Ramucirumab in combination with pembrolizumab shown to be promising in lung cancer

“I think we have a cocktail here in lung cancer that is worthy of further study,” said Professor Roy Herbst, study lead investigator, and Chief of Medical Oncology, Yale Cancer Center, New Haven, US.

“When I began my career in lung cancer, 20 years ago, I would never have thought we would not use chemotherapy frontline.” Professor Roy Herbst, Chief of Medical Oncology, Yale Cancer Center, New Haven, US.

The addition of ramucirumab to pembrolizumab did not generate any new safety signals and showed a 30% response rate in NSCLC.

Ramucirumab is a human IgG1 monoclonal antibody, vascular endothelial growth factor receptor-2 (VEGFR-2) antagonist. Ramucirumab has shown prolonged survival used either as monotherapy or in combination in gastric/ gastroesophageal junction cancer, colorectal cancer and NSCLC. The Food and Drug Association has already approved ramucirumab in combination with docetaxel for the treatment of metastatic NSCLC disease progression on or after platinum-containing chemptherapy.

In this early study, ramucirumab was combined with the anti-PD-1 agent, pembrolizumab, a drug that has already shown striking results in other tumour types including bladder and lung cancer which were also part of this multi-cohort study.

Professor Herbst recounted that preclinical data suggested modulating VEGF recruits T cells to a tumour and improves their activation. “These are all things that are needed for a positive immune response.”

“This trial is trying to improve use of immunotherapy even more by looking at combinations that aim to improve immunotherapy in those already benefiting, as well as expanding to new populations,” he clarified.

The majority of patients with NSCLC have advanced or metastatic disease at diagnosis. “We know that pembrolizumab has some activity in this group of patients, and it works best in those with a high PD-L1 standing in the tumour,” Professor Herbst pointed out. “We also know that ramucirumab has activity in combination with chemotherapy. The question we asked here was if we combined the two together, would we see any activity in combination versus activity of either drug alone?”

The study enrolled patients with a variety of cancers: gastric or gastroesophageal junction (G/GEJ), NSCLC, urothelial carcinoma (UC) or biliary tract cancer (BTC) following progression on systemic therapy. “The aim was a phase I/II design to figure out the dose required first and then to expand to a cohort of 30 lung cancer patients, to look for early signs of efficacy,” said Professor Herbst.

During the phase Ib cohort expansion part of the study, patients with NSCLC (n=155) received ramucirumab 10 mg/kg, on day 1, and pembrolizumab 200 mg fixed, on day 1. Both therapies were given intravenously every 3 weeks.

The primary endpoint was to define safety and tolerability of adding ramucirumab to pembrolizumab; the secondary endpoints included pharmacokinetics and preliminary efficacy. Biomarkers and immunogenicity were exploratory endpoints. Response was assessed every 6 weeks for the first 24 weeks and was measured every 12 weeks thereafter according to RECIST (Response Evaluation Criteria In Solid Tumours) 1.1 and ir (immune related) RECIST criteria.

Professor Herbst presented results of safety and early efficacy data. He reinforced that it was early and hard to conclude much from a single arm study. “That said, the response rate in these 27 patients was 30%, and the stability and disease control rate added in made an 85% disease control rate. The median PFS [progression-free survival] in these heavily pre-treated lung cancer patients, third-, fourth- and fifth-line patients, the median was not reached.” Median time to response was 1.5 months.

Regarding adverse events, treatment-emergent adverse events of grade 3-4 status numbered six, and there were two (7%) treatment-related adverse event of grade 3-4. There was one endocrine disorder (hypothyroidism) and one infusion related reaction.

Professor Herbst gave his considered opinion of the potential impact of the combination in NSCLC. “My sense is that there is activity here, could it need patient selection? Absolutely. Does it need a phase II trial to compare it to? Absolutely. But clearly with the safety presented that wasn’t much more than the two drugs alone, I think there is a viable combination to move forward.”

“It’s an interesting time, the fact that immunotherapy works amazingly well in 25% of lung cancer,” remarked Professor Herbst. “When I began my career in lung cancer, 20 years ago, I would never have thought we would not use chemotherapy frontline.”

He continued by saying that the challenge now was to determine how to improve the response to pembrolizumab, and for the 70% of patients that do not get immunotherapy, “we also need to consider patients who develop resistance to immunotherapy and this combination is one step in this direction.”

Based on Gronchi A, Ferrari S et al. Full-dose neoadjuvant anthracycline + ifosfamide chemotherapy is associated with a relapse free survival (RFS) and overall survival (OS) benefit in localized high-risk adult soft tissue sarcomas (STS) of the extremities and trunk wall: Interim analysis of a prospective randomized trial (LBA6_PR). Presented on Monday 10 October 2016.

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