Immunotherapy Continues to Touch All Areas of Lung Cancer Treatment

David Spigel, MD

Although trials such as the phase 3 CheckMate 816 (NCT02998528) and POSEIDON (NCT03164616) studies are generating significant excitement for the future of neoadjuvant therapy and combination chemoimmunotherapy, respectively, it is the phase 3 IMpower010 trial (NCT02486718) that has made the largest splash in the field of non–small cell lung cancer (NSCLC), said David Spigel, MD.

“[IMpower010] is the biggest trial news because it led to a paradigm shift. Now we are talking about immunotherapy not just in advanced disease or unresectable stage III disease but in a curable setting of resected, stage II and III disease,” Spigel said in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on lung cancer, which he co-chaired.

In the interview, Spigel, chief scientific officer and director of the Lung Cancer Research Program and principal investigator at Sarah Cannon Research Institute, discussed the focus of each presentation, which centered on immunotherapy vs chemoimmunotherapy in the frontline metastatic setting, the surgical perspective of treatment in early-stage NSCLC, best practices for molecular testing, and EGFR- and KRAS-targeted therapies for patients with advanced disease.

OncLive®: What developments have been made with regard to frontline therapy for patients with advanced NSCLC without actionable genetic alterations?

Spigel: We had several great presentations at the Institutional Perspectives in Cancer webinar. My focus was on the state of affairs in the first-line setting for NSCLC and where we are at now with immunotherapy options and chemoimmunotherapy options in the first-line setting. I focused on our non-TKI targeted therapy options. We have a lot of regimens to choose from [in this setting]. Cemiplimab-rwlc [Libtayo] is a new PD-1 inhibitor that was FDA approved in the first-line setting as a monotherapy based on findings from the EMPOWER-Lung1 trial [NCT03088540]. The study compared cemiplimab with platinum-doublet chemotherapy in patients with PD-L1 expression of 50% or higher. The results showed a survival advantage in the cemiplimab arm hence the FDA approval.

Now we have 3 monotherapies in the first-line setting with pembrolizumab [Keytruda], atezolizumab [Tecentriq], and cemiplimab. Each agent is approved for patients with high PD-L1 expression, and pembrolizumab is also approved for patients with PD-L1 expression of 1% to 49%.

In terms of chemotherapy combinations, the only thing that is new but not FDA approved yet is a regimen from the POSEIDON study. This was a trial that looked at a combination of dual immunotherapy with chemotherapy as first-line therapy. In the trial, patients with NSCLC with adenocarcinoma and squamous histologies were randomized to platinum-doublet chemotherapy, platinum-doublet chemotherapy with durvalumab [Imfinzi], which is a PD-L1 inhibitor, or platinum-doublet chemotherapy with durvalumab and tremelimumab, which is a CTLA-4 antibody. The take-home here is at the 2021 ESMO Congress we saw data presented by my partner, Melissa Johnson, MD, of Sarah Cannon Research Institute, showing a survival advantage for the 4-drug regimen compared with the platinum doublet. Will that lead to the FDA approval of that regimen? It seems like it should, but we don’t have that approval yet.

Denis Gilmore, MD, of TriStar Medical Group, discussed the phase 3 CheckMate 816 and the IMpower010 trials. What has been most exciting about these studies?

Dr Gilmore is a thoracic surgeon I have the privilege of working with in Nashville. Dr Gilmore did a fantastic job summarizing 2 pivotal studies from this past year: the CheckMate 816 study and the IMpower010 study. The CheckMate 816 study evaluated preoperative chemoimmunotherapy, in this case, chemotherapy with nivolumab [Opdivo] in patients with squamous and nonsquamous lung cancer that was deemed resectable, so stage 1B through stage IIIA disease. The IMpower010 study was an adjuvant trial, which evaluated patients with any histology of resected, early-stage lung cancer who received platinum-doublet chemotherapy where appropriate. Then, patients were randomized to 1 year of adjuvant atezolizumab or not.

CheckMate 816 was pivotal because it showed that pathologic complete response rates are significantly higher, approximately tenfold higher with chemoimmunotherapy vs just chemotherapy alone. Another interesting take-home is that operative outcomes don’t appear to be negatively impacted by the introduction of immunotherapy. In fact, there’s a suggestion or statistical improvement in the ability to do less surgery, so smaller surgeries, minimally invasive surgeries, and no worse outcomes with immunotherapy. This was a positive trial that hasn’t yet led to an FDA approval. We did recently see a press release on disease-free survival [DFS] improvements with the nivolumab arm, so hopefully that will lead to an FDA approval.

