Immunotherapy Combinations Continue to Deliver in Lung Cancer

Immunotherapy combinations are inducing higher and more durable responses for patients with non-small cell lung cancer (NSCLC), sparking excitement in the oncology community.

The large, phase 2 KEYNOTE-021 study has been of particular interest in the field, as findings from cohort G of the trial led to the accelerated approval of Keytruda (pembrolizumab) in combination with carboplatin and pemetrexed. Results with this regimen showed significantly higher response rates. Moreover, the combination reduced the risk of progression or death by 50 percent and nearly doubled objective response rates (ORR) compared with chemotherapy alone.

Following 14.5 months of follow-up, the median progression-free survival in the Keytruda arm was not reached compared with 8.9 months with the chemotherapy arm. The 12-month overall survival (OS) rate with Keytruda was 76 percent compared with 69.3 percent for those treated with chemotherapy.

“Pembrolizumab is being tested with chemotherapy but almost all agents are, such as atezolizumab (Tecentriq), nivolumab (Opdivo) and durvalumab (Imfinzi),” noted Jyoti D. Patel, M.D.

Can you discuss your recent presentation on combination trials with immunotherapy in patients with lung cancer?

What are some combination strategies that you find particularly interesting?

In an interview with CURE, Patel, professor of medicine, director of thoracic oncology, the University of Chicago Medicine, discussed ongoing research investigating immunotherapy in combination with chemotherapy for patients with NSCLC. We have seen dramatic responses in subsets of patients with checkpoint blockade, particularly with the PD-1/PD-L1 axis. However, only about 20 percent of patients achieve responses. Efforts are now looking at how to bring this therapy to a broader subset of patients. We need to understand whether we can use dual-checkpoint inhibition to improve outcomes for tumors that may not be inflamed. [We also need to] better understand how to add immunotherapy to chemotherapy to give a greater number of patients a chance at response.The idea of upfront treatment with chemotherapy plus immunotherapy has been exciting. There is a scientific basis for this, as we see increased toxicity and neoantigen presentation. This is an area that people have been following since the inception of PD-1 blockade.

There are many ongoing trials, such as some large phase 3 trials. The most compelling data we have that have come to the clinical arena are the combination of Keytruda with carboplatin and pemetrexed. This is a subset analysis of a large study called KEYNOTE-021. In this study, patients who were not selected for PD-L1 status were randomized to chemotherapy or chemotherapy plus immunotherapy. Those who received the triplet combination had significantly higher response rates. When these findings were revealed one year ago, we all took note. The FDA then gave the regimen conditional approval in April 2017.

What impact could an FDA approval of Imfinzi (durvalumab) have on the field?

Are there any challenges that you would like to see addressed in the nexnt five to 10 years?

Most recently at the 2017 ESMO Congress, updated analyses were presented in which there was an OS benefit. Even a small subgroup of patients were seeing a true OS benefit with the triplet combination. We all eagerly await confirmatory phase 3 studies.The most compelling data for Imfinzi are in the phase 3 [PACIFIC] study after chemoradiation, which is a game changer. If Imfinzi is approved, it would have a rapid uptake in this patient population. Almost 30 percent of patients who have locally advanced disease are treated with chemoradiation. We have made impactful improvements in survival with changing the chemotherapy backbone or changing the radiation dose. The Imfinzi study after radiation showed a significant survival in PFS, but we await OS data. For patients who can be symptomatic from the disease, this PFS benefit is significant and a new standard of care. Since only a subset of patients sees those dramatic, deep and durable responses to immunotherapy, efforts [are needed] to understand what patients will never respond or will [develop] resistance.

We are learning that there is a tumor-inflamed environment and are looking at one part of that PD-L1 expression that may not be the best indicator. There may be ways to release the breaks with other mechanisms, stimulate T cells, or overcome T-cell exhaustion.

What else would you like to add about this evolving paradigm?

There are compelling data that tumor volume correlates with response to immunotherapy. We have seen this play out in melanoma. It may be that using other things decreases tumor volume, such as chemotherapy and radiation, and may help these patients overcome the hump of T-cell exhaustion.The KEYNOTE-021 data are intriguing; longer follow-up show an OS benefit but it is such a small group of patients. We await the phase 3 trials. Currently, in my practice for the patient who has high PD-L1 expression off the clinical trial, I would treat that patient with Keytruda. There is less toxicity and we have a better idea of what that agent is doing.

For someone with lower expression who may not have access to a clinical trial, the triplet regimen is certainly reasonable, but we are waiting to see how trials pan out before we put all of our resources into particular regimens.