Various Immunotherapy Combinations Continue to Be Explored in NSCLC

Daniel E. Haggstrom, MD

Immunotherapy combinations have potential as a treatment approach for patients with non—small-cell lung cancer (NSCLC), as select regimens continue to improve responses and outcomes in a number of clinical trials.

For example, cohort G of the phase II KEYNOTE-021 study investigated the combination of carboplatin/pemetrexed with pembrolizumab (Keytruda), which ultimately led to the FDA approval for this regimen in May 2017. The findings showed that the immunotherapy/chemotherapy combination reduced the risk of progression or death by 50% and nearly doubled objective response rates versus chemotherapy alone.

The median progression-free survival for the combination was not reached versus 8.9 months in the chemotherapy arm at 14.5 months of follow-up. The 12-month overall survival rate with pembrolizumab was 76% compared with 69.3% in the chemotherapy arm.

The future is likely to include similar combinations for patients with NSCLC, experts say.

“We are still searching for the right combinations including immunotherapy for NSCLC,” said Daniel E. Haggstrom, MD. “We have proven efficacy as single agents and in combination with chemotherapy; however, as newer agents are improved, the landscape continues to shift, at times rapidly. In community practice, outside of a clinical trial, it is not yet approved to provide combination therapy with CTLA-4 and PD-1 antibodies for NSCLC, yet adding PD-1 therapy to chemotherapy appears to be superior in patients who can tolerate aggressive upfront treatment and who are PD-L1 negative.”

OncLive: Combination strategies with immunotherapy have shown potential in frontline NSCLC. Could you give an overview?

Can you give examples of some combinations that are particularly compelling?

What significant challenges are researchers facing in combining immunotherapy in NSCLC?

How have the results been with nivolumab (Opdivo) combinations?

In an interview during the 2017 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Haggstrom, a medical oncologist at Levine Cancer Institute, Carolinas HealthCare System, discussed the developing area of immunotherapy combinations for patients with NSCLC. Haggstrom: After first being found effective in cytokine driven malignancies, such as renal cell carcinoma and melanoma, immunotherapy has moved to the forefront in NSCLC therapy. Once the activity against this type of cancer was shown in studies, the idea of using combinations to extend the benefit has become an attractive area of research. Which agents to combine, what classes of drugs for such combinations, and how to administer those with the least amount of toxicity remains a focus of ongoing research. The published data from the KEYNOTE-021 trial, which utilized carboplatin, pemetrexed, and pembrolizumab, showed a significant response compared with chemotherapy alone in patients with NSCLC. Specifically, this data changed how we care for a subset of patients with PD-L1—negative lung cancer, and how it has the potential to shape how combinations are provided for PD-L1–negative or PD-L1–positive patients moving forward.We are finding that if you combine 2 agents, notably CTLA-4 antibody and PD-L1 therapies, there is an increase in the risk of unique immune-related toxicities, such as colitis, rash, and liver function abnormalities. Thus far, such a strategy has not yielded responses clinically to overcome the toxicities encountered. As the class of agents is new, oncologically speaking, all oncologists are having to become aware of the risks and of the presentations of side effects for immunotherapy agents. Nivolumab combinations to date have been largely negative with combining immunotherapy strategies. However, as the market unfolds, we are going to see more of those take the forefront. Unfortunately, the initial portions of the combination with CTLA-4 antibodies and nivolumab were negative and did not meet the criteria to proceed to fast track [designation status]. At this point, the use of nivolumab with a CTLA-4 antibody, such as ipilimumab (Yervoy), is not being done unless it is on a study.

What is the current state of liquid biopsies?

PD-L1 antibodies, such as atezolizumab (Tecentriq) and durvalumab (Imfinzi), might have different molecular characteristics in terms of how they act and function. It is an attractive idea to use those agents when first-line immunotherapy does not work.There are scenarios in which decision making is complicated by inadequate tissue samples present for molecular testing. The science of liquid biopsy is evolving and improving so rapidly, especially in regard to detection of circulating tumor DNA and targetable mutations, such that in the future, the timing of salvage therapy and the selection of that therapy may be accomplished without the risk of repeat biopsy.

What advice can you provide for community oncologists in approaching combinations for their patients?

Is there anything else you would like to add?

In the case of EGFR mutations and specifically T790M mutations, literature suggests that liquid biopsy may replace the need for solid tissue acquisition. As the technology improves, we will see decreased need for repeat biopsies when the appropriate answers and choices can be gleaned serologically.As with any patient with NSCLC, one wants to ensure that the patient has adequate performance status to be challenged with aggressive treatment, and that the tissue or serum analysis supports the frontline choice. It also remains important to enroll patients in trials of combinations for this disease, as the many remaining questions will likely only be answered by such results in the future. At the Levine Cancer Institute, we are dedicated to providing therapy for patients with NSCLC as well as other cancer types. Within the next calendar year, we will be opening a neoadjuvant study of a PD-L1 antibody to be provided in potentially resectable patients which, given their stated efficacy in advanced disease, improving the opportunity for cure in early stage disease is critical.

Papadimitrakopoulou V, Gadgeel SM, Borghaei H, et al. First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: updated results of KEYNOTE-021 cohort G. J Clin Oncol. 2017;35(15 suppl; abstr 9094). doi: 10.1200/JCO.2017.35.15_suppl.9094.