented at the multidisciplinary European cancer congresses.

The therapeutic tumor cell cancer vaccine belagenpumatucel-L (Lucanix) was no better than placebo at improving the primary endpoint of overall survival after frontline, platinum-based chemotherapy in the STOP study. A total of 532 patients with stable stage III or IV non–small cell lung cancer (NSCLC) participated in the study.

Sara Freeman/IMNG Medical Media

Median overall survival was 20.3 months in the vaccinated patients and 17.8 months in those who had received placebo over a 2-year period (hazard ratio, 0.54; P = .0595).

There was an indication that overall survival might be improved, however, if patients were given the vaccine within 12 weeks of stopping their frontline chemotherapy. Indeed, overall survival was 20.7 months in 169 patients who were vaccinated within 12 weeks of stopping chemotherapy versus 13.3 months in 149 patients who did not receive the vaccine until after that time (HR, 0.77; P = .0092).

"Prospective subset data support further development of belagenpumatucel-L in NSCLC," said Dr. Giuseppe Giaccone, the presenting investigator and associate director of clinical research at the Lombardi Comprehensive Cancer Center at Georgetown University, Washington.

Dr. Giaccone said that the trial was not appropriately powered to meet its primary endpoint. The trial design presumed that the placebo-treated patients would achieve a median survival of around 10.5 months, which was the norm at the time the trial was conceived.

The somewhat disappointing findings in the STOP trial follow those of the phase III START trial, which found no overall survival benefit with a different investigational lung cancer vaccine, tecemotide (Stimuvax). Development of tecemotide also continues, however, as there was an indication that the vaccine might work if given concurrently with chemoradiation rather than after it. The START2 trial will be investigating that hypothesis.

The STOP trial was a randomized, double blind, placebo-controlled investigation performed in eight countries that ran for 46 months and involved patients with late-stage NSCLC; 490 patients had stage IIIB/IV cancer and 42 had stage IIIA cancers. Patients could be enrolled in the trial if they had stable disease after up to six cycles of platinum-based chemotherapy. The aim of the study was to determine if vaccination with belagenpumatucel-L could prevent progression after successful first-line chemotherapy.

Belagenpumatucel-L consists of four allogeneic NSCLC cell lines that have been modified to express an antisense DNA molecule that binds to the gene responsible for producing transforming growth factor beta (TGF-beta), thus blocking production of the protein. TGF-beta has immunosuppressive properties and helps tumor cells evade immune defenses. During the study, the vaccine was given as 18-month intradermal injections followed by a further two injections given 3 months apart. Each dose contained 2.5 × 10⁷ cells.

"Overall, the response rate to the vaccination was low, at 2.6%," Dr. Giaccone reported. There were only one (0.4%) complete and six (2.2%) partial responses. "Progression-free survival did not correlate with overall survival, and there was a trend in some of the subgroups toward an improved PFS, but this was not statistically significant."

The most common side effects were injection-site reactions (grade 1-2), occurring in 260 of the vaccinated and 62 of the placebo-treated patients. Unexpected effects included abdominal pain, constipation, decreased appetite, nasopharyngitis, and noncardiac chest pain, all affecting more patients who received belagenpumatucel-L than those who received placebo. Five serious adverse events occurred, three of which were in patients treated with the vaccine, and only one of these, an allergic reaction, was probably due to the vaccine itself.

NovaRx sponsored the study. Dr. Giaccone said he had no conflicts of interest but noted his coinvestigators included employees of NovaRx.