Emerging Data Show Promise With Immunotherapy Combos in NSCLC

Jyoti D. Patel, MD

Immunotherapy combination regimens continue to generate excitement as a treatment approach for patients with non—small cell lung cancer (NSCLC), as they may induce higher and more durable responses.

The large, phase II 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 pembrolizumab (Keytruda) 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% 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 pembrolizumab arm was not reached (95% CI, 8.5-not reached) compared with 8.9 months with the chemotherapy arm (95% CI, 6.2-10.3). The 12-month overall survival (OS) rate with pembrolizumab was 76% compared with 69.3% 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, MD.

OncLive: Can you discuss your 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 OncLive® at the 2017 State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, 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. Patel: We have seen dramatic responses in subsets of patients with checkpoint blockade, particularly with the PD-1/PD-L1 axis. However, only about 20% 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 III trials. The most compelling data we have that have come to the clinical arena are the combination of pembrolizumab 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 1 year ago, we all took note. The FDA then gave the regimen conditional approval in April 2017.

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

What do you hope that community oncologists who attended this meeting took away from your talk?

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 III studies.The most compelling data for durvalumab are in the phase III [PACIFIC] study after chemoradiation, which is a game changer. If durvalumab is approved, it would have a rapid uptake in this patient population. Almost 30% 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 durvalumab 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. The data support that we have good drugs with immunotherapeutics in the second-line setting. Perhaps we can enrich a subset of patients with high PD-L1 in the frontline setting; a large proportion of patients either never respond to immunotherapy or develop resistance. They need to know that we have multiple strategies for how to improve immunogenicity of the tumor and to inflame the tumor, so that the T-cell checkpoint inhibition would be a successful strategy for controlling cancer.

Most promising now are chemotherapy and immunotherapy compounds. The dual-checkpoint inhibition and immunotherapy combinations with either CTLA-4 inhibitors or IDO1 inhibitors are also intriguing. We are looking at combinations of immunotherapy and radiation, as well as VEGF inhibition.

Are there any challenges that you would like to see addressed in the next 5 to 10 years?

The field is large. All of these are early data, but they are certainly thought provoking. We are looking for data from those larger randomized trials, but this is a rapidly changing field. 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 III trials. Currently, in my practice for the patient who has high PD-L1 expression off the clinical trial, I would treat that patient with pembrolizumab. 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.

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 (suppl; abstr 9094). doi: 10.1200/JCO.2017.35.15_suppl.9094.