Patel Provides Perspective on Immunotherapy Developments in NSCLC

Sandip P. Patel, MD

Immunotherapy’s introduction into the field of non—small cell lung cancer has revolutionized the treatment landscape, most recently following the phase III results of clinical trials such as PACIFIC and KEYNOTE-189, said Sandip P. Patel, MD. Yet, clinicians are working to refine existing and emerging immunologic agents.

“Bringing these therapies into the first-line metastatic setting and second-line space with the potential of durable remissions, and some patients potentially living years on these therapies with metastatic disease, has transformed medical oncology—in particular NSCLC,” explained Patel. A lot of drug development will be looking at novel combinatorial strategies to better improve outcomes for patients.”

He added that there are novel strategies that are also beginning to show signs of efficacy, including targeting NKTR-214, CSF1R, and OX40.

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In an interview during the 2018 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Patel, a medical oncologist and assistant professor of medicine at the University of California, San Diego, discussed existing and emerging immunotherapy approaches for patients with locally advanced and metastatic NSCLC.Patel: Cancer immunotherapy has revolutionized a variety of different cancers, including NSCLC. There is a wealth of options for our patients. Historically, these options had been chemotherapy. In the age of immunotherapy, including anti—PD-1 agents, we see a variety of different therapeutics in different disease stages.

In the stage III setting of NSCLC, durvalumab (Imfinzi) can be used as per the PACIFIC study, which showed that patients can receive 1 year of durvalumab consolidation therapy after chemoradiation. This is an FDA-approved regimen that looks highly effective.

In the metastatic setting, there are a variety of different options in the frontline and second-line settings. In the first-line space, we recently saw data from the KEYNOTE-189 study combining carboplatin, pemetrexed, and pembrolizumab (Keytruda) followed by pemetrexed and pembrolizumab maintenance. There was an OS benefit whether patients had greater than 50%, greater than 1%, or even less than 1% PD-L1 expression. This has become one of the standard FDA-approved regimens in the frontline space for nonsquamous NSCLC.

For patients who have PD-L1 expression greater than 50%, there remains a question as to whether pembrolizumab monotherapy or chemotherapy with pembrolizumab is the ideal combination. This is one of the questions we'll be answering over the next several years in terms of optimal sequencing.

How do you determine what therapy to give patients with PD-L1 expression?

In terms of refractory NSCLC in patients who have received frontline chemotherapy, there are 3 different options with nivolumab (Opdivo), pembrolizumab, and atezolizumab (Tecentriq). Now, we [also] have the ability to use immunotherapy to treat patients with stage III NSCLC [with durvalumab].For patients with greater than 50% PD-L1 expression, the question [remains] whether these patients are better served by pembrolizumab monotherapy in the first-line metastatic setting or [a combination of] carboplatin, pemetrexed, and pembrolizumab.

What are your thoughts on the IMpower150 study findings?

Based on current data, my practice for more indolent, asymptomatic disease has been to do a trial of pembrolizumab monotherapy by itself for patients with greater than 50% PD-L1 expression. For patients with a visceral crisis that is highly symptomatic from their bulky disease, I'll typically utilize carboplatin, pemetrexed, and pembrolizumab because the time to response is about 2 months less in that population. The IMpower150 trial [examined regimens involving] carboplatin, paclitaxel, bevacizumab (Avastin), and atezolizumab. It’s a 3-arm study. The data we have seen is the atezolizumab quadruplet compared with carboplatin, paclitaxel, and bevacizumab. In this study, there was improved progression-free survival (PFS) for patients who received the quadruplet. One of the most interesting things about this study was that patients with EGFR mutations or ALK rearrangements seemed to have a similar PFS benefit as the remainder of the treated population.

What other immunotherapy agents are in development?

This has led to much interest in developing a potential quadruplet strategy for this particular subset of patients. There are also questions on whether carboplatin could substitute pemetrexed in the United States. This is being studied in several clinical trials that are about to start. The majority of agents currently being investigated aside from PD-1 relate to novel immunologic mechanisms. These are drugs that target the IDO pathway. There have been some questions with the recent negative melanoma data with IDO inhibitors and pembrolizumab, in particular with epacadostat.

