2014 ASCO Annual Meeting

CHICAGO – Adding the kinase inhibitor ruxolitinib to capecitabine improved overall survival of a subset of patients with metastatic pancreatic cancer, compared with capecitabine and placebo.

In a randomized phase II trial in 127 patients with metastatic pancreatic ductal adenocarcinoma, the second-line therapy combination of ruxolitinib (Jakafi) and capecitabine (Xeloda) was not associated with better outcomes than capecitabine and placebo in the overall population.

But among 60 patients with high levels of C-reactive protein indicative of systemic inflammation, adding ruxolitinib improved median overall survival to 83 days, compared with 55 days for controls, reported Dr. Herbert I. Hurwitz, professor of medicine in the division of oncology at Duke University, Durham, N.C.

"These data support the role of inflammation and the JAK-STAT pathway in particular for patients with pancreatic cancer," Dr. Hurwitz said at the annual meeting of the American Society of Clinical Oncology.

Ruxolitinib is an inhibitor of the Janus kinases (JAK) 1 and 2, which have been shown to mediate cytokine signaling through activation of STAT transcription factors. In preclinical models, pro-inflammatory cytokine signaling has been shown to contribute to pancreatic cancer initiation and progression.

Systemic inflammation is also associated with weight loss, decreased muscle mass, and poor performance status, all of which can shorten survival in patients with advanced pancreatic cancer.

The investigators hypothesized that ruxolitinib could improve survival of advanced pancreatic cancer patients when added to standard chemotherapy by dampening inflammation and thereby reducing cachexia and its related effects on patients’ overall health.

In tumor xenograft models of pancreatic cancer, the combination of ruxolitinib and capecitabine showed antitumor activity, prompting investigators to evaluate the drugs in human clinical trials.

Recap of RECAP

The phase II RECAP study (A Randomized Phase II Study of Ruxolitinib Efficacy and Safety in Combination With Capecitabine for Subjects With Recurrent or Treatment Refractory Metastatic Pancreatic Cancer) enrolled 127 patients with histologically confirmed metastatic pancreatic ductal adenocarcinoma and a Karnofsky performance score of 60 or greater who had disease progression on gemcitabine (Gemzar).

The patients were randomized to capecitabine 1,000 mg/m² twice daily for 14 days, plus either ruxolitinib 15 mg twice daily for 21 days, or placebo.

The median overall survival was 136.5 days for patients treated with the combination, and 129.5 days for those treated with capecitabine/placebo. The hazard ratio (HR) was 0.79, but the difference was not statistically significant (P = .25, above the prespecified 2-sided P value of .20).

However, when the authors performed the prespecified analysis of patients with C-reactive protein (CRP) levels above 13 mg/L, they saw a significant difference: 83.0 days for patients on the combination, vs. 55.0 days for capecitabine/placebo (HR, 0.47; 2-sided P = .01).

The 6-month overall survival rate for patients treated with the combination was 42%, compared with 11% for patients treated with capecitabine/placebo.

In a multivariate analysis of patients with high CRP levels – controlling for age, serum lactate dehydrogenase and albumin levels, liver and lung metastases, performance score, prior erlotinib (Tarceva), prior radiation or surgery, and sex – they found that the association of the combination therapy with better overall survival remained (adjusted HR, 0.50; 2-sided P = .037).

In addition, an analysis of survival according to modified Glasgow Prognostic Score (mGPS), a combination of CRP and albumin measures, showed that patients with a higher score indicative of higher degrees of systemic inflammation had better survival when treated with ruxolitinib than with placebo.

The median progression-free survival (PFS), a secondary endpoint, was in the overall population (intention to treat) 51.0 days for combination-treated patients, compared with 46.9 days for those treated with capecitabine/placebo (HR, 0.75; 2-sided P = .14). In the prespecified population with a high CRP level, the respective PFS was 48.0, vs. 41.5 days (HR, 0.62; 2-sided P = .10).

Grade 3 or 4 adverse events occurred in 74.6% of patients on the combination and 81.7% of those on capecitabine/placebo. More patients discontinued the study drug because of adverse events in the placebo group (12 patients, vs. 7 in the ruxolitinib group).

Adverse events were generally lower in frequency among patients treated with the combination, except for pulmonary embolism (a common side effect of JAK/STAT inhibitors), which occurred in seven patients on the combination, compared with three on placebo, and anemia (9 vs. 1 patient, respectively).

Invited discussant Dr. Andrew Ko of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, applauded the investigators for their "smart trial design and drug development strategy."

He said that the preplanned analysis of a subgroup of interest allowed investigators to better plan for patient selection in a phase III trial, called JANUS.

He noted, however, that the cutoff point for CRP is lower for the phase III study, which could allow for greater enrollment but with the potential trade-off in lower overall efficacy.

In addition, he questioned the wisdom of a capecitabine-only reference arm, "which may be a deterrent to study enrollment and may even be obsolete at some point."

Results of the RECAP trials also suggest that the "survival benefit of ruxolitinib may relate to alleviating cachexia and inanition, as much as reducing tumor burden," he added.

The study was sponsored by Incyte. Dr Hurwitz disclosed serving as a consultant/adviser to, and receiving research funding from, Genentech, maker of capecitabine, and Novartis, which markets ruxolitinib in Europe. Dr. Ko reported no disclosures relevant to the study.

CHICAGO – Adding the kinase inhibitor ruxolitinib to capecitabine improved overall survival of a subset of patients with metastatic pancreatic cancer, compared with capecitabine and placebo.

In a randomized phase II trial in 127 patients with metastatic pancreatic ductal adenocarcinoma, the second-line therapy combination of ruxolitinib (Jakafi) and capecitabine (Xeloda) was not associated with better outcomes than capecitabine and placebo in the overall population.

But among 60 patients with high levels of C-reactive protein indicative of systemic inflammation, adding ruxolitinib improved median overall survival to 83 days, compared with 55 days for controls, reported Dr. Herbert I. Hurwitz, professor of medicine in the division of oncology at Duke University, Durham, N.C.

"These data support the role of inflammation and the JAK-STAT pathway in particular for patients with pancreatic cancer," Dr. Hurwitz said at the annual meeting of the American Society of Clinical Oncology.

Ruxolitinib is an inhibitor of the Janus kinases (JAK) 1 and 2, which have been shown to mediate cytokine signaling through activation of STAT transcription factors. In preclinical models, pro-inflammatory cytokine signaling has been shown to contribute to pancreatic cancer initiation and progression.

Systemic inflammation is also associated with weight loss, decreased muscle mass, and poor performance status, all of which can shorten survival in patients with advanced pancreatic cancer.

The investigators hypothesized that ruxolitinib could improve survival of advanced pancreatic cancer patients when added to standard chemotherapy by dampening inflammation and thereby reducing cachexia and its related effects on patients’ overall health.

In tumor xenograft models of pancreatic cancer, the combination of ruxolitinib and capecitabine showed antitumor activity, prompting investigators to evaluate the drugs in human clinical trials.

Recap of RECAP

The phase II RECAP study (A Randomized Phase II Study of Ruxolitinib Efficacy and Safety in Combination With Capecitabine for Subjects With Recurrent or Treatment Refractory Metastatic Pancreatic Cancer) enrolled 127 patients with histologically confirmed metastatic pancreatic ductal adenocarcinoma and a Karnofsky performance score of 60 or greater who had disease progression on gemcitabine (Gemzar).

The patients were randomized to capecitabine 1,000 mg/m² twice daily for 14 days, plus either ruxolitinib 15 mg twice daily for 21 days, or placebo.

The median overall survival was 136.5 days for patients treated with the combination, and 129.5 days for those treated with capecitabine/placebo. The hazard ratio (HR) was 0.79, but the difference was not statistically significant (P = .25, above the prespecified 2-sided P value of .20).

However, when the authors performed the prespecified analysis of patients with C-reactive protein (CRP) levels above 13 mg/L, they saw a significant difference: 83.0 days for patients on the combination, vs. 55.0 days for capecitabine/placebo (HR, 0.47; 2-sided P = .01).

