Elsevier

The Lancet Oncology

Volume 20, Issue 8, August 2019, Pages 1109-1123
The Lancet Oncology

Articles
Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial

https://doi.org/10.1016/S1470-2045(19)30458-9Get rights and content

Summary

Background

Pre-clinical and clinical evidence suggests that simultaneous blockade of VEGF receptor-2 (VEGFR-2) and PD-1 or PD-L1 enhances antigen-specific T-cell migration, antitumour activity, and has favourable toxicity. In this study, we aimed to assess the safety and preliminary antitumour activity of ramucirumab (an IgG1 VEGFR-2 antagonist) combined with pembrolizumab (an IgG4 PD-1 antagonist) in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, or urothelial carcinoma.

Methods

We did a multicohort, non-randomised, open-label, phase 1a/b trial at 16 academic medical centres, hospitals, and clinics in the USA, France, Germany, Spain, and the UK. We enrolled adult patients aged 18 years or older with histologically confirmed gastric or gastro-oesophageal junction adenocarcinoma (cohorts A and B), non-small-cell lung cancer (cohort C), or urothelial carcinoma (cohort D), whose disease had progressed on one or two lines of previous therapy (for those with gastric or gastro-oesophageal junction adenocarcinoma) or one to three lines of previous therapy (for those with non-small-cell lung cancer and urothelial carcinoma) that included platinum (for all tumour types) or fluoropyrimidine or both (for gastric or gastro-oesophageal junction adenocarcinoma). Eligibility criteria included presence of measurable disease and an Eastern Cooperative Oncology Group performance status of 0–1. Patients with previously untreated gastric or gastro-oesophageal junction adenocarcinoma and non-small-cell lung cancer were also enrolled (in two additional separate cohorts); the results for these cohorts will be reported separately. The first 21-day treatment cycle was a dose-limiting toxicity observation period (phase 1a; safety run-in), followed by a phase 1b cohort expansion stage. Pembrolizumab 200 mg was administered intravenously on day 1, and intravenous ramucirumab was administered at 8 mg/kg on days 1 and 8 for cohort A or at 10 mg/kg on day 1 for cohorts B, C, and D, every 3 weeks, until disease progression or other discontinuation criteria were met. The primary endpoint was the safety and tolerability of ramucirumab in combination with pembrolizumab assessed by the incidence of adverse events in both phase 1a and 1b and as dose-limiting toxicities during phase 1a. The safety and activity analysis set included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02443324, and is no longer enrolling patients.

Findings

Between July 30, 2015 and June 24, 2016, we enrolled and treated 92 patients (41 with gastric or gastro-oesophageal junction adenocarcinoma, 27 with non-small-cell lung cancer, and 24 with urothelial carcinoma). Median follow-up was 32·8 months (IQR 28·1–33·6). During the first cycle of treatment (phase 1a safety run-in; n=11), one patient with gastro-oesophageal junction adenocarcinoma who received the 8 mg/kg dose of ramucirumab had grade 3 abdominal pain, colitis, hepatitis, interstitial lung disease, and jaundice, and grade 4 cholestasis, and died on treatment on day 40; the death was deemed related to progressive disease. No additional dose-limiting toxicities occurred and the decision was made to maintain the full planned doses of ramucirumab and pembrolizumab in phase 1b (n=81). Treatment-related adverse events occurred in 75 (82%) of 92 patients, the most common of which was fatigue (in 33 patients [36%]), predominantly of grade 1 or 2 severity. 22 patients (24%) had one or more treatment-related adverse events of grade 3 or worse, most commonly hypertension (six patients; 7%) and colitis (five patients; 5%). Serious adverse events occurred in 53 (58%) of 92 patients, and were deemed related to treatment in 22 (24%) patients. The most common treatment-related serious adverse events were abdominal pain in patients with gastric or gastro-oesophageal junction adenocarcinoma (in three [7%] of 41 patients); asthenia and myocardial infarction in patients with non-small-cell lung cancer (two [7%] of 27 patients), and colitis in patients with urothelial carcinoma (two [8%] of 24 patients). Six (7%) of 92 patients discontinued treatment because of treatment-related adverse events, and one death (from pulmonary sepsis in a patient with gastric or gastro-oesophageal junction adenocarcinoma) was deemed related to treatment. The number of patients achieving an objective response was three (7%; 95% CI 1·5–19·9) of 41 in the gastric or gastro-oesophageal junction adenocarcinoma cohort, eight (30%; 13·8–50·2) of 27 in the non-small-cell lung cancer cohort, and three (13%, 2·7–32·4) in the urothelial carcinoma cohort.

