Unanswered Questions Spur Future Lung Cancer Research Efforts

Edward B. Garon, MD, MS

Compared with other chemoimmunotherapy regimens for patients with non–small cell lung cancer (NSCLC), tremelimumab (Imjudo) plus durvalumab (Imfinzi) and chemotherapy has a favorable toxicity profile that may stem from its shortened course of CTLA-4 inhibition, according to Edward B. Garon, MD, MS. Further study of these combinations may clarify the role of CTLA-4 inhibition in NSCLC management and define optimal treatment durations.

“Historically, there has been negativism about systemic therapy for patients with advanced disease. However, over the past several years, there have been improvements,” Garon said in an interview with OncLive® following an OncLive^® State of the Science Summit^™ (SOSS) on lung cancer, which he chaired.

In the interview, Garon discussed future considerations for immunotherapy across NSCLC subsets, nuances to consider regarding radiation in advanced NSCLC, and how lurbinectedin (Zepzelca) offers patients with small cell lung cancer (SCLC) a convenient treatment option.

In the phase 3 POSEIDON study (NCT03164616), patients with metastatic NSCLC who received tremelimumab plus durvalumab and chemotherapy experienced a median overall survival (OS) of 14.0 months vs 11.7 months in those who received chemotherapy alone.¹ Garon described how this regimen’s unique treatment schedule may contribute to greater tolerability compared with other dual checkpoint inhibitor approaches. He also highlighted further research combining angiogenesis and PD-1/PD-L1 inhibition stemming from the phase 3 IMpower150 trial (NCT02366143), in which atezolizumab (Tecentriq) plus bevacizumab (Avastin) and chemotherapy demonstrated an OS of 19.5 months vs 14.7 months with bevacizumab plus chemotherapy in patients with metastatic nonsquamous NSCLC.²

Garon is a professor of medicine in the Department of Medicine in the Division of Hematology/Oncology at the David Geffen School of Medicine at UCLA.

OncLive^®: Despite treatment advances, what questions remain regarding leveraging immunotherapy in NSCLC?

Garon: It’s been an exciting several years. I remember giving a talk on treatment with immunotherapy when a small number of datasets were available. Now, we have several datasets available. Particularly in NSCLC, we have incorporated immunotherapy in almost all aspects of advanced disease management, at least in the frontline setting, even in patients who have undergone resection or received chemoradiotherapy.

I focused on remaining clinical questions. In whom is frontline single-agent immunotherapy still considered the standard of care [SOC]? In whom are we looking at additional therapies? Are there patients for whom immunotherapy should not be included in frontline therapy? Who are those patients?

One question still vexing to the field is: What is the role of CTLA-4 inhibition? [Several] clinical trials have evaluated the role of CTLA-4 inhibition. Despite all those datasets, we still haven’t addressed the fundamental question: What, if anything, is the benefit of specifically adding a CTLA-4 inhibitor? That has been a source of frustration across the field and has led to differences in practice patterns.

We also asked: What is the optimal duration of therapy? Most datasets stop after a couple years, but that is not a universal approach. That is not a standard that everyone uses. [Some clinicians do but others] extend beyond [this time frame] and have justification from available literature.

[This SOSS was] a nice discussion with multiple experts in medical and radiation oncology, as well as an engaged audience.

What makes the POSEIDON regimen potentially favorable compared with other chemoimmunotherapy approaches?

Two approved therapeutic approaches combine a PD-1 or PD-L1 inhibitor with a CTLA-4 inhibitor. One [uses] nivolumab [Opdivo] and ipilimumab [Yervoy] in patients with PD-L1–positive disease and has data supporting approval in patients with PD-L1 expression of at least 1%. Interestingly, the data look at least as good in patients who are negative for PD-L1. [This combination is also approved with chemotherapy] regardless of PD-L1 expression.