The 6-month overall survival rate for patients treated with the combination was 42%, compared with 11% for patients treated with capecitabine/placebo.

In a multivariate analysis of patients with high CRP levels – controlling for age, serum lactate dehydrogenase and albumin levels, liver and lung metastases, performance score, prior erlotinib (Tarceva), prior radiation or surgery, and sex – they found that the association of the combination therapy with better overall survival remained (adjusted HR, 0.50; 2-sided P = .037).

In addition, an analysis of survival according to modified Glasgow Prognostic Score (mGPS), a combination of CRP and albumin measures, showed that patients with a higher score indicative of higher degrees of systemic inflammation had better survival when treated with ruxolitinib than with placebo.

The median progression-free survival (PFS), a secondary endpoint, was in the overall population (intention to treat) 51.0 days for combination-treated patients, compared with 46.9 days for those treated with capecitabine/placebo (HR, 0.75; 2-sided P = .14). In the prespecified population with a high CRP level, the respective PFS was 48.0, vs. 41.5 days (HR, 0.62; 2-sided P = .10).

Grade 3 or 4 adverse events occurred in 74.6% of patients on the combination and 81.7% of those on capecitabine/placebo. More patients discontinued the study drug because of adverse events in the placebo group (12 patients, vs. 7 in the ruxolitinib group).

Adverse events were generally lower in frequency among patients treated with the combination, except for pulmonary embolism (a common side effect of JAK/STAT inhibitors), which occurred in seven patients on the combination, compared with three on placebo, and anemia (9 vs. 1 patient, respectively).

Invited discussant Dr. Andrew Ko of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, applauded the investigators for their "smart trial design and drug development strategy."

He said that the preplanned analysis of a subgroup of interest allowed investigators to better plan for patient selection in a phase III trial, called JANUS.

He noted, however, that the cutoff point for CRP is lower for the phase III study, which could allow for greater enrollment but with the potential trade-off in lower overall efficacy.

In addition, he questioned the wisdom of a capecitabine-only reference arm, "which may be a deterrent to study enrollment and may even be obsolete at some point."

Results of the RECAP trials also suggest that the "survival benefit of ruxolitinib may relate to alleviating cachexia and inanition, as much as reducing tumor burden," he added.

The study was sponsored by Incyte. Dr Hurwitz disclosed serving as a consultant/adviser to, and receiving research funding from, Genentech, maker of capecitabine, and Novartis, which markets ruxolitinib in Europe. Dr. Ko reported no disclosures relevant to the study.

CHICAGO – Adding the kinase inhibitor ruxolitinib to capecitabine improved overall survival of a subset of patients with metastatic pancreatic cancer, compared with capecitabine and placebo.

In a randomized phase II trial in 127 patients with metastatic pancreatic ductal adenocarcinoma, the second-line therapy combination of ruxolitinib (Jakafi) and capecitabine (Xeloda) was not associated with better outcomes than capecitabine and placebo in the overall population.

But among 60 patients with high levels of C-reactive protein indicative of systemic inflammation, adding ruxolitinib improved median overall survival to 83 days, compared with 55 days for controls, reported Dr. Herbert I. Hurwitz, professor of medicine in the division of oncology at Duke University, Durham, N.C.

"These data support the role of inflammation and the JAK-STAT pathway in particular for patients with pancreatic cancer," Dr. Hurwitz said at the annual meeting of the American Society of Clinical Oncology.

Ruxolitinib is an inhibitor of the Janus kinases (JAK) 1 and 2, which have been shown to mediate cytokine signaling through activation of STAT transcription factors. In preclinical models, pro-inflammatory cytokine signaling has been shown to contribute to pancreatic cancer initiation and progression.

Systemic inflammation is also associated with weight loss, decreased muscle mass, and poor performance status, all of which can shorten survival in patients with advanced pancreatic cancer.

The investigators hypothesized that ruxolitinib could improve survival of advanced pancreatic cancer patients when added to standard chemotherapy by dampening inflammation and thereby reducing cachexia and its related effects on patients’ overall health.

In tumor xenograft models of pancreatic cancer, the combination of ruxolitinib and capecitabine showed antitumor activity, prompting investigators to evaluate the drugs in human clinical trials.

Recap of RECAP

The phase II RECAP study (A Randomized Phase II Study of Ruxolitinib Efficacy and Safety in Combination With Capecitabine for Subjects With Recurrent or Treatment Refractory Metastatic Pancreatic Cancer) enrolled 127 patients with histologically confirmed metastatic pancreatic ductal adenocarcinoma and a Karnofsky performance score of 60 or greater who had disease progression on gemcitabine (Gemzar).

The patients were randomized to capecitabine 1,000 mg/m² twice daily for 14 days, plus either ruxolitinib 15 mg twice daily for 21 days, or placebo.

The median overall survival was 136.5 days for patients treated with the combination, and 129.5 days for those treated with capecitabine/placebo. The hazard ratio (HR) was 0.79, but the difference was not statistically significant (P = .25, above the prespecified 2-sided P value of .20).

However, when the authors performed the prespecified analysis of patients with C-reactive protein (CRP) levels above 13 mg/L, they saw a significant difference: 83.0 days for patients on the combination, vs. 55.0 days for capecitabine/placebo (HR, 0.47; 2-sided P = .01).

The 6-month overall survival rate for patients treated with the combination was 42%, compared with 11% for patients treated with capecitabine/placebo.

In a multivariate analysis of patients with high CRP levels – controlling for age, serum lactate dehydrogenase and albumin levels, liver and lung metastases, performance score, prior erlotinib (Tarceva), prior radiation or surgery, and sex – they found that the association of the combination therapy with better overall survival remained (adjusted HR, 0.50; 2-sided P = .037).

In addition, an analysis of survival according to modified Glasgow Prognostic Score (mGPS), a combination of CRP and albumin measures, showed that patients with a higher score indicative of higher degrees of systemic inflammation had better survival when treated with ruxolitinib than with placebo.

The median progression-free survival (PFS), a secondary endpoint, was in the overall population (intention to treat) 51.0 days for combination-treated patients, compared with 46.9 days for those treated with capecitabine/placebo (HR, 0.75; 2-sided P = .14). In the prespecified population with a high CRP level, the respective PFS was 48.0, vs. 41.5 days (HR, 0.62; 2-sided P = .10).

Grade 3 or 4 adverse events occurred in 74.6% of patients on the combination and 81.7% of those on capecitabine/placebo. More patients discontinued the study drug because of adverse events in the placebo group (12 patients, vs. 7 in the ruxolitinib group).

Adverse events were generally lower in frequency among patients treated with the combination, except for pulmonary embolism (a common side effect of JAK/STAT inhibitors), which occurred in seven patients on the combination, compared with three on placebo, and anemia (9 vs. 1 patient, respectively).

Invited discussant Dr. Andrew Ko of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, applauded the investigators for their "smart trial design and drug development strategy."

He said that the preplanned analysis of a subgroup of interest allowed investigators to better plan for patient selection in a phase III trial, called JANUS.

He noted, however, that the cutoff point for CRP is lower for the phase III study, which could allow for greater enrollment but with the potential trade-off in lower overall efficacy.

In addition, he questioned the wisdom of a capecitabine-only reference arm, "which may be a deterrent to study enrollment and may even be obsolete at some point."

Results of the RECAP trials also suggest that the "survival benefit of ruxolitinib may relate to alleviating cachexia and inanition, as much as reducing tumor burden," he added.

The study was sponsored by Incyte. Dr Hurwitz disclosed serving as a consultant/adviser to, and receiving research funding from, Genentech, maker of capecitabine, and Novartis, which markets ruxolitinib in Europe. Dr. Ko reported no disclosures relevant to the study.

CHICAGO – Molecular testing of patients with metastatic colorectal cancer for activating mutations in KRAS and NRAS oncogenes can help clinicians choose the most appropriate first-line therapy, findings of a mutational analysis study suggest.

In the CRYSTAL study, the addition of cetuximab (Erbitux) to the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) improved survival in patients with wild-type KRAS (codons 12 and 13 in exon 2) compared with FOLFIRI alone, but not those with mutations in KRAS exon 2.

