Optimizing Immunotherapy in Lung Cancer

Claude Denham, MD

Immunotherapy continues to establish itself in the treatment of patients with non—small cell lung cancer (NSCLC), yet physicians continue to face challenges in later-line settings with resistance, hyperprogression, and optimal responders.

The second-line PD-1/PD-L1 agents in the landscape include nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq) for patients who progress on platinum-based chemotherapy. The FDA recently approved durvalumab (Imfinzi) for treating those with locally advanced, unresectable stage III disease who have not progressed following chemoradiotherapy.

Moreover, frontline pembrolizumab is also approved by the FDA for patients with metastatic NSCLC who harbor ≥50% PD-L1 expression and as a frontline treatment in combination with carboplatin/pemetrexed, regardless of PD-L1 status, for patients with advanced or metastatic nonsquamous NSCLC.

However, selecting patients for second-line immunotherapy can be challenging, says Claude Denham, MD, because PD-L1 and tumor mutation burden (TMB) are not as reliable as indicators of response. Patients with driver mutations often do not respond as well to immunotherapy in the second-line setting.

Although strides have been made in the past few years, some patients with NSCLC remain resistant to immunotherapy or potentially may experience hyperprogression. A subset of patients experience long-term remission with immunotherapy agents alone, but combinations with immunomodulatory drugs or anti—CTLA-4 agents might hold promise, says Denham.

OncLive: Can you give an overview of your presentation?

In a presentation during the 2018 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Denham, a medical oncologist at Baylor Charles A. Sammons Cancer Center, discussed the use of immunotherapy beyond the first-line setting in NSCLC. In an interview during the event, he dove deeper into the challenges with immunotherapy in this disease, as well as the promise of combination therapy.Denham: My topic lays the groundwork for a lot of the others—it is the use of immunotherapy, largely anti—PD-1 therapy, for NSCLC. I reviewed the pivotal trials that have demonstrated that this is essentially the standard of care for most patients in the second-line setting for NSCLC, both adenocarcinoma and squamous cell carcinoma.

Which patients will benefit most from immunotherapy in the second-line setting?

Is there enough evidence to warrant concern about hyperprogression?

What about resistance?

What key ideas should be kept in mind as we explore later-line immunotherapies in the future?

Also, I looked at some of the strategies being investigated that are incorporating other immunotherapies and immunomodulatory drugs, as well as incorporating more conventional cancer treatments such as radiation therapy and possibly chemotherapy.In the second-line setting, we don’t typically use PD-L1 or TMB as a way to predict whether patients should get immunotherapy. The 1 thing that does seem to help us is that patients with driver mutations—EGFR mutations, ALK rearrangements—don’t do as well with immunotherapy as others. Therefore, if a patient has a driver mutation, there are probably better strategies for second-line treatment, such a rebiopsy, targeted therapy, or chemotherapy. There is a correlation between benefit and the TMB and PD-L1, however, so it can still be useful.I absolutely have concern because I have seen it. It is a very striking phenomenon that I don’t think anyone fully understands, but fortunately, it is rare. One of the challenges is that many patients with NSCLC have a lot of smoking-related comorbidities that make separating out the more nonspecific inflammatory events of immunotherapy with hyperprogression or autoimmune-related adverse events somewhat complicated. I had a patient where I could see the trajectory of their cancer change markedly after their first dose of immunotherapy.Resistance is, unfortunately, pretty common. The majority of patients do not respond to therapy. We talked about single-mutation or driver- mutation patients, but in terms of what is happening to the others, I do not think we have a great handle on that right now. We do know that there are certain subsets of patients with certain mutations who don’t seem to respond well to PD-1 therapy. It may be that those patients need an anti—CTLA-4 and anti–PD-1 therapy in combination.Everyone who practices clinical oncology is aware of this new tool that we have in our tool kit. What is so great about it right now is that a patient can be completely refractory to chemotherapy and have dramatic benefit from these agents. Therefore, you no longer have the downcast look on your face when you walk into the room to tell a patient that they have progressed on first-line chemotherapy. This is a tremendous advance in the field of solid tumor oncology.

There is certainly still a lot of room for improvement. Immunotherapy has sort of disrupted a lot of our paradigms that looked purely at performance status or age as a way of predicting who is appropriate for chemotherapy or systemic therapy for metastatic cancers. We have been thinking about this shift in the paradigm with the advent of targeted therapies, which have a dramatic effect in some patients that you wouldn’t historically offer chemotherapy. We are having that same sort of challenge in decision making with the immunotherapies, as well.