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
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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This study (HARMONi-5) aimed to evaluate the safety and efficacy of ivonescimab (a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor) as first- or second-line monotherapy in patients with advanced immunotherapy-naive NSCLC.
Eligible patients received intravenous ivonescimab 10 mg/kg every 3 weeks (Q3W), 20 mg/kg every 2 weeks (Q2W), 20 mg/kg Q3W, or 30 mg/kg Q3W. The primary end points were safety and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1.
At data cutoff (October 5, 2022), 108 patients were enrolled and received ivonescimab. Programmed death ligand-1 tumor proportion score (TPS) was greater than or equal to 1% in 74 patients (68.5%), including 35 (32.4%) with TPS greater than or equal to 50%. The median follow-up was 10.4 months (range: 8.4–10.9 mo). For all patients, ORR and disease control rate were 39.8% and 86.1%, respectively. ORR by TPS was 14.7%, 51.4%, and 57.1% in patients with TPS less than 1%, greater than or equal to 1%, and greater than or equal to 50%, respectively. In the 67 programmed death ligand-1–positive patients receiving first-line ivonescimab, the ORR was 33.3%, 52.6%, 60.0%, and 75.0% at the doses of 10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W, and 30 mg/kg Q3W, respectively. Grade greater than or equal to 3 treatment-related adverse events (TRAEs) were observed in 24 patients (22.2%). TRAEs leading to treatment discontinuation occurred in one patient (0.9%). TRAEs leading to death occurred in three patients (2.8%) with squamous NSCLC. The occurrence of grade greater than or equal to 3 TRAEs and grade greater than or equal to 3 bleeding events in squamous versus nonsquamous NSCLC patients was 25.5% versus 18.9% and 0.0% versus 1.9%, respectively.
Ivonescimab monotherapy was well tolerated and found to have a promising efficacy in patients with advanced or metastatic NSCLC. ClinicalTrials.gov identifier: NCT04900363.
Cholangiocarcinoma (CCA) is a highly aggressive hepatobiliary malignancy, second only to hepatocellular carcinoma in prevalence. Despite surgical treatment being the recommended method to achieve a cure, it is not viable for patients with advanced CCA. Gene sequencing and artificial intelligence (AI) have recently opened up new possibilities in CCA diagnosis, treatment, and prognosis assessment. Basic research has furthered our understanding of the tumor-immunity microenvironment and revealed targeted molecular mechanisms, resulting in immunotherapy and targeted therapy being increasingly employed in the clinic. Yet, the application of these remedies in CCA is a challenging endeavor due to the varying pathological mechanisms of different CCA types and the lack of expressed immune proteins and molecular targets in some patients. AI in medical imaging has emerged as a powerful tool in this situation, as machine learning and deep learning are able to extract intricate data from CCA lesion images while assisting clinical decision making, and ultimately improving patient prognosis. This review summarized and discussed the current immunotherapy and targeted therapy related to CCA, and the research progress of AI in this field.
Colorectal cancer (CRC) is the third most prevalent cancer in the world. The PD-1/PD-L1 pathway plays a crucial role in modulating immune response to cancer, and PD-L1 expression has been observed in tumor and immune cells within the tumor microenvironment of CRC. Thus, immunotherapy drugs, specifically checkpoint inhibitors, have been developed to target the PD-1/PD-L1 signaling pathway, thereby inhibiting the interaction between PD-1 and PD-L1 and restoring T-cell function in cancer cells. However, the emergence of resistance mechanisms can reduce the efficacy of these treatments. To counter this, monoclonal antibodies (mAbs) have been used to improve the efficacy of CRC treatments. mAbs such as nivolumab and pembrolizumab are currently approved for CRC treatment. These antibodies impede immune checkpoint receptors, including PD-1/PD-L1, and their combination therapy shows promise in the treatment of advanced CRC. This review presents a concise overview of the use of the PD-1/PD-L1 blockade as a therapeutic strategy for CRC using monoclonal antibodies and combination therapies. Additionally, this article outlines the function of PD-1/PD-L1 as an immune response suppressor in the CRC microenvironment as well as the potential advantages of administering inflammatory agents for CRC treatment. Finally, this review analyzes the outcomes of clinical trials to examine the challenges of anti-PD-1/PD-L1 therapeutic resistance.
Cabozantinib is approved for previously treated advanced hepatocellular carcinoma (aHCC) and has been investigated in gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJ). Atezolizumab plus bevacizumab is approved for unresectable or metastatic HCC untreated with prior systemic therapy. We evaluated efficacy and safety of cabozantinib plus atezolizumab in aHCC previously untreated with systemic anticancer therapy or previously treated GC/GEJ.