The current study, a retrospective analysis of a subgroup of patients with wild-type KRAS who had mutations in other KRAS or NRAS exons, showed that any RAS mutation neutralized the benefit of cetuximab, reported Dr. Eric Van Cutsem of University Hospitals Gasthuisberg Leuven and KU Leuven, Belgium.

"I think it’s fair to say that exclusion of patients with other RAS mutations from the KRAS codon 12/13 wild-type exon 2 treatment population improves the benefit-risk ratio associated with the addition of cetuximab to FOLFIRI. We believe therefore that all patients with colorectal cancer should be treated for a full, extensive RAS analysis from today on, and that this marker testing of tumors for all activating mutations of KRAS and NRAS is therefore essential in selecting the most appropriate first-line treatment in patients with metastatic colorectal cancer," he said at the annual meeting of the American Society of Clinical Oncology.

Dr. Van Cutsem and his colleagues conducted an exploratory analysis looking at the treatment effect of adding cetuximab to FOLFIRI in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer.

BEAMing up RAS

They identified 430 patients with tumor samples evaluable for other RAS mutations using BEAMing (Beads, Emulsions, Amplification, Magnetics) technology. The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 molecules in plasma, according to the American Association for Cancer Research.

Among all 430 RAS evaluable patients, FOLFIRI plus cetuximab was associated with better progression-free survival (PFS; 11.3 vs. 7.7 months for FOLFIRI alone, hazard ratio [HR] 0.58, P = .0001), overall survival (OS; 26.1 vs. 20.2 months, HR 0.75, P = .0080), and objective response rate (ORR; 61.4% vs. 38.2%, HR 2.64, P less than .0001).

But in a subanalysis of the 63 patients (14.7%) with wild-type KRAS exon 2 but new RAS mutations in KRAS exons 3 and 4, or NRAS exons, 2, 3 and 4, they found that any RAS mutation appeared to nullify the benefit of adding cetuximab, with no significant differences between FOLFIRI with or without cetuximab in either PFS, OS, or ORR.

For example, for patients with RAS wild type, median PFS for those treated with FOLFIRI plus cetuximab was 11.4 months vs. 8.4 months for those treated with FOLFIRI only (HR 0.50, 95% confidence interval [CI] 0.41-0.76). But for patients with any RAS mutation, the PFS was 7.4 and 7.5 months respectively (HR 1.10, CI, 0.85-1.4).

Similarly, median overall survival among all RAS wild-type patients in the subgroup was 28.4 months vs. 20.2 months (HR 0.69, CI 0.54-0.88), but among those with any RAS mutation was 16.4 vs. 17.7 months (HR 1.05, CI, 0.86-1.28)

Although cetuximab did not benefit patients with RAS mutations, neither did it cause harm, as evidenced by a similar safety profile among RAS wild-type and mutant subgroups, Dr Van Cutsem said.

Evidence from this and five other clinical trials suggests that clinicians should not use epidermal growth factor receptor (EGFR) inhibitors in patients with tumors that harbor any RAS mutations, said Dr. Neal J. Meropol, chief of hematology and oncology at the University Hospitals Seidman Cancer Center at Case Western Reserve University, Cleveland.

"I view this as a four-star [out of five] recommendation. As each of the new mutations are rare, and real differences in biologic behavior and response to treatment are still possible within these rare sub [mutations]," he said.

Although the differences in outcomes between various studies may be attributable to the use of different testing platforms, "it seems very unlikely to me that the benefit of treatment in one of these rare [mutations] will be great enough to conclude that this is a high-value treatment for these patients. Further pooled analyses across studies are needed to provide additional insight into this question," he said.

The study was supported by Merck. Dr. Van Cutsem reported receiving research funding from Merck Serono. Dr. Meropol disclosed serving as consultant/adviser to Precision Therapeutics.

CHICAGO – Molecular testing of patients with metastatic colorectal cancer for activating mutations in KRAS and NRAS oncogenes can help clinicians choose the most appropriate first-line therapy, findings of a mutational analysis study suggest.

In the CRYSTAL study, the addition of cetuximab (Erbitux) to the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) improved survival in patients with wild-type KRAS (codons 12 and 13 in exon 2) compared with FOLFIRI alone, but not those with mutations in KRAS exon 2.

The current study, a retrospective analysis of a subgroup of patients with wild-type KRAS who had mutations in other KRAS or NRAS exons, showed that any RAS mutation neutralized the benefit of cetuximab, reported Dr. Eric Van Cutsem of University Hospitals Gasthuisberg Leuven and KU Leuven, Belgium.

"I think it’s fair to say that exclusion of patients with other RAS mutations from the KRAS codon 12/13 wild-type exon 2 treatment population improves the benefit-risk ratio associated with the addition of cetuximab to FOLFIRI. We believe therefore that all patients with colorectal cancer should be treated for a full, extensive RAS analysis from today on, and that this marker testing of tumors for all activating mutations of KRAS and NRAS is therefore essential in selecting the most appropriate first-line treatment in patients with metastatic colorectal cancer," he said at the annual meeting of the American Society of Clinical Oncology.

Dr. Van Cutsem and his colleagues conducted an exploratory analysis looking at the treatment effect of adding cetuximab to FOLFIRI in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer.

BEAMing up RAS

They identified 430 patients with tumor samples evaluable for other RAS mutations using BEAMing (Beads, Emulsions, Amplification, Magnetics) technology. The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 molecules in plasma, according to the American Association for Cancer Research.

Among all 430 RAS evaluable patients, FOLFIRI plus cetuximab was associated with better progression-free survival (PFS; 11.3 vs. 7.7 months for FOLFIRI alone, hazard ratio [HR] 0.58, P = .0001), overall survival (OS; 26.1 vs. 20.2 months, HR 0.75, P = .0080), and objective response rate (ORR; 61.4% vs. 38.2%, HR 2.64, P less than .0001).

But in a subanalysis of the 63 patients (14.7%) with wild-type KRAS exon 2 but new RAS mutations in KRAS exons 3 and 4, or NRAS exons, 2, 3 and 4, they found that any RAS mutation appeared to nullify the benefit of adding cetuximab, with no significant differences between FOLFIRI with or without cetuximab in either PFS, OS, or ORR.

For example, for patients with RAS wild type, median PFS for those treated with FOLFIRI plus cetuximab was 11.4 months vs. 8.4 months for those treated with FOLFIRI only (HR 0.50, 95% confidence interval [CI] 0.41-0.76). But for patients with any RAS mutation, the PFS was 7.4 and 7.5 months respectively (HR 1.10, CI, 0.85-1.4).

Similarly, median overall survival among all RAS wild-type patients in the subgroup was 28.4 months vs. 20.2 months (HR 0.69, CI 0.54-0.88), but among those with any RAS mutation was 16.4 vs. 17.7 months (HR 1.05, CI, 0.86-1.28)

Although cetuximab did not benefit patients with RAS mutations, neither did it cause harm, as evidenced by a similar safety profile among RAS wild-type and mutant subgroups, Dr Van Cutsem said.

Evidence from this and five other clinical trials suggests that clinicians should not use epidermal growth factor receptor (EGFR) inhibitors in patients with tumors that harbor any RAS mutations, said Dr. Neal J. Meropol, chief of hematology and oncology at the University Hospitals Seidman Cancer Center at Case Western Reserve University, Cleveland.

"I view this as a four-star [out of five] recommendation. As each of the new mutations are rare, and real differences in biologic behavior and response to treatment are still possible within these rare sub [mutations]," he said.

Although the differences in outcomes between various studies may be attributable to the use of different testing platforms, "it seems very unlikely to me that the benefit of treatment in one of these rare [mutations] will be great enough to conclude that this is a high-value treatment for these patients. Further pooled analyses across studies are needed to provide additional insight into this question," he said.

The study was supported by Merck. Dr. Van Cutsem reported receiving research funding from Merck Serono. Dr. Meropol disclosed serving as consultant/adviser to Precision Therapeutics.