There are a variety of other novel agents, such as NKTR-214, which is an IL2 immuno-conjugate, CSF1R, and OX40. These immunologically targeted agents show preliminary signals of efficacy, though it remains to be seen if these responses will be durable. Resistance comes in 2 forms following PD-1 inhibitor therapy. There are patients who have primary resistance to PD-1—directed strategies as a result of "cold" tumor microenvironments. These patients may benefit from vaccination strategies, such as tumor-infiltrating lymphocyte therapies; this and other novel approaches can make "cold" tumors "hot."

How have clinicians addressed resistance to immunotherapy?

Patients who have adaptive resistance may benefit from strategies that upregulate interferon gamma and increase antigen presentation. It’s very likely that, in this setting, there are at least 2 different pathways of resistance mechanisms that will require novel agents to best help these patients who have not fully achieved the benefit we hope from PD-1-directed therapy. Resistance to PD-1 inhibitors in NSCLC recapitulates some of the data we've seen in metastatic melanoma. Oftentimes, patients who initially have a response to [these agents], but ultimately develop adaptive resistance, have similar downregulation in the human leukocyte antigen and beta-2 microglobulin. This is characteristic in metastatic melanoma.

What are your thoughts on the emergence of tumor mutational burden (TMB) as a potential biomarker?

However, the majority of patients with NSCLC who benefit from PD-1/PD-L1 strategies have primary resistance. These are patients who lack the T-cell infiltrate, which can have its break removed by getting PD-1 inhibition. For these patients, vaccination strategies and other modalities to best determine which therapeutic strategy makes the most sense to inflame an otherwise “cold” tumor microenvironment will be key. This is one of the biggest areas of research in cancer immunotherapy, in particular for NSCLC. All biomarkers in cancer are imperfect, whether we are talking about estrogen receptor, progesterone receptor, or HER2 in breast cancer, PD-L1 staining in NSCLC, or TMB. We recently saw some data from CheckMate-227 evaluating patients with TMB greater than 10 mutations/megabase by the Foundation Medicine assay. These patients had a benefit to combinatorial nivolumab/ipilimumab (Yervoy) therapy compared with chemotherapy.

When we look at biomarkers in general, we have to think about them in the context of the patient. PD-L1 can be overexpressed in never smokers who have EGFR mutations or ALK rearrangements, but that does not mean that those patients will benefit from anti—PD-1 agents. Thinking about the patient holistically, their smoking status, and biomarker status, both in terms of their PD-L1 status as well as their next-generation sequencing (NGS), is crucially important.

Is there anything else that you would like to emphasize?

TMB is an assay that can be done on existing NGS platforms. Foundation Medicine was the platform selected for the CheckMate-227 study. We need to take TMB score, which is objective and quantitative, and standardize that across different molecular platforms, so that [you can use] your local NGS assay or a different vendor. Otherwise, methods such as cell-free DNA that can be done to look at TMB in a tube as opposed to the tissue will help standardize the field. [It’s] similar to what's done with BCR-ABL monitoring in CML. We have to be vigilant about immune-related adverse events (irAEs). Contrary to chemotherapy, which has more common and predictable side effects, cancer immunotherapy, especially anti—PD-1 strategies—though they have a low rate of irAEs compared with other immunotherapeutic combinations or chemoimmunotherapy—can still lead to very severe side effects.

In patients with lung cancer, immune-related pneumonitis tends to be one of the most difficult side effects to discern and manage in the clinic. Could a patient have a chronic obstructive pulmonary disease exacerbation, influenza, pneumonia, pulmonary embolism, or progression of their disease? You have to have a low threshold. Make sure you’re utilizing imaging, chest x-rays and CT to discern whether the patient has an irAE, progression of their disease, thromboembolic phenomenon, or infection; it’s hugely important. Our [imaging] threshold for these patients needs to be very low to keep them safe while they remain on immunotherapy.