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Numerous ESMO Presentations Focused on Anti–PD-1 Therapy in Lung Cancer and Melanoma


The 2016 European Society for Medical Oncology (ESMO) Congress was jam-packed with studies of the anti–programmed cell death protein 1 (PD-1) antibodies in non–small cell lung cancer and melanoma, where they have clearly changed the treatment paradigm. Here is a roundup of some of those trials, which includes updates of pivotal studies and a peek at what’s to come.

Long-Term Follow-up of COMBI-v Melanoma Trial


These data support the long-term use of dabrafenib plus trametinib as a standard first-line targeted treatment for patients with BRAF V600–mutant metastatic melanoma.
— Caroline Robert, MD, PhD

In the updated 3-year analysis of the COMBI-v trial, first-line dabrafenib (Tafinlar) plus trametinib (Mekinist) yielded an overall survival rate of 45%, vs 31% for vemurafenib (Zelboraf) alone, without an increase in toxicity.1 The study randomized 704 patients with BRAF-mutant treatment-naive advanced melanoma. The 3-year survival results were reported by Caroline Robert, MD, PhD, of Gustave Roussy Comprehensive Cancer Center, Villejuif, France.

Median overall survival was 26.1 months for the combination vs 17.8 months for vemurafenib (hazard ratio [HR] = 0.68). Median progression-free survival was 12.1 months vs 7.3 months (HR = 0.61), with 24% and 10%, respectively, progression-free at 3 years. Approximately half the patients in each arm received immunotherapy post progression.

“Durable benefit was seen regardless of prognostic group but was particularly striking in patients with normal baseline lactate dehydrogenase (LDH),” Dr. Robert indicated. In patients with normal LDH, the 3-year overall survival rate was 56%, and the progression-free survival rate was 33%. Patients with normal LDH and less than 3 metastatic organ sites had a 70% overall survival rate and a 39% progression-free survival rate with the combination. Complete responses were observed in 19% of the doublet arm, with responses prolonged to almost 40 months.

“These data support the long-term use of dabrafenib plus trametinib as a standard first-line targeted treatment for patients with BRAF V600–mutant metastatic melanoma,” Dr. Robert said.

Survival Analysis for Pembrolizumab in Melanoma

In the final overall survival analysis for KEYNOTE-002, which compared pembrolizumab (Keytruda) to chemotherapy in ipilimumab (Yervoy)-refractory melanoma patients, overall survival was prolonged. However, with a 55% crossover rate, the study did not meet the protocol-specified significance threshold (P < .01).2


Pembrolizumab responses continue to be more durable [vs chemotherapy in melanoma], and the safety profile remained favorable for pembrolizumab, with minimal accrual of immune-mediated adverse events since the previous analysis.
— Omid Hamid, MD

Median overall survival was 14.7 months with pembrolizumab at 10 mg/kg (HR = 0.74, P = .0106), 13.4 months with pembrolizumab at 2 mg/kg (HR = 0.86, P = .1173), and 11.0 months with chemotherapy. When censored at crossover, there was a 33% reduction in deaths with the 10-mg/kg dose (P = .0068) and a nonsignificant 21% reduction with the lower dose (P = .0683), reported Omid Hamid, MD, of The Angeles Clinic in Santa Monica, California.At 24 months, median progression-free survival was 21.9% with pembrolizumab at 10 mg/kg (HR = 0.47, P < .0001), 16.0% with pembrolizumab at 2 mg/kg (HR = 0.58, P < .0001), and 0.6% with chemotherapy. Duration of response was still not reached with the higher-dose pembrolizumab and was 22.8 months with 2 mg/kg, compared to 6.8 months with chemotherapy.

“Pembrolizumab responses continue to be more durable, and the safety profile remained favorable for pembrolizumab, with minimal accrual of immune-mediated adverse events since the previous analysis,” Dr. Hamid said.

Updated Survival Data for Nivolumab vs Docetaxel in Second-Line NSCLC

CheckMate 017 and CheckMate 057 found superior survival for nivolumab (Opdivo) over docetaxel in previously treated non–small cell lung cancer (NSCLC), leading to U.S. Food and Drug Administration approval of the agent. Updated results based on a minimum follow-up of 2 years confirmed higher rates of overall survival, progression-free survival, and response in the nivolumab arm.3


Updated results based on a minimum follow-up of 2 years confirmed higher rates of overall survival, progression-free survival, and response in the nivolumab arm [vs docetaxel in NSCLC].
— Fabrice Barlesi, MD, PhD

Median duration of response was at least three times longer with nivolumab. Approximately one-third of nivolumab responders, compared to no patients receiving docetaxel, had ongoing responses after 2 years. Durable responses were observed regardless of programmed cell death ligand 1 (PD-L1) expression level, according to the study presented by Fabrice Barlesi, MD, PhD, of Aix-Marseille University and the Public Assistance Hospital in Marseilles.