Interpretation

Ramucirumab in combination with pembrolizumab showed a manageable safety profile with favourable antitumour activity in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, and urothelial carcinoma. Our results contribute to the growing evidence that supports dual inhibition of the VEGF–VEGFR2 and PD-1–PD-L1 pathways. This combination could be further explored with or without chemotherapy, especially for patients with tumours for which single-agent checkpoint inhibitors have shown no additional benefit over chemotherapy.

Funding

Eli Lilly and Company, and Merck and Co.

Introduction

Tumours can evade T cell-mediated killing through upregulation of PD-L1, which interacts with inhibitory receptor PD-1 expressed on tumour-infiltrating T cells, leading to their functional inactivation. Immune checkpoint inhibitors targeting the PD-L1–PD-1 axis show durable activity in a subset of patients with cancer.1, 2, 3 However, many patients with cancer treated with checkpoint inhibitors have progressive disease as their best response and novel combination treatments are needed. The PD-1 inhibitor pembrolizumab has shown durable antitumour activity in some patients, including those with previously treated advanced non-small-cell lung cancer, gastric or gastro-oesophageal junction adenocarcinomas, and urothelial carcinoma.1, 2, 4

Mechanisms of resistance to checkpoint inhibitors are probably multifactorial and can include an absence of PD-L1, inhibitory effects in the tumour microenvironment, or both. Antiangiogenic therapies targeting VEGF or VEGF receptor-2 (VEGFR-2) can increase trafficking of T cells into tumours and reduce immuno-suppressive cytokines and regulatory T cells, and might help to overcome resistance to checkpoint inhibitors.5, 6 Clinical studies with antiangiogenic drugs in combination with checkpoint inhibitors have shown enhanced antigen-specific T-cell migration, antitumour activity, and a favourable toxicity profile.7, 8, 9, 10, 11, 12, 13 A translational study13 showed that bevacizumab (anti-VEGF) increased antigen-specific T-cell migration and expression of MHC-1 and PD-L1. The addition of atezolizumab to bevacizumab augmented this process and led to deep and durable responses in patients with metastatic renal cell carcinoma.13 A randomised phase 2 trial of this treatment combination showed longer median progression-free survival of 11·7 months (95% CI 8·4–17·3) with first-line bevacizumab plus atezolizumab versus 8·4 months (7·0–14·0) with sunitinib in patients with metastatic renal cell carcinoma.9 In a phase 3 study,11 combining the antiangiogenic drug axitinib with pembrolizumab in patients with metastatic renal cell carcinoma improved progression-free survival and objective response, compared with sunitinib (median progression-free survival 15·1 months with pembrolizumab–axitinib vs 11·1 months with sunitinib [HR for disease progression or death 0·69, 95% CI 0·57–0·84; p<0·001]; proportion of patients achieving an objective response was 59·3%, 95% CI 54·5–63·9 with pembrolizumab–axitinib and 35·7%, 31·1–40·4 with sunitinib group; p<0·001). Furthermore, the boosting effects of bevacizumab on atezolizumab in combination with chemotherapy have been noted in patients with non-small-cell lung cancer, suggesting clinical effectiveness of combining antiangiogenics with checkpoint inhibitors.12

Research in context

Evidence before this study

Before trial enrolment began, we searched PubMed, the abstracts of the American Society of Clinical Oncology and European Society for Medical Oncology congresses, and ClinicalTrials.gov with the terms “carcinoma”, “cancer”, “immune checkpoint inhibitor”, “anti-PD-1”, “anti-PD-L1”, “trials”, “clinical trials”, “VEGF”, and “VEGFR-2” for preclinical reports and clinical trials published in English up to Jan 1, 2015 with no restrictions on the earliest date. We identified reports showing that immune checkpoint inhibitors targeting the PD-L1–PD-1 axis have durable activity in various subsets of patients with cancer, although many patients treated with checkpoint inhibitors had progressive disease as their best response. Much evidence suggests that mechanisms of resistance to checkpoint inhibitors are probably multifactorial, and could potentially be overcome through the addition of anti-angiogenic therapies targeting VEGF or VEGF receptor-2 (VEGFR-2). Preclinical studies provided evidence for a synergistic antitumour effect from blocking VEGFR2 and PD-1 simultaneously in a murine colon cancer model, with this dual blockade inhibiting tumour growth significantly compared with each treatment, individually. Furthermore, in two clinical studies in patients with metastatic colorectal cancer and melanoma, the combination of bevacizumab (anti-VEGF) and immune checkpoint blockade was well tolerated with no unexpected toxicities.