CHICAGO – Molecular testing of patients with metastatic colorectal cancer for activating mutations in KRAS and NRAS oncogenes can help clinicians choose the most appropriate first-line therapy, findings of a mutational analysis study suggest.

In the CRYSTAL study, the addition of cetuximab (Erbitux) to the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) improved survival in patients with wild-type KRAS (codons 12 and 13 in exon 2) compared with FOLFIRI alone, but not those with mutations in KRAS exon 2.

The current study, a retrospective analysis of a subgroup of patients with wild-type KRAS who had mutations in other KRAS or NRAS exons, showed that any RAS mutation neutralized the benefit of cetuximab, reported Dr. Eric Van Cutsem of University Hospitals Gasthuisberg Leuven and KU Leuven, Belgium.

"I think it’s fair to say that exclusion of patients with other RAS mutations from the KRAS codon 12/13 wild-type exon 2 treatment population improves the benefit-risk ratio associated with the addition of cetuximab to FOLFIRI. We believe therefore that all patients with colorectal cancer should be treated for a full, extensive RAS analysis from today on, and that this marker testing of tumors for all activating mutations of KRAS and NRAS is therefore essential in selecting the most appropriate first-line treatment in patients with metastatic colorectal cancer," he said at the annual meeting of the American Society of Clinical Oncology.

Dr. Van Cutsem and his colleagues conducted an exploratory analysis looking at the treatment effect of adding cetuximab to FOLFIRI in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer.

BEAMing up RAS

They identified 430 patients with tumor samples evaluable for other RAS mutations using BEAMing (Beads, Emulsions, Amplification, Magnetics) technology. The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 molecules in plasma, according to the American Association for Cancer Research.

Among all 430 RAS evaluable patients, FOLFIRI plus cetuximab was associated with better progression-free survival (PFS; 11.3 vs. 7.7 months for FOLFIRI alone, hazard ratio [HR] 0.58, P = .0001), overall survival (OS; 26.1 vs. 20.2 months, HR 0.75, P = .0080), and objective response rate (ORR; 61.4% vs. 38.2%, HR 2.64, P less than .0001).

But in a subanalysis of the 63 patients (14.7%) with wild-type KRAS exon 2 but new RAS mutations in KRAS exons 3 and 4, or NRAS exons, 2, 3 and 4, they found that any RAS mutation appeared to nullify the benefit of adding cetuximab, with no significant differences between FOLFIRI with or without cetuximab in either PFS, OS, or ORR.

For example, for patients with RAS wild type, median PFS for those treated with FOLFIRI plus cetuximab was 11.4 months vs. 8.4 months for those treated with FOLFIRI only (HR 0.50, 95% confidence interval [CI] 0.41-0.76). But for patients with any RAS mutation, the PFS was 7.4 and 7.5 months respectively (HR 1.10, CI, 0.85-1.4).

Similarly, median overall survival among all RAS wild-type patients in the subgroup was 28.4 months vs. 20.2 months (HR 0.69, CI 0.54-0.88), but among those with any RAS mutation was 16.4 vs. 17.7 months (HR 1.05, CI, 0.86-1.28)

Although cetuximab did not benefit patients with RAS mutations, neither did it cause harm, as evidenced by a similar safety profile among RAS wild-type and mutant subgroups, Dr Van Cutsem said.

Evidence from this and five other clinical trials suggests that clinicians should not use epidermal growth factor receptor (EGFR) inhibitors in patients with tumors that harbor any RAS mutations, said Dr. Neal J. Meropol, chief of hematology and oncology at the University Hospitals Seidman Cancer Center at Case Western Reserve University, Cleveland.

"I view this as a four-star [out of five] recommendation. As each of the new mutations are rare, and real differences in biologic behavior and response to treatment are still possible within these rare sub [mutations]," he said.

Although the differences in outcomes between various studies may be attributable to the use of different testing platforms, "it seems very unlikely to me that the benefit of treatment in one of these rare [mutations] will be great enough to conclude that this is a high-value treatment for these patients. Further pooled analyses across studies are needed to provide additional insight into this question," he said.

The study was supported by Merck. Dr. Van Cutsem reported receiving research funding from Merck Serono. Dr. Meropol disclosed serving as consultant/adviser to Precision Therapeutics.

CHICAGO – Patients with metastatic colorectal cancer who had at least stable disease after induction chemotherapy fared better on maintenance therapy with capecitabine and bevacizumab than on observation alone.

That’s the conclusion reached by investigators in a phase III trial conducted in the Netherlands. They found that patients who were randomly assigned to maintenance therapy after six cycles of induction therapy with capecitabine (Xeloda), oxaliplatin (Eloxatin), and bevacizumab (Avastin) – the CAPOX-B regimen – had better progression-free survival (PFS) and time to progression (TTP) than did patients assigned to observation alone.

With maintenance therapy, "the quality of life is maintained and clinically not inferior to observation," said lead author Dr. Miriam Koopman of the University Medical Center Utrecht Cancer Center, the Netherlands. She presented the final results of the CAIRO3 (Maintenance Treatment With Capecitabine and Bevacizumab Versus Observation After Induction Treatment With Chemotherapy and Bevacizumab as First-line Treatment) trial at the annual meeting of the American Society of Clinical Oncology.

The investigators enrolled 588 patients with metastatic colorectal cancer who had a response of stable-disease or better following six cycles of CAPOX-B to either observation or maintenance with oral capecitabine 625 mg/m² twice daily and intravenous bevacizumab 7.5 mg/kg on day 1 every 3 weeks. The patients were stratified by prior adjuvant therapy, serum lactate dehydrogenase, response to induction therapy, World Health Organization performance status, and institution.

In both arms, CAPOX-B reintroduction was planned at the time of first progression. The primary endpoint was progression-free survival following reintroduction of CAPOX-B (dubbed PFS2). For those patients who for any reason did not receive CAPOX-B after the first PFS, PFS2 was considered to be equal to PFS1, Dr. Koopman explained.

Of the 279 patients assigned to observation, 168 (60%) had CAPOX-B reintroduced. Of the remaining 111 (40%) of patients in this arm, seven had ongoing observation, 31 received no treatment, and 73 received treatment other than CAPOX-B.

Of the 279 assigned to maintenance, 132 (47%) had CAPOX-B reintroduced. Of the remaining 147 patients (53%) in this arm, 13 continued on maintenance, 45 had no further treatment, 88 had other treatments, and 1 withdrew.

The median PFS from the time of randomization (not including induction) to first progression was 4.1 months in the observation arm and 8.5 months in the maintenance arm (stratified hazard ratio 0.43, P less than .0001).

The benefits of maintenance were also seen with the primary endpoint of PFS2, with a median of 8.5 months for observation, compared with 11.7 months for maintenance (stratified HR 0.67, P less than .0001)

The median time to second progression was 11.1 months among patients randomized to observation, vs. 13. 9 months for those randomized to maintenance (stratified HR 0.68, P less than .0001).

There were no significant differences in median overall survival (OS), however, at 18.1 months for the observation arm and 21.6 months for the maintenance arm.

There was a small but significant difference in quality of life scores between the groups (3.9 point difference on a 100-point scale, P = .004), but this difference was too small to be considered clinically meaningful, Dr. Koopman said.

In preplanned subgroup analyses, the authors found evidence to suggest that patients with synchronous metastases who had resection of the primary tumor had a greater OS benefit from maintenance therapy than did patients with metachronous disease, and that those who had complete or partial response as best response to induction therapy seemed to do better than did patients with stable disease after induction.

"We do not have a clear-cut explanation for this subgroup analysis," Dr. Koopman said.

The investigators hypothesize that the differences between patients with synchronous and metachronous disease could be due to differences in sensitivity to systemic treatment, the prognostic role of resection of the primary tumor, dependence of the angiogenic environment in metastases on the resection status of the primary tumor, or co-option of the local vasculature by the tumor, leading to decreased sensitivity of metachronous metastases to bevacizumab.

