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Various Immunotherapy Combinations Continue to Be Explored in NSCLC

Danielle Bucco
Published: Thursday, Dec 28, 2017

Daniel E. Haggstrom, MD
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.”

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. 

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

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. 

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

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.

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

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. 

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

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. 


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