In addition, the combination of chemotherapy, durvalumab, and tremelimumab is approved based on the POSEIDON study. I was [an investigator on] that study. Patients [in POSEIDON] received more chemotherapy cycles than those in the study with ipilimumab, nivolumab, and chemotherapy, [who received only 2 cycles]. However, whereas in the ipilimumab study, ipilimumab was continued, [patients received] only 1 cycle of post-chemotherapy treatment with tremelimumab in POSEIDON.

Those [treatment schedules] have tolerability implications. One has an earlier cessation of chemotherapy and therefore an earlier cessation of the toxicities associated with chemotherapy. The other has an earlier cessation of tremelimumab, the CTLA-4 inhibitor [that may] majorly contribute to the toxicity of these dual immune checkpoint inhibitor approaches.

How might biomarker testing influence the decision to treat certain patients with CTLA-4 inhibitors going forward?

Biomarkers will still be important. Over the years, we have done a reasonable job of identifying patients who are more likely to benefit from PD-1 or PD-L1 inhibition. That still requires much refinement. As we look forward with the regimen from the POSEIDON trial, or the [phase 3] CheckMate 227 [NCT02477826] or CheckMate 9LA [NCT03215706] trials, it will be important to identify patients who benefit disproportionately from CTLA-4 inhibition.

Regarding the presentation by Amy Cummings, MD, of UCLA, how does immunotherapy fit into the treatment paradigm for EGFR-mutant NSCLC?

The incorporation of immunotherapy into [the treatment of] patients with EGFR mutation–positive disease has been a challenge. Aaron Lisberg, MD, [of UCLA], conducted a study investigating frontline immunotherapy in patients with EGFR mutations and showed that it was not an effective approach and increased toxicity in patients who received an EGFR inhibitor after a PD-1 inhibitor.

We now have 2 datasets showing that angiogenesis inhibition plus PD-1 or PD-L1 inhibition and chemotherapy can be effective in this population. The original dataset was the IMpower150 regimen of carboplatin, paclitaxel, bevacizumab, and atezolizumab that has now been replicated by a group in China looking at a Chinese PD-1 inhibitor plus a biosimilar of the anti-angiogenic agent. [The IMpower150 regimen] led to [improvements in OS and] progression-free survival.

As data mature, particularly from the Chinese study, it will be important to see if there are biomarkers that can help select patients. The response rates to single-agent PD-1 or PD-L1 inhibitors in patients with EGFRmutations have not been high. It’s been difficult to show that the incorporation of CTLA-4 inhibition reverses that population’s decreased sensitivity. There are some early intriguing data, but this remains a challenge.

Regarding Dr Lisberg’s presentation, how prevalent are EGFR exon 20 insertion mutations in NSCLC?

Dr Lisberg addressed a group that we used to think of as rare. However, as we have tested more extensively and [developed] more comprehensive EGFR mutational testing, we have found many exon 20 insertion mutations. We tend to have a greater population of patients with smoking history here in Los Angeles, as well as a greater population of patients with Asian ancestry. Those are both associated with an increased likelihood of having EGFR exon 20 insertion mutations or EGFR mutations in general.

It’s exciting that in a small patient population that we have typically had difficulties addressing, we now have 2 drugs approved that specifically address this subset of a subset, patients with EGFR mutations that are exon 20 insertions.

Regarding the presentation by Drew Moghanaki, MD, MPH, of UCLA, what factors are challenging the current radiation SOC?

One area with wide agreement is that in patients with locally advanced disease who are not candidates for surgery, radiation plus chemotherapy, in most cases followed by durvalumab, is considered the SOC. This is nuanced [because the factors determining] who is not a candidate for surgery are not absolute, and different surgeons may view that differently. It varies from institution to institution.

The bigger questions arise in oligometastatic disease, where approaches are investigating managing a single lesion. We have used that often in patients who, for instance, are well controlled with targeted therapy or immunotherapy, but have 1 or a limited number of escape lesions. That’s a situation where we’ve used radiation even in advanced settings. There is some enthusiasm, particularly among radiation oncologists, of moving radiation earlier, to address remnant disease. Those are controversial areas. Discussing these cases with your radiation oncologist makes sense.