COSMIC-021 (ClinicalTrials.gov, NCT03170960) is an open-label, phase 1b study in solid tumours with a dose-escalation stage followed by tumour-specific expansion cohorts, including aHCC (cohort 14) and GC/GEJ (cohort 15). Eligible patients were aged ≥18 years with measurable locally advanced, metastatic, or recurrent disease per RECIST version 1.1. Patients received oral cabozantinib 40 mg daily and intravenous atezolizumab 1200 mg once every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1.
Patients were screened between February 14, 2019, and May 7, 2020, and 61 (30 aHCC, 31 GC/GEJ) were enrolled and received at least one dose of study treatment. Median duration of follow-up was 31.2 months (IQR 28.5–32.7) for aHCC and 30.4 months (28.7–31.9) for GC/GEJ. Objective response rate was 13% (4/30, 95% CI 4–31) for aHCC and 0% (95% CI 0–11) for GC/GEJ. Six (20%) aHCC patients and three (10%) GC/GEJ patients had treatment-related adverse events resulting in discontinuation of either study drug.
Cabozantinib plus atezolizumab had clinical activity with a manageable safety profile in aHCC previously untreated with systemic anticancer therapy. Clinical activity of cabozantinib plus atezolizumab was minimal in previously treated GC/GEJ.
Immune monotherapy as second-line treatment confers only modest survival benefit on non-small cell lung cancer (NSCLC) patients with no mutated driver genes, necessitating combination treatment strategies. This phase Ib trial investigated the efficacy and safety of anti-PD-L1 antibody TQB2450 plus antiangiogenic drug anlotinib for NSCLC.
Pretreated stage IIIB or IV NSCLC patients with wild-type EGFR/ALK and minimally one measurable lesion were randomized 1:1:1 to receive TQB2450 1200 mg plus placebo, or TQB2450 1200 mg plus anlotinib 10 or 12 mg. The primary outcome was progression-free survival (PFS) and the secondary outcomes included objective response rate (ORR).
Thirty-three patients received TQB2450 plus placebo and 34 patients each received TQB2450 plus anlotinib 10 mg and 12 mg. At the data cutoff, the median PFS was 8.7 months (95% CI 6.1–17.1) in the TQB2450 plus anlotinib group and 2.8 months (95% CI 1.4–4.7) in the TQB2450 only group. The ORR reached 30.9% (95% CI 20.2%-43.3%) in the TQB2450 plus anlotinib group and was 3.0% (95% CI 0.1%-15.8%) in the TQB2450 only group. In patients with PD-L1 ≥ 1%, the ORR was 50.0% (95% CI 33.4%-66.6%) for TQB2450 plus anlotinib and 5.3% (95% CI 0.1%-26.0%) for TQB2450 plus placebo. No new safety signals were observed.
Anlotinib plus TQB2450 demonstrated promising antitumor activities in advanced NSCLC patients without EGFR and ALK alterations and the toxicities were overall manageable. The study findings support the continued development of TQB2450 plus anlotinib for advanced NSCLC patients without driver gene alterations.
Immune checkpoint inhibitors (ICIs) with angiogenesis inhibitors have been used to treat advanced lung cancer. Their associated treatment-related adverse events (trAEs) are currently considered acceptable; however, no conclusion has been reached. We aimed to summarize the trAEs caused by ICIs combined with angiogenesis inhibitors in patients with advanced lung cancer.
Pulled studies met the following criteria: patients with advanced lung cancer who received treatment involving ICIs combined with angiogenesis inhibitors (with or without chemotherapy) in interventional or observational studies. Results included the type and number of trAEs or immune-related adverse events (irAEs), treatment-associated discontinuation and mortality, overall survival (OS), and progression-free survival (PFS). PROSPERO: CRD42022337656.
The study enrolled 32 trials involving 2313 patients who had 7768 any-grade trAEs and 1078 grade ≥3 trAEs. The pooled incidences were 87.33% (95% confidence interval [CI]: 79.49–93.65; I2 = 94.04%) for any-grade trAEs, and 38.63% (95% CI: 28.28–49.50; I2 = 95.61%) for grade ≥3 trAEs. There were 132 kinds of any-grade trAEs involving 18 systems, and 99 kinds of grade ≥3 trAEs involving 16 systems. For all trAEs, we observed significant differences in the line of therapy, trial design, therapy combination, and types of angiogenesis inhibitors (all P < 0.05). The rate of trAEs increased with dosage and frequency of medication. Pooled incidences of discontinuation and mortality were 10.64% and 0.81%, respectively. Nearly 647 patients experienced irAEs, including 636 any-grade irAEs and 154 grade ≥3 irAEs.
Overall, the incidence of trAEs caused by ICIs combined with angiogenesis inhibitors is generally acceptable. These trAEs have a wide spectrum nearly covering the full range of adverse events. Grade ≥3 trAEs are more closely associated with angiogenesis inhibitors than any grade. However, treatment-associated mortality remains concerning.