The CAIRO3 results suggest that "treatment breaks for all patients at 4 months may be too many breaks, and too early," said Dr. Leonard Saltz, chief of the gastrointestinal oncology service at Memorial Sloan-Kettering Cancer Center, New York.

"Responding patients likely benefit from treatment at least until maximal response, and that’s an aspect to consider in terms of figuring out how to utilize a treatment strategy. And treatment-break strategies will need to be individualized, but should not be abandoned," said Dr. Saltz, who was the invited discussant.

He also cautioned that the quality of life results reported by Dr. Koopman and colleagues may not accurately reflect how patients feel.

"In terms of the quality of life, what we have to conclude is that as our instruments can measure it we do not see a detriment in quality of life. But intuitively, we can conjecture that being on chemotherapy has some negative aspects – just ask any of our patients. So the idea that there is no detriment in quality of life when we’re comparing chemotherapy to nonchemotherapy suggests that we need more sensitive and specific tools for the question," he said.

The CAIRO3 study was supported by the Dutch Cancer Foundation and by unrestricted scientific grants from Roche and Sanofi-Aventis. Dr. Koopman disclosed ties with Roche/Genentech and Sanofi. Dr. Saltz disclosed ties with Roche, Genentech, and Sanofi.

CHICAGO – Patients with metastatic colorectal cancer who had at least stable disease after induction chemotherapy fared better on maintenance therapy with capecitabine and bevacizumab than on observation alone.

That’s the conclusion reached by investigators in a phase III trial conducted in the Netherlands. They found that patients who were randomly assigned to maintenance therapy after six cycles of induction therapy with capecitabine (Xeloda), oxaliplatin (Eloxatin), and bevacizumab (Avastin) – the CAPOX-B regimen – had better progression-free survival (PFS) and time to progression (TTP) than did patients assigned to observation alone.

With maintenance therapy, "the quality of life is maintained and clinically not inferior to observation," said lead author Dr. Miriam Koopman of the University Medical Center Utrecht Cancer Center, the Netherlands. She presented the final results of the CAIRO3 (Maintenance Treatment With Capecitabine and Bevacizumab Versus Observation After Induction Treatment With Chemotherapy and Bevacizumab as First-line Treatment) trial at the annual meeting of the American Society of Clinical Oncology.

The investigators enrolled 588 patients with metastatic colorectal cancer who had a response of stable-disease or better following six cycles of CAPOX-B to either observation or maintenance with oral capecitabine 625 mg/m² twice daily and intravenous bevacizumab 7.5 mg/kg on day 1 every 3 weeks. The patients were stratified by prior adjuvant therapy, serum lactate dehydrogenase, response to induction therapy, World Health Organization performance status, and institution.

In both arms, CAPOX-B reintroduction was planned at the time of first progression. The primary endpoint was progression-free survival following reintroduction of CAPOX-B (dubbed PFS2). For those patients who for any reason did not receive CAPOX-B after the first PFS, PFS2 was considered to be equal to PFS1, Dr. Koopman explained.

Of the 279 patients assigned to observation, 168 (60%) had CAPOX-B reintroduced. Of the remaining 111 (40%) of patients in this arm, seven had ongoing observation, 31 received no treatment, and 73 received treatment other than CAPOX-B.

Of the 279 assigned to maintenance, 132 (47%) had CAPOX-B reintroduced. Of the remaining 147 patients (53%) in this arm, 13 continued on maintenance, 45 had no further treatment, 88 had other treatments, and 1 withdrew.

The median PFS from the time of randomization (not including induction) to first progression was 4.1 months in the observation arm and 8.5 months in the maintenance arm (stratified hazard ratio 0.43, P less than .0001).

The benefits of maintenance were also seen with the primary endpoint of PFS2, with a median of 8.5 months for observation, compared with 11.7 months for maintenance (stratified HR 0.67, P less than .0001)

The median time to second progression was 11.1 months among patients randomized to observation, vs. 13. 9 months for those randomized to maintenance (stratified HR 0.68, P less than .0001).

There were no significant differences in median overall survival (OS), however, at 18.1 months for the observation arm and 21.6 months for the maintenance arm.

There was a small but significant difference in quality of life scores between the groups (3.9 point difference on a 100-point scale, P = .004), but this difference was too small to be considered clinically meaningful, Dr. Koopman said.

In preplanned subgroup analyses, the authors found evidence to suggest that patients with synchronous metastases who had resection of the primary tumor had a greater OS benefit from maintenance therapy than did patients with metachronous disease, and that those who had complete or partial response as best response to induction therapy seemed to do better than did patients with stable disease after induction.

"We do not have a clear-cut explanation for this subgroup analysis," Dr. Koopman said.

The investigators hypothesize that the differences between patients with synchronous and metachronous disease could be due to differences in sensitivity to systemic treatment, the prognostic role of resection of the primary tumor, dependence of the angiogenic environment in metastases on the resection status of the primary tumor, or co-option of the local vasculature by the tumor, leading to decreased sensitivity of metachronous metastases to bevacizumab.

The CAIRO3 results suggest that "treatment breaks for all patients at 4 months may be too many breaks, and too early," said Dr. Leonard Saltz, chief of the gastrointestinal oncology service at Memorial Sloan-Kettering Cancer Center, New York.

"Responding patients likely benefit from treatment at least until maximal response, and that’s an aspect to consider in terms of figuring out how to utilize a treatment strategy. And treatment-break strategies will need to be individualized, but should not be abandoned," said Dr. Saltz, who was the invited discussant.

He also cautioned that the quality of life results reported by Dr. Koopman and colleagues may not accurately reflect how patients feel.

"In terms of the quality of life, what we have to conclude is that as our instruments can measure it we do not see a detriment in quality of life. But intuitively, we can conjecture that being on chemotherapy has some negative aspects – just ask any of our patients. So the idea that there is no detriment in quality of life when we’re comparing chemotherapy to nonchemotherapy suggests that we need more sensitive and specific tools for the question," he said.

The CAIRO3 study was supported by the Dutch Cancer Foundation and by unrestricted scientific grants from Roche and Sanofi-Aventis. Dr. Koopman disclosed ties with Roche/Genentech and Sanofi. Dr. Saltz disclosed ties with Roche, Genentech, and Sanofi.

CHICAGO – Patients with metastatic colorectal cancer who had at least stable disease after induction chemotherapy fared better on maintenance therapy with capecitabine and bevacizumab than on observation alone.

That’s the conclusion reached by investigators in a phase III trial conducted in the Netherlands. They found that patients who were randomly assigned to maintenance therapy after six cycles of induction therapy with capecitabine (Xeloda), oxaliplatin (Eloxatin), and bevacizumab (Avastin) – the CAPOX-B regimen – had better progression-free survival (PFS) and time to progression (TTP) than did patients assigned to observation alone.

With maintenance therapy, "the quality of life is maintained and clinically not inferior to observation," said lead author Dr. Miriam Koopman of the University Medical Center Utrecht Cancer Center, the Netherlands. She presented the final results of the CAIRO3 (Maintenance Treatment With Capecitabine and Bevacizumab Versus Observation After Induction Treatment With Chemotherapy and Bevacizumab as First-line Treatment) trial at the annual meeting of the American Society of Clinical Oncology.

The investigators enrolled 588 patients with metastatic colorectal cancer who had a response of stable-disease or better following six cycles of CAPOX-B to either observation or maintenance with oral capecitabine 625 mg/m² twice daily and intravenous bevacizumab 7.5 mg/kg on day 1 every 3 weeks. The patients were stratified by prior adjuvant therapy, serum lactate dehydrogenase, response to induction therapy, World Health Organization performance status, and institution.

In both arms, CAPOX-B reintroduction was planned at the time of first progression. The primary endpoint was progression-free survival following reintroduction of CAPOX-B (dubbed PFS2). For those patients who for any reason did not receive CAPOX-B after the first PFS, PFS2 was considered to be equal to PFS1, Dr. Koopman explained.

Of the 279 patients assigned to observation, 168 (60%) had CAPOX-B reintroduced. Of the remaining 111 (40%) of patients in this arm, seven had ongoing observation, 31 received no treatment, and 73 received treatment other than CAPOX-B.