Added value of this study

Our study combined ramucirumab (a VEGFR2 antagonist) and pembrolizumab (a PD-1 antagonist) to simultaneously target both the angiogenesis or tumour microenvironment and immune checkpoint inhibition in biomarker-unselected patients with previously treated advanced non-small-cell lung cancer, gastric or gastrooesophageal junction adenocarcinoma, and urothelial carcinoma. The combination of ramucirumab and pembrolizumab showed a manageable safety profile, with no indication that ramucirumab potentiates pembrolizumab toxicity (or vice versa), and full doses of each individual drug could be administered in combination. Efficacy endpoints in our study showed favourable outcomes compared with immune checkpoint inhibitor monotherapy in other studies.

Implications of all the available evidence

Our results contribute to the growing evidence that supports dual inhibition of the VEGF–VEGFR2 and PD-1–PD-L1 pathways in patients with previously treated advanced or metastatic cancer. Given its manageable safety profile and clinical activity, this combination could be explored in future trials either with or without chemotherapy, especially in patients with tumours for which single-agent immune checkpoint inhibitors have shown no additional benefit to chemotherapy.

After initial treatment with cytotoxic chemotherapy, persistent toxicities can affect the ability of many patients with cancer to receive second-line therapy; in some tumour types, such as gastric or gastro-oesophageal junction adenocarcinomas, up to 50% of patients do not receive second-line therapy.14 In these patients, there is an unmet need for possible chemotherapy-free options with similar activity to standard chemotherapeutic regimens but improved toxicity profiles.

Ramucirumab is an IgG1 monoclonal antibody that binds to the extracellular domain of VEGFR2 and has shown antitumour activity in phase 3 trials,15, 16, 17, 18 as monotherapy or in combination with chemotherapy, for several tumour types including non-small-cell lung cancer, gastric or gastro-oesophageal junction adenocarcinomas, and urothelial carcinomas. Here, we describe results from the JVDF study, a phase 1 trial of ramucirumab with pembrolizumab for patients with previously treated advanced solid tumours. We reported results for patients with previously treated advanced or metastatic biliary tract cancer separately; our results showed that the combination showed no unexpected safety findings but did not improve overall survival when compared with historical controls.7 Results for ongoing cohorts of untreated non-small-cell lung cancer and gastric or gastro-oesophageal junction adenocarcinoma will be reported separately. Here, we report results for patients with previously treated non-small-cell lung cancer, gastric or gastro-oesophageal junction adenocarcinomas, and urothelial carcinomas.

Section snippets

Study design and participants

We did the multicohort, non-randomised, open-label, phase 1a/b JVDF trial at 16 academic medical centres, hospitals, and clinics in the USA, France, Germany, Spain, and the UK. We enrolled adult patients aged at least 18 years with histologically confirmed gastric or gastro-oesophageal junction adenocarcinomas (cohorts A and B; no differences in criteria between these two cohorts), non-small-cell lung cancer (cohort C), or urothelial carcinoma (cohort D); unresectable or metastatic disease; and

Results

Between July 30, 2015, and June 24, 2016, 138 patients were screened, of whom 46 were excluded (figure 1). 92 eligible patients were assigned to receive study treatment (11 in phase 1a, 81 in phase 1b); 41 with gastric or gastro-oesophageal junction adenocarcinoma (24 in cohort A, 17 in cohort B), 27 with non-small-cell lung cancer, and 24 with urothelial carcinoma. Baseline demographic and disease characteristics are summarised in table 1 (with additional detail on previous treatments shown in

Discussion

In 92 patients with advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (second-line to thirdline), non-small-cell lung cancer (second-line to fourthline), or urothelial carcinoma (second-line to fourthline), ramucirumab in combination with pembrolizumab showed no unexpected safety findings. The most common toxic effects were of grade 1 or 2 severity and were manageable with supportive care or with dose reductions or delays, with few patients discontinuing treatment

Data sharing

Eli Lilly provides access, after anonymisation, to all individual participant data collected during the trial, except for pharmacokinetic and genetic data. Data can be requested 6 months after the indication studied has been approved in the USA and EU or after primary publication acceptance, whichever is later. No expiration date for data requests is set once the data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this

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