Regarding the presentation by Jonathan Goldman, MD, of UCLA, how has the addition of lurbinectedin to the SCLC treatment landscape broadened disease management options?

SCLC has been well addressed with frontline chemotherapy. At least regarding likelihood of response, patients are likely to have disease shrinkage. The real challenge is that at the time of disease recurrence, there are no great options.

The established standard would be topotecan. The problem with topotecan is that the tolerability and efficacy are poor. The approved approach for topotecan in SCLC is to give it 5 days in a row, which is inconvenient.

We don’t have data to indicate that lurbinectedin’s efficacy is superior to topotecan, but from a convenience perspective, the fact that patients don’t have to come in continually is a benefit. There are still tolerability concerns, although this is a novel approach. I still, in my practice, consider it a chemotherapy. However, it has expanded the options beyond topotecan.

Dr Goldman also addressed innovative new investigational approaches. At UCLA, we are aggressive about trying to put patients with previously treated SCLC on clinical trials with the hope of further improving their outcomes.

What ongoing lung cancer research is UCLA involved in?

Like many institutions, we have a robust evaluation of clinical trials. In the targeted therapy area, 1 is a study of a novel RET inhibitor. With 2 RET inhibitors now approved, we have made a significant improvement in [RET-positive] disease. We were involved in some of the early trials of selpercatinib [Retevmo] and were gratified to see how well patients did. Unfortunately, as with all targeted therapies, eventually resistance occurs. We have a second-generation inhibitor from Loxo Oncology that’s looking specifically at RET inhibitors. That’s 1 of several trials we have in the frontline and previously treated settings for patients with specific oncogene drivers.

In patients without those drivers, a challenge has been what to do when they progress after chemoimmunotherapy. We have multiple studies in that setting. Two are innovative in the immunotherapy area.

One is a homegrown protocol funded by a large grant from the California Institute for Regenerative Medicine. We are harvesting patients’ monocytes, differentiating them into dendritic cells, the most potent antigen-presenting cells, doing gene therapy on those cells to insert a proinflammatory cytokine, CCL21, and injecting it back into the tumor, trying to allow the patient’s own dendritic cells to sample the tumor and inform the immune response against it.

Another innovative immunotherapy approach is the [phase 2] IOV-LUN-202 study [NCT04614103], sponsored by Iovance Biotherapeutics, Inc., which is investigating tumor infiltrating lymphocytes [TILs]. This is not a patient-friendly study. Patients undergo a nontherapeutic surgery to harvest lymphocytes that are infiltrating into the tumor that are then expanded. Patients receive lymphodepleting chemotherapy followed by infusion of the expanded TILs and high-dose aldesleukin.

This is a significant investment; patients need to be committed. However, for young patients who are naïve to PD-1 inhibition or have received PD-1 inhibition monotherapy in the frontline setting, this high-risk, high-reward study is a good option.

What is your main message for colleagues?

[A nice aspect of] this SOSS is we can address clinicians across specialties. We have a long way to go, but we’re excited about the strides we have made as a field. The opportunity to disseminate information about them to our colleagues across different specialties is exciting.

Editor’s Note: Garon has consulting or advisory roles with Abbvie, ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Ipsen, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio; and has received grant/research support from ABL-Bio, AstraZeneca, Bristol Myers Squibb, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon Therapeutics, and Novartis.

References

1. Johnson ML, Cho BC, Luft A, et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: the phase III POSEIDON study. J Clin Oncol. Published online November 3, 2022. doi:10.1200/JCO.22.00975
2. Socinski MA, Nishio M, Jotte RM, et al. IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J Thorac Oncol. 2021;16(11):1909-1924. doi:10.1016/j.jtho.2021.07.009