Of the 279 assigned to maintenance, 132 (47%) had CAPOX-B reintroduced. Of the remaining 147 patients (53%) in this arm, 13 continued on maintenance, 45 had no further treatment, 88 had other treatments, and 1 withdrew.

The median PFS from the time of randomization (not including induction) to first progression was 4.1 months in the observation arm and 8.5 months in the maintenance arm (stratified hazard ratio 0.43, P less than .0001).

The benefits of maintenance were also seen with the primary endpoint of PFS2, with a median of 8.5 months for observation, compared with 11.7 months for maintenance (stratified HR 0.67, P less than .0001)

The median time to second progression was 11.1 months among patients randomized to observation, vs. 13. 9 months for those randomized to maintenance (stratified HR 0.68, P less than .0001).

There were no significant differences in median overall survival (OS), however, at 18.1 months for the observation arm and 21.6 months for the maintenance arm.

There was a small but significant difference in quality of life scores between the groups (3.9 point difference on a 100-point scale, P = .004), but this difference was too small to be considered clinically meaningful, Dr. Koopman said.

In preplanned subgroup analyses, the authors found evidence to suggest that patients with synchronous metastases who had resection of the primary tumor had a greater OS benefit from maintenance therapy than did patients with metachronous disease, and that those who had complete or partial response as best response to induction therapy seemed to do better than did patients with stable disease after induction.

"We do not have a clear-cut explanation for this subgroup analysis," Dr. Koopman said.

The investigators hypothesize that the differences between patients with synchronous and metachronous disease could be due to differences in sensitivity to systemic treatment, the prognostic role of resection of the primary tumor, dependence of the angiogenic environment in metastases on the resection status of the primary tumor, or co-option of the local vasculature by the tumor, leading to decreased sensitivity of metachronous metastases to bevacizumab.

The CAIRO3 results suggest that "treatment breaks for all patients at 4 months may be too many breaks, and too early," said Dr. Leonard Saltz, chief of the gastrointestinal oncology service at Memorial Sloan-Kettering Cancer Center, New York.

"Responding patients likely benefit from treatment at least until maximal response, and that’s an aspect to consider in terms of figuring out how to utilize a treatment strategy. And treatment-break strategies will need to be individualized, but should not be abandoned," said Dr. Saltz, who was the invited discussant.

He also cautioned that the quality of life results reported by Dr. Koopman and colleagues may not accurately reflect how patients feel.

"In terms of the quality of life, what we have to conclude is that as our instruments can measure it we do not see a detriment in quality of life. But intuitively, we can conjecture that being on chemotherapy has some negative aspects – just ask any of our patients. So the idea that there is no detriment in quality of life when we’re comparing chemotherapy to nonchemotherapy suggests that we need more sensitive and specific tools for the question," he said.

The CAIRO3 study was supported by the Dutch Cancer Foundation and by unrestricted scientific grants from Roche and Sanofi-Aventis. Dr. Koopman disclosed ties with Roche/Genentech and Sanofi. Dr. Saltz disclosed ties with Roche, Genentech, and Sanofi.

CHICAGO – A combination of two immune checkpoint inhibitors – ipilimumab and nivolumab – produced durable responses in patients with metastatic renal cell carcinoma in a phase I trial.

At 40.1 weeks of follow-up, the median duration of response for patients treated with nivolumab 3 mg/kg and ipilimumab (Yervoy) 1 mg/kg for four cycles followed by nivolumab maintenance was 31weeks, and for patients treated with nivolumab 1 mg/kg/ and ipilimumab 3 mg/kg the median duration of response had not been reached, reported Dr. Hans J. Hammers of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.

"The objective response rate suggests greater activity than reported previously with nivolumab or ipilimumab monotherapy," Dr. Hammers said at the annual meeting of the American Society of Clinical Oncology.

"Responses appear durable even after discontinuation of study drug," he added.

Nonredundant checkpoints

Both drugs are monoclonal antibodies directed against receptors in immune system checkpoints. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor that acts as an early brake point in the immune response; nivolumab is a programmed cell death-1 (PD-1) inhibitor that serves as a late brake. By releasing the brakes, the drugs allow the immune system to operate full throttle against cancer.

Ipilimumab is approved by the Food and Drug Administration for the treatment of metastatic melanoma. Nivolumab is an investigational agent that has been shown to have good antitumor activity in monotherapy against melanoma and other malignancies.

At ASCO 2014, investigators reported that the combinations resulted in "unprecedented" 2-year overall survival rates for patients with metastatic melanoma.

Dr. Hammers and his colleagues investigated the combination in a phase I trial comparing two different combinations of the checkpoint inhibitors.

Patients with untreated or previously treated metastatic renal cell carcinoma (mRCC) with clear-cell histology were randomly assigned to receive intravenous induction therapy every 3 weeks for four cycles with either nivolumab 3 mg/kg and ipilimumab 1 mg/kg (N3/I1) or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (N1/I3). Patients received two infusions during each induction, with nivolumab first, followed by ipilimumab started at least 30 minutes after completion of the nivolumab infusion.

Following induction, all patients went on to continuous nivolumab 3 mg/kg every 2 weeks until disease progression.

Adverse events

Treatment-related adverse events, the primary endpoint, occurred in 16 of the 21 patients (76.2%) assigned to N3/I1) and in all 23 patients assigned to N1/I3. Grade 3 or 4 adverse events occurred in 5 of 21 (23.8%) and 14 of 23 (60.9%), respectively. There were no treatment-related deaths.

The grade 3 or 4 adverse events included diarrhea in one patient in N3/I1 and eight patients in N1/I3, increased lipase in three and six patients, respectively, and increased amylase in one and three patients. There were no other grade 3 or 4 adverse events in either study arm. In addition, there were no high-grade pulmonary adverse events or cases of pneumonitis, which are often seen with immunotherapy, Dr. Hammers noted.

The confirmed objective response rate (ORR) was 43% (9 of 21) in N3/I1 and 48% (11 of 23) in N1/I3. As noted before, the median duration of response was 31.1 weeks in N3/I1 and not reached in N1/I3.

Of the patients who had objective response, the responses were ongoing at last follow-up in 7 of 9 on N3/I1 and 9 of 11 on N1/I3.

There was only one complete response, however, occurring in a patient who received N1/I3. Partial responses occurred in nine patients on N3/I1 and 10 in N1/I3.

The respective progression-free survival rates at 24 weeks were 65% and 64%, which "compares favorably with the nivolumab monotherapy experience," Dr. Hammers said.

The majority of patients in each study arm had significant reductions in tumor burden of the target lesions, he added.

Of the patients with ongoing responses, 3 of 9 in the N3/I1 arm and 5 of 11 in the N1/I3 arm continued to have responses after discontinuing therapy for reasons other than disease progression.

"This encouraging antitumor activity reported with this combination is the basis for a planned phase III combination trial in the first-line setting for the treatment of metastatic renal cell carcinoma patients," Dr. Hammers said.

‘Gutsy move’

Dr. Primo Lara, professor of medicine at the University of California, Davis, who was the invited discussant, commented that, "at least for now, I think we could say that combination checkpoint blockade in RCC is at least additive, recalling that the single-agent response rate in this disease for nivo[lumab] is about 20%-29%, and for ipi[limumab] is about 13%, and some of these responses are encouragingly durable."

He cautioned, however, that the toxicities with the combined drugs, primarily driven by ipilimumab, "are not inconsequential."

"We heard today that a phase III trial has been initiated, presumably with a lower-dose ipi[limumab] arm, but I think that’s really a gutsy move, considering that there were only 21 patients in that subset of patients that led to this phase III decision. Just a fair warning to everyone that toxicities observed in a phase I trial tend to magnify in a larger phase III when you have more centers, different eligibility criteria, and less experienced folks administering a pretty toxic combination," he said.

The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Hammers has received research funding from BMS. Dr. Lara disclosed serving as a consultant/advisor, and receiving honoraria and research funding from many companies, but not BMS.