The IMpower010 study did lead to an FDA approval recently. Patients with stage II to IIIA resected NSCLC with 1% or higher PD-L1 expression are now candidates for immunotherapy, because in that group in the study, there was a DFS advantage in favor of atezolizumab, which was the primary end point of the trial. Now, there’s some caveats in that that benefit appears to be greatest or largely due to patients that have 50% or higher expression, but the approval is in patients with a PD-L1 expression level of 1% or higher. That’s the biggest trial news because it led to a paradigm shift. Now we’re talking about immunotherapy not just in advanced disease or unresectable stage III disease, but in a curable setting of resected, stage II and III disease.

Andrew McKenzie, PhD, of Sarah Cannon Research Institute, discussed testing for biomarkers. What mindset should be applied to molecular testing in NSCLC?

Dr McKenzie leads our personalized medicine program at Sarah Cannon Research Institute and is a fantastic colleague. I wouldn’t add much else other than what everyone already appreciates, and that is the importance of testing. We certainly advocate for broad or comprehensive NGS [next-generation sequencing] testing in our patients with advanced disease, in this case, advanced NSCLC. I don’t think that’s limited to adenocarcinoma; testing should be done in squamous carcinoma, if for no other reason than to look for things like MET exon 14 [skipping mutations], which you can see in squamous histology and even the rare things like RET and NTRK [alterations].

Ideally, the gold standard still is tissue, but if you can only [test] one thing, get whatever can be done that works for you, and largely that is turning into plasma-based testing. I recently met a woman with advanced disease, and [she and her family were] eager to get going [with treatment]. How do you make decisions based on somebody who has a new diagnosis? You need to know their molecular results, and the fastest way to get on that is plasma-based testing. That’s become a standard part of my workup with patients while tissue testing is cooking, and with that is PD-L1 testing.

Dr McKenzie gave a nice summary on that landscape of tissue- and blood-based testing, and they’re not going away. We don’t know a lot about how to use it, and understanding resistance mechanisms or minimal residual disease, but those are exciting emerging areas for everybody and likely will become new standards in the years to come. For now, we just kind of want to focus on getting testing done. There are so many markers, at least 8 that we want to know about in lung cancer. Knowing those will help guide the best treatment decisions for those patients.

Your co-chair, Melissa Johnson, MD, of Sarah Cannon Research Institute, shared insight into some of the more recently approved targeted therapies for patients with KRAS G12C mutations and EGFR exon 20 insertions. What has been learned about these agents in clinic since their approvals?

We’re still talking about HER2, RET, and ROS alterations, and even sensitizing mutations in EGFR and what to do after [progression on standard therapy]. However, Dr Johnson’s important message was that we had an FDA approval in 2021 in the treatment of KRAS G12C–mutant lung cancer with sotorasib [Lumakras], which selectively inhibits that genetic alteration, which can be found in plasma or tissue NGS testing. The agent is now approved for use in the refractory setting, so anything beyond first-line treatment, which often is chemoimmunotherapy based.

Sotorasib has an FDA approval now as an oral therapy for use in patients with KRAS G12C mutations, which speaks to the importance of testing and getting answers to try to be ready to use those therapies. We know sotorasib is associated with efficacy in the form of responses in about 40% to 50% of patients as well as extended durations of disease control that extend to a little bit under 1 year. Depending on the circumstance, some patients can get well beyond that, so that’s a big story.

Dr Johnson talked also about another agent called adagrasib, which is an agent being developed that also is showing early promise in the same patient population. It’s not yet FDA approved, but hopefully it will be soon.

The other big story has been in patients with EGFR exon 20 insertions. These molecular alterations can be found with NGS testing, and we know drugs like osimertinib [Tagrisso], which are ideal for patients with sensitizing mutations in exon 19 and 21 are not effective in exon 20 insertions although there has been some data with high-dose osimertinib. The numbers are very small, but high-dose osimertinib may have benefit there. We have 2 FDA-approved drugs for patients with exon 20 insertions in EGFR: one is amivantamab-vmjw [Rybrevant], which is a bispecific antibody that targets EGFR and MET and then a TKI called mobocertinib [Ekivity], which is an oral agent. These 2 FDA-approved strategies