Median overall survival in CheckMate 017, which was conducted in squamous cell NSCLC patients, was 9.2 months with nivolumab vs 6.0 with docetaxel (HR = 0.62). In CheckMate 057, which studied patients with nonsquamous histology, median survival was 12.2 vs 9.5 months, respectively (HR = 0.75). Two-year survival rates were 23% vs 8% in squamous histology patients and 29% vs 16%, respectively, in patients with nonsquamous disease.

Ramucirumab Plus Pembrolizumab in NSCLC


We think the data support the continued development of [ramucirumab plus pembrolizumab] in NSCLC.
— Roy S. Herbst, MD, PhD

In a phase I study presented by Roy S. Herbst, MD, PhD, of Yale University School of Medicine, the addition of ramucirumab (Cyramza) to pembrolizumab showed promising clinical activity, including durable responses, in the second- to fourth-line treatment of nonsquamous and squamous NSCLC.4

The combination is based on preclinical studies showing that simultaneous blockade of PD-1 and the vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic antitumor effects. Ramucirumab is a human IgG1 monoclonal antibody VEGFR2 antagonist that has been shown to prolong survival in four phase III studies of NSCLC, gastric/gastroesophageal junction cancer, and colorectal cancer.

The ongoing phase Ia/b study presented at ESMO has enrolled 27 patients with NSCLC, gastric/gastroesophageal junction cancer, urothelial cancer, and biliary tract cancer who had disease progression on systemic therapy. PD-L1 expression was positive (n = 11), negative (n = 10), or unknown (n = 6). Depending on the tumor type, patients received ramucirumab at 8 to 10 mg/kg and pembrolizumab at 200 mg, for up to 35 cycles.

ESMO Reports on Checkpoint Inhibitors

  • In the updated 3-year analysis of COMBI-v in advanced melanoma, dabrafenib plus trametinib yielded an overall survival rate of 45%, vs 31% for vemurafenib alone, with no increase in toxicity.
  • In the final overall survival analysis for KEYNOTE-002 in ipilimumab-refractory melanoma patients, the significance threshold for overall survival was not met due to a 55% crossover rate; however, a numerical advantage was clear. Median overall survival was 14.7 months with pembrolizumab at 10 mg/kg (HR = 0.74; P =.0106) and 11.0 months with chemotherapy.
  • After a minimum of 2 years’ follow-up, median overall survival in CheckMate 017 in NSCLC patients with squamous histology was 9.2 months with nivolumab vs 6.0 with docetaxel (HR = 0.62). In CheckMate 057, which was in patients with nonsquamous histology, median survival was 12.2 vs 9.5 months, respectively (HR = 0.75).
  • In a phase I study, the addition of ramucirumab to pembrolizumab showed promising clinical activity, including durable responses, in the second- to fourth-line treatment of nonsquamous and squamous NSCLC.

A reduction in target lesions among the NSCLC cohort was achieved by 77%, including many patients with PD-L1–negative disease. One PD-L1–negative patient, in fact—a former smoker with adenocarcinoma—had a complete response to the combination as fourth-line treatment. Among the whole study population, median progression-free survival was not reached and did not appear to be compromised by negative PD-L1 expression.

The addition of ramucirumab generated no new safety signals. Grade 3 treatment-related toxicities were low (7%), with no grade 4/5 events.

“We think the data support the continued development of this combination in NSCLC,” Dr. Herbst said. The study protocol has been amended to include a first-line treatment cohort. ■

Disclosure: Dr. Robert has been a consultant for Novartis, Amgen, Bristol-Myers Squibb, Merck, and Roche and has received honoraria from Novartis, Amgen, Bristol-Myers Squibb, Merck, and Roche. Dr. Hamid has served as an advisory board member for Amgen, Novartis, Roche, Bristol-Myers Squibb, and Merck and has been on the speakers bureau for Bristol-Myers Squibb, Genentech, and Novartis. Dr. Barlesi has received honoraria and research funding and has had a consulting/advisory role with Bristol-Myers Squibb. Dr. Herbst has received research funding from Merck and Lilly and has served as an advisory board member for AstraZeneca, Bristol-Myers Squibb, Genentech, Roche, and Lilly.

References

1. Robert C, Karaszewska B, Schachter J, et al: Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib + trametinib in patients with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. 2016 ESMO Congress. Abstract LBA40. Presented October 8, 2016.

2. Hamid O, Puzanov I, Dummer R, et al: Final overall survival for KEYNOTE-002: Pembrolizumab vs investigator-choice chemotherapy for ipilimumab-refractory melanoma. 2016 ESMO Congress. Abstract 1107O. Presented October 8, 2016.

3. Barlesi F, Steins M, Horn L, et al: Long-term outcomes with nivolumab versus docetaxel in patients with advanced non-small cell lung cancer: CheckMate 017 and CheckMate 057 2-year update. 2016 ESMO Congress. Abstract 1215PD. Presented October 9, 2016.

4. Herbst RS, Martin-Liberal J, Calvo E, et al: Interim safety and clinical activity in patients with advanced NSCLC from a multi-cohort phase 1 study of ramucirumab plus pembrolizumab. 2016 ESMO Congress. Abstract LBA38. Presented October 10, 2016.



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