CHICAGO – A combination of two immune checkpoint inhibitors – ipilimumab and nivolumab – produced durable responses in patients with metastatic renal cell carcinoma in a phase I trial.

At 40.1 weeks of follow-up, the median duration of response for patients treated with nivolumab 3 mg/kg and ipilimumab (Yervoy) 1 mg/kg for four cycles followed by nivolumab maintenance was 31weeks, and for patients treated with nivolumab 1 mg/kg/ and ipilimumab 3 mg/kg the median duration of response had not been reached, reported Dr. Hans J. Hammers of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.

"The objective response rate suggests greater activity than reported previously with nivolumab or ipilimumab monotherapy," Dr. Hammers said at the annual meeting of the American Society of Clinical Oncology.

"Responses appear durable even after discontinuation of study drug," he added.

Nonredundant checkpoints

Both drugs are monoclonal antibodies directed against receptors in immune system checkpoints. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor that acts as an early brake point in the immune response; nivolumab is a programmed cell death-1 (PD-1) inhibitor that serves as a late brake. By releasing the brakes, the drugs allow the immune system to operate full throttle against cancer.

Ipilimumab is approved by the Food and Drug Administration for the treatment of metastatic melanoma. Nivolumab is an investigational agent that has been shown to have good antitumor activity in monotherapy against melanoma and other malignancies.

At ASCO 2014, investigators reported that the combinations resulted in "unprecedented" 2-year overall survival rates for patients with metastatic melanoma.

Dr. Hammers and his colleagues investigated the combination in a phase I trial comparing two different combinations of the checkpoint inhibitors.

Patients with untreated or previously treated metastatic renal cell carcinoma (mRCC) with clear-cell histology were randomly assigned to receive intravenous induction therapy every 3 weeks for four cycles with either nivolumab 3 mg/kg and ipilimumab 1 mg/kg (N3/I1) or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (N1/I3). Patients received two infusions during each induction, with nivolumab first, followed by ipilimumab started at least 30 minutes after completion of the nivolumab infusion.

Following induction, all patients went on to continuous nivolumab 3 mg/kg every 2 weeks until disease progression.

Adverse events

Treatment-related adverse events, the primary endpoint, occurred in 16 of the 21 patients (76.2%) assigned to N3/I1) and in all 23 patients assigned to N1/I3. Grade 3 or 4 adverse events occurred in 5 of 21 (23.8%) and 14 of 23 (60.9%), respectively. There were no treatment-related deaths.

The grade 3 or 4 adverse events included diarrhea in one patient in N3/I1 and eight patients in N1/I3, increased lipase in three and six patients, respectively, and increased amylase in one and three patients. There were no other grade 3 or 4 adverse events in either study arm. In addition, there were no high-grade pulmonary adverse events or cases of pneumonitis, which are often seen with immunotherapy, Dr. Hammers noted.

The confirmed objective response rate (ORR) was 43% (9 of 21) in N3/I1 and 48% (11 of 23) in N1/I3. As noted before, the median duration of response was 31.1 weeks in N3/I1 and not reached in N1/I3.

Of the patients who had objective response, the responses were ongoing at last follow-up in 7 of 9 on N3/I1 and 9 of 11 on N1/I3.

There was only one complete response, however, occurring in a patient who received N1/I3. Partial responses occurred in nine patients on N3/I1 and 10 in N1/I3.

The respective progression-free survival rates at 24 weeks were 65% and 64%, which "compares favorably with the nivolumab monotherapy experience," Dr. Hammers said.

The majority of patients in each study arm had significant reductions in tumor burden of the target lesions, he added.

Of the patients with ongoing responses, 3 of 9 in the N3/I1 arm and 5 of 11 in the N1/I3 arm continued to have responses after discontinuing therapy for reasons other than disease progression.

"This encouraging antitumor activity reported with this combination is the basis for a planned phase III combination trial in the first-line setting for the treatment of metastatic renal cell carcinoma patients," Dr. Hammers said.

‘Gutsy move’

Dr. Primo Lara, professor of medicine at the University of California, Davis, who was the invited discussant, commented that, "at least for now, I think we could say that combination checkpoint blockade in RCC is at least additive, recalling that the single-agent response rate in this disease for nivo[lumab] is about 20%-29%, and for ipi[limumab] is about 13%, and some of these responses are encouragingly durable."

He cautioned, however, that the toxicities with the combined drugs, primarily driven by ipilimumab, "are not inconsequential."

"We heard today that a phase III trial has been initiated, presumably with a lower-dose ipi[limumab] arm, but I think that’s really a gutsy move, considering that there were only 21 patients in that subset of patients that led to this phase III decision. Just a fair warning to everyone that toxicities observed in a phase I trial tend to magnify in a larger phase III when you have more centers, different eligibility criteria, and less experienced folks administering a pretty toxic combination," he said.

The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Hammers has received research funding from BMS. Dr. Lara disclosed serving as a consultant/advisor, and receiving honoraria and research funding from many companies, but not BMS.

CHICAGO – A combination of two immune checkpoint inhibitors – ipilimumab and nivolumab – produced durable responses in patients with metastatic renal cell carcinoma in a phase I trial.

At 40.1 weeks of follow-up, the median duration of response for patients treated with nivolumab 3 mg/kg and ipilimumab (Yervoy) 1 mg/kg for four cycles followed by nivolumab maintenance was 31weeks, and for patients treated with nivolumab 1 mg/kg/ and ipilimumab 3 mg/kg the median duration of response had not been reached, reported Dr. Hans J. Hammers of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.

"The objective response rate suggests greater activity than reported previously with nivolumab or ipilimumab monotherapy," Dr. Hammers said at the annual meeting of the American Society of Clinical Oncology.

"Responses appear durable even after discontinuation of study drug," he added.

Nonredundant checkpoints

Both drugs are monoclonal antibodies directed against receptors in immune system checkpoints. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor that acts as an early brake point in the immune response; nivolumab is a programmed cell death-1 (PD-1) inhibitor that serves as a late brake. By releasing the brakes, the drugs allow the immune system to operate full throttle against cancer.

Ipilimumab is approved by the Food and Drug Administration for the treatment of metastatic melanoma. Nivolumab is an investigational agent that has been shown to have good antitumor activity in monotherapy against melanoma and other malignancies.

At ASCO 2014, investigators reported that the combinations resulted in "unprecedented" 2-year overall survival rates for patients with metastatic melanoma.

Dr. Hammers and his colleagues investigated the combination in a phase I trial comparing two different combinations of the checkpoint inhibitors.

Patients with untreated or previously treated metastatic renal cell carcinoma (mRCC) with clear-cell histology were randomly assigned to receive intravenous induction therapy every 3 weeks for four cycles with either nivolumab 3 mg/kg and ipilimumab 1 mg/kg (N3/I1) or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (N1/I3). Patients received two infusions during each induction, with nivolumab first, followed by ipilimumab started at least 30 minutes after completion of the nivolumab infusion.

Following induction, all patients went on to continuous nivolumab 3 mg/kg every 2 weeks until disease progression.

Adverse events

Treatment-related adverse events, the primary endpoint, occurred in 16 of the 21 patients (76.2%) assigned to N3/I1) and in all 23 patients assigned to N1/I3. Grade 3 or 4 adverse events occurred in 5 of 21 (23.8%) and 14 of 23 (60.9%), respectively. There were no treatment-related deaths.

The grade 3 or 4 adverse events included diarrhea in one patient in N3/I1 and eight patients in N1/I3, increased lipase in three and six patients, respectively, and increased amylase in one and three patients. There were no other grade 3 or 4 adverse events in either study arm. In addition, there were no high-grade pulmonary adverse events or cases of pneumonitis, which are often seen with immunotherapy, Dr. Hammers noted.

The confirmed objective response rate (ORR) was 43% (9 of 21) in N3/I1 and 48% (11 of 23) in N1/I3. As noted before, the median duration of response was 31.1 weeks in N3/I1 and not reached in N1/I3.

Of the patients who had objective response, the responses were ongoing at last follow-up in 7 of 9 on N3/I1 and 9 of 11 on N1/I3.

