Promising Results With Combination Immunotherapies, but Biomarkers Elusive

As immunotherapy—particularly the checkpoint inhibitors—continues to show promise in solid as well as liquid tumors, clinicians have been evaluating the efficacy of these agents in combination, to improve efficacy and outcomes. During a session on the second day of the ongoing annual meeting of the American Society of Clinical Oncology, in Chicago, IL, the results from some of these trials were shared. Some of the questions that were addressed during the session included

• How do we use these increasing number of next-generation checkpoint inhibitors?
• How do we use them in combination with vaccines, radiation, chemotherapy, and other modalities?
• Do we need investigate biomarkers beyond the programmed death ligand-1 (PD-L1) expression?

Combining nivolumab and ipilimumab in SCLC

Scott Joseph Antonia, MD, PhD, chair, Department of Thoracic Oncology Department and program leader of the Immunology Program, H. Lee Moffitt Cancer Center, discussed results of the CheckMate 032 trial, in which the programmed death-1 (PD-1) receptor inhibitor, nivolumab, was used alone or combined with ipilimumab for the treatment of recurrent small cell lung cancer (SCLC).¹

More than a year back, nivolumab was approved in the United States for the treatment of patients who have progressed on their treatment for metastatic non-small cell lung cancer (NSCLC), but was rejected by the National Institute for Health and Care Excellence, or NICE, for patients with advanced NSCLC. Antonia said that there’s been trivial progress with SCLC, which he described as being a very stubborn disease. While majority of patients respond to frontline chemotherapy, a majority of them relapse and then the response rates for the next line of treatment plummets.

Antonia said that CheckMate 032 was designed to evaluate nivolumab +/- ipilimumab in advanced tumors including SCLC. Eligibility criteria for trial participation was advanced SCLC with progressive disease after 1 or more platinum-based chemotherapy, regardless of platinum sensitivity or tumor PD-1 ligand 1 (PD-L1) expression. The primary endpoint of the trial was objective response rate (ORR), with secondary endpoints of safety, overall survival (OS), progression-free survival (PFS), and biomarkers. The 216 patients enrolled in the trial were divided into 3 cohorts:

• 98 patients were treated with nivolumab alone, at a dose of 3 mg/kg (N3)
• 61 patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg (N1/I3)
• 54 patients were treated with nivolumab 3 mg/kg and ipilimumab 1 mg/kg (N3/I1).

Based on the data presented, a majority of the patients in each cohort expressed less than 1% PD-L1. Additionally, 59% of patients in the nivolumab-alone cohort, 48% in the N1/I3 cohort, and 58% in the N3/I1 cohort had received 2 or more prior lines of treatment.

Antonia showed toxicity data for the trial, saying that toxicity was greater in the combination arms. “Three treatment-related deaths were observed among the 114 patients treated with the combination therapy. However, patients were willing to remain on their treatment despite the toxicity,” he said. Response rates doubled with the combination therapy, including in platinum-resistant patients. Majority of the responders had a rapid response, which was also durable, and response was independent of PD-L1 expression. Antonia said that PD-L1 negative patients responded just as well. Median OS, he showed, was 7.7 months for the N1/I3 cohort and 6 months for the N3/I1 cohort—significantly greater than the 4 months observed in patients treated with nivolumab alone. Further, the 1-year OS rate was:

• 33% in the single-drug arm
• 43% in the N1/I3 arm
• 35% in the N3/I1 arm.

Antonias concluded that the survival rates are encouraging from this early study. Safety profile observed in the CheckMate 032 trial for SCLC was similar to that observed in other diseases treated with the combination, which of course showed higher rates of adverse events (AEs). Dose expansion trials and studies in combination with other agents are ongoing, which include:

• CheckMate 032 expansion study in 250 patients
• CheckMate 331, nivolumab versus chemotherapy (topotecan or amrubicin) in patients with relapsed SCLC
• CheckMate 451 nivolumab vs N1/I3 vs placebo in patients with extensive SCLC following platinum-based first-line.

Based on the results of this study, nivolumab 1 mg/kg and ipilimumab 3 mg/kg was the dose of choice for a phase 3 study with this combination in SCLC patients.

Combining PD-L1 inhibitors with OX40 agonists

Jeffrey R. Infante, MD, director of the drug development program at Sarah Cannon Research Institute presented a phase lb dose escalation study of an OX40 receptor agonist in combination with a PD-L1 inhibitor in patients with advanced solid tumors.

OX40 agonists, Infante said, have a dual mechanism of action: they inhibit regulatory T cells and co-stimulate effector T cells. This can definitely be complemented by the PD-L1 inhibition. Being a phase 1 study, the primary objective of their trial was to evaluate the safety and tolerability of combining the PD-L1 inhibitor atezolizumab, with the OX40 inhibitor MOXR0916. MOXR0916 is a humanized effector-competent agonist IgG1 monoclonal antibody. The secondary objectives were to come up with a phase 2 dose, pharmacokinetics and immunogenicity, and preliminary efficacy. The trial also attempted to identify any biomarkers.

A total of 51 patients were enrolled in the study, with a median age of 58 years. The most common tumor types were NSCLC, renal cell carcinoma (RCC), ovarian, GE junction, and soft tissue sarcoma. A log of whether patients had received prior treatment with an anti—PD-1 or anti–PD-L1 agent, was also maintained. A 3+3 dose-escalation was conducted with a 21-day window to evaluate dose-limiting toxicity (DLT). Escalating doses of MOXR0916 in combination with a fixed 1200 mg dose of atezolizumab were administered every 3 weeks. An expansion cohort to enable immune profiling of serial tumor biopsies was also enrolled. Prior immunotherapy with adequate washout was allowed if there was no history of grade 3 or greater immune-mediated adverse events (AEs).

Infante said that the combination was well tolerated overall, with no DLT, deaths, or grade 4 or higher toxicity. A grade 3 pneumonitis in 1 patient could be controlled with antibiotics and steroids. “No truly dose-dependent AE was observed,” he concluded.

The current expansion regimen, he said, is MOXR0918 at 300 mg, in combination with atezolizumab 1200 mg, every 3 weeks. Significantly, the study did observe PD-L1 modulation in patients who had had immediate prior therapy with single agent anti-OX40 or anti—PD-1.

Efficacy studies, Infante said, are ongoing for the combination in melanoma, RCC, NSCLC, urothelial carcinoma, and triple-negative breast cancer.

Dr Wolchok’s comments

Commenting on the 2 studies, Jedd D. Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, was quite excited ith the results. But he said that questions remain. “We need additional numbers on patients,” he said, adding, and further information on the nature of the response. “Is the response deeper with the combination treatment? Information on the PD-L1 status in each group is also important to understand, Wolchok said. “We also need studies that evaluate other agents for combination studies.”

With respect to the OX40 study, Wolchok said that lab-based studies have shown a 100% survival response in mice treated with an OX40 agonist with azetolizumab. He was quite impressed by the biomarker analysis done by the study group, evaluating the upregulation of PD-L1. “OX-40 is a potentially promising agent,” Wolchok concluded.