New classes of immunotherapies emerging in lung cancer are building on previous success with PD-1/PD-L1 inhibitors.
Suresh S. Ramalingam, MD
The PD-1/PD-L1 inhibitors now available are merely the first step in what is likely to be a very exciting time for treatment advances in the field of non—small cell lung cancer (NSCLC), according to Suresh S. Ramalingam, MD.
“Besides PD-L1, we are beginning to see data from some of the agents that block other aspects of the immune checkpoint pathway,” said Ramalingam, professor of Hematology and Medical Oncology, assistant dean for Cancer Research, Emory University School of Medicine, deputy director, Winship Cancer Institute. “We have some combination data and some single-agent data. It’s early, but there are interesting responses and promise with these combinations that, in the next year, are going to be talked about and tested a lot.”
Ramalingam spoke about these novel agents, including indoleamine 2,3-dioxygenase (IDO) pathway inhibitors and OX40 and CD27 agonists, during his lecture at the 2016 International Lung Cancer Conference.
Nivolumab and Pembrolizumab are the 2 available anti—PD-1 immunotherapy agents in the field.
Nivolumab (Opdivo) is FDA approved for patients with nonsquamous NSCLC who progress on or following platinum-based chemotherapy, or EGFR- or ALK-targeted agents in patients with these mutations. For patients with squamous cell NSCLC, nivolumab is approve for patients who have progressed on or after platinum-based chemotherapy.
Pembrolizumab (Keytruda) is approved by the FDA as a treatment for patients with advanced NSCLC across all histologies whose tumors express PD-L1. The indication is for patients who progressed on or after platinum-containing chemotherapy or EGFR-or ALK-targeted agents in patients harboring those mutations.
Researchers are now looking to build upon these successes.
“We are going to have to find multiple ways to activate the immune signals,” he said. “The agents that are going to be studied in combination are first tested as monotherapy, [for example] the IDO-1 and IDO-2 inhibitors and a couple of other agents, such as CD27 agonists.”
Combination regimens being studied include the IDO-1 inhibitor epacadostat plus pembrolizumab, which, in the phase I/II KEYNOTE-037 trial, demonstrated an overall response rate (ORR) of 53% across cohorts of patients with NSCLC, melanoma, renal cell carcinoma (RCC), transitional cell carcinoma, endometrial adenocarcinoma, and squamous cell carcinoma of the head and neck.1 In the NSCLC cohort, 1 patient had a partial response and 1 had stable disease.
The most common grade 3 adverse events (AEs) observed with the combination were rash, arthralgia, aspartate aminotransferase increased, mucosal inflammation, and nervous system disorder. Three patients discontinued treatment due to AEs, but there were not any grade 4 treatment-related AEs or deaths with the combination.
Additionally, OX40 agonists are being explored in the field, Ramalingam said. Most recently, phase I data of the OX40 agonist MOXR0916 plus the PD-L1 inhibitor atezolizumab (Tecentriq) in patients with advanced solid tumors were presented at the 2016 ASCO Annual Meeting.2 Results showed that following OX40 activation, PD-L1 induction was observed in the tumor biopsy, but further evaluations are ongoing.
Pembrolizumab was combined with the 4-1BB agonist utomilumab (PF-05082566) in a phase Ib dose-escalation study for patients with advanced solid tumors.3 The regimen was found to be safe and effective, with a 26% ORR among 23 patients. This included 2 complete responses, which were experienced by patients with small cell lung cancer and RCC.
“It seems that if patients have PD-L1 expression, OX40 activates T cells and when you give a PD-L1 inhibitor, there seems to be a higher response,” said Ramalingam. “It’s the same thing with 4-1BB agonists—it’s a very costimulatory pathway. There are a handful of compounds in this space, as well. They are certainly being studied as monotherapy in various settings, but they are also studied in combination with PD-1/PD-L1 drugs.”
“The nice thing about all of these combinations is that they seem to be tolerated very well,” said Ramalingam. “You don’t even see any dose-limiting toxicities with some of these combinations; it has been very encouraging.”
However, the biggest challenge with these novel immunotherapy agents will be determining a biomarker, said Ramalingam.
“We are still trying to understand how to best select patients for PD-1 inhibitors, and now we’re talking about combinations that have a slightly different spectrum of sensitivity in all patient characteristics,” he added. “Looking at which patients will benefit from combination ‘A’ versus combination ‘B’ is going to be the next set of challenges.”
Ramalingam said it is likely that these newer antibodies will not compete with, but complement, the efficacy of PD-1/PD-L1 inhibitors. However, he added, it should be noted that these developments should not alter the roles of targeted therapies and chemotherapy.
“We are not curing lung cancer,” Ramalingam said. “We have patients with a variety of biological characteristics. For a patient with an EGFR mutation, EGFR inhibitors still remain the best treatment option. We have some exciting developments in that area with a newer generation of targeted drugs. It’s the same thing with ALK-positive disease. We have seen some great positioning of the agents that could result in better outcomes for patients. Targeted therapies are going to be critical for patients with driver mutations. For patients who do not have driver mutations, or have certain driver mutations such as KRAS, where we don’t have good treatment options, chemotherapy and immunotherapy will continue to play a role. We will still use all of these drugs.”
In his concluding remarks, Ramalingam said that having more patients enrolled on the clinical trials to receive these novel agents is key.
“The more we enroll patients to these combination trials, the sooner we will know how they fit in with this treatment paradigm,” he said.
In a phase I study, the CD27 agonist varlilumab, a fully human agonist IgG1k antibody, is being studied in combination with nivolumab in patients with advanced refractory solid tumors, including NSCLC (NCT02335918).