There was only one complete response, however, occurring in a patient who received N1/I3. Partial responses occurred in nine patients on N3/I1 and 10 in N1/I3.

The respective progression-free survival rates at 24 weeks were 65% and 64%, which "compares favorably with the nivolumab monotherapy experience," Dr. Hammers said.

The majority of patients in each study arm had significant reductions in tumor burden of the target lesions, he added.

Of the patients with ongoing responses, 3 of 9 in the N3/I1 arm and 5 of 11 in the N1/I3 arm continued to have responses after discontinuing therapy for reasons other than disease progression.

"This encouraging antitumor activity reported with this combination is the basis for a planned phase III combination trial in the first-line setting for the treatment of metastatic renal cell carcinoma patients," Dr. Hammers said.

‘Gutsy move’

Dr. Primo Lara, professor of medicine at the University of California, Davis, who was the invited discussant, commented that, "at least for now, I think we could say that combination checkpoint blockade in RCC is at least additive, recalling that the single-agent response rate in this disease for nivo[lumab] is about 20%-29%, and for ipi[limumab] is about 13%, and some of these responses are encouragingly durable."

He cautioned, however, that the toxicities with the combined drugs, primarily driven by ipilimumab, "are not inconsequential."

"We heard today that a phase III trial has been initiated, presumably with a lower-dose ipi[limumab] arm, but I think that’s really a gutsy move, considering that there were only 21 patients in that subset of patients that led to this phase III decision. Just a fair warning to everyone that toxicities observed in a phase I trial tend to magnify in a larger phase III when you have more centers, different eligibility criteria, and less experienced folks administering a pretty toxic combination," he said.

The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Hammers has received research funding from BMS. Dr. Lara disclosed serving as a consultant/advisor, and receiving honoraria and research funding from many companies, but not BMS.

CHICAGO – Adding the recently approved stomach cancer drug, ramucirumab (Cyramza) to docetaxel reduced the risk of death in second-line, non–small cell lung cancer by 14% in the phase III REVEL study.

This is the first therapy in roughly a decade to improve the outcome of lung cancer patients in the second-line setting, according to study author Dr. Maurice Perol, head of thoracic oncology at Cancer Research Center of Lyon, France.

In addition, the recombinant human monoclonal antibody showed benefits in nonsquamous carcinoma as well as the squamous subtype, where treatments are limited.

Still, the median survival gain of just 1.4 months did not impress all at the annual meeting of the American Society of Clinical Oncology, where the study was highlighted in a press briefing before its formal presentation.

To hear Dr. Perol wade through the data and controversy, listen to our interview online.

The study was supported by ImClone, a subsidiary of Eli Lilly, which markets ramucirumab. Dr. Perol reported serving as a consultant or adviser with Lilly, Pfizer, Roche, Boehringer Ingelheim, and Genentech.

CHICAGO – Adding the recently approved stomach cancer drug, ramucirumab (Cyramza) to docetaxel reduced the risk of death in second-line, non–small cell lung cancer by 14% in the phase III REVEL study.

This is the first therapy in roughly a decade to improve the outcome of lung cancer patients in the second-line setting, according to study author Dr. Maurice Perol, head of thoracic oncology at Cancer Research Center of Lyon, France.

In addition, the recombinant human monoclonal antibody showed benefits in nonsquamous carcinoma as well as the squamous subtype, where treatments are limited.

Still, the median survival gain of just 1.4 months did not impress all at the annual meeting of the American Society of Clinical Oncology, where the study was highlighted in a press briefing before its formal presentation.

To hear Dr. Perol wade through the data and controversy, listen to our interview online.

The study was supported by ImClone, a subsidiary of Eli Lilly, which markets ramucirumab. Dr. Perol reported serving as a consultant or adviser with Lilly, Pfizer, Roche, Boehringer Ingelheim, and Genentech.

CHICAGO – Adding the recently approved stomach cancer drug, ramucirumab (Cyramza) to docetaxel reduced the risk of death in second-line, non–small cell lung cancer by 14% in the phase III REVEL study.

This is the first therapy in roughly a decade to improve the outcome of lung cancer patients in the second-line setting, according to study author Dr. Maurice Perol, head of thoracic oncology at Cancer Research Center of Lyon, France.

In addition, the recombinant human monoclonal antibody showed benefits in nonsquamous carcinoma as well as the squamous subtype, where treatments are limited.

Still, the median survival gain of just 1.4 months did not impress all at the annual meeting of the American Society of Clinical Oncology, where the study was highlighted in a press briefing before its formal presentation.

To hear Dr. Perol wade through the data and controversy, listen to our interview online.

The study was supported by ImClone, a subsidiary of Eli Lilly, which markets ramucirumab. Dr. Perol reported serving as a consultant or adviser with Lilly, Pfizer, Roche, Boehringer Ingelheim, and Genentech.

CHICAGO – For the first time, researchers have shown that immunotherapy using adoptive T-cell therapy can induce complete remission in metastatic cervical cancer.

The study involved just nine patients given a single infusion of human papillomavirus (HPV)-targeted T cell therapy, but is sparking enormous excitement.

To learn more, watch our interview at the annual meeting of the American Society of Clinical Oncology with lead study author Dr. Christian Hinrichs of the National Cancer Institute.

The study was supported by the National Cancer Institute, National Institutes of Health. The authors reported no financial disclosures.

[email protected]

CHICAGO – For the first time, researchers have shown that immunotherapy using adoptive T-cell therapy can induce complete remission in metastatic cervical cancer.

The study involved just nine patients given a single infusion of human papillomavirus (HPV)-targeted T cell therapy, but is sparking enormous excitement.

To learn more, watch our interview at the annual meeting of the American Society of Clinical Oncology with lead study author Dr. Christian Hinrichs of the National Cancer Institute.

The study was supported by the National Cancer Institute, National Institutes of Health. The authors reported no financial disclosures.

[email protected]

CHICAGO – For the first time, researchers have shown that immunotherapy using adoptive T-cell therapy can induce complete remission in metastatic cervical cancer.

The study involved just nine patients given a single infusion of human papillomavirus (HPV)-targeted T cell therapy, but is sparking enormous excitement.

To learn more, watch our interview at the annual meeting of the American Society of Clinical Oncology with lead study author Dr. Christian Hinrichs of the National Cancer Institute.

The study was supported by the National Cancer Institute, National Institutes of Health. The authors reported no financial disclosures.

[email protected]

CHICAGO – Research demonstrating that immunotherapy can be harnessed to treat metastatic cervical cancer was one of the highlights of the annual meeting of the American Society of Clinical Oncology.

We spoke with gynecologic cancer expert Dr. Don Dizon to learn more about why human papillomavirus-targeted T-cell therapy could work in cervical cancer and if this same cellular-based approach could be used in other virally mediated tumors.

Dr. Dizon is director of the Oncology Sexual Health Clinic at Massachusetts General Hospital Cancer Center in Boston.

He reported having no financial disclosures.

[email protected]

CHICAGO – Research demonstrating that immunotherapy can be harnessed to treat metastatic cervical cancer was one of the highlights of the annual meeting of the American Society of Clinical Oncology.

We spoke with gynecologic cancer expert Dr. Don Dizon to learn more about why human papillomavirus-targeted T-cell therapy could work in cervical cancer and if this same cellular-based approach could be used in other virally mediated tumors.

Dr. Dizon is director of the Oncology Sexual Health Clinic at Massachusetts General Hospital Cancer Center in Boston.

He reported having no financial disclosures.

[email protected]

CHICAGO – Research demonstrating that immunotherapy can be harnessed to treat metastatic cervical cancer was one of the highlights of the annual meeting of the American Society of Clinical Oncology.

We spoke with gynecologic cancer expert Dr. Don Dizon to learn more about why human papillomavirus-targeted T-cell therapy could work in cervical cancer and if this same cellular-based approach could be used in other virally mediated tumors.

Dr. Dizon is director of the Oncology Sexual Health Clinic at Massachusetts General Hospital Cancer Center in Boston.

He reported having no financial disclosures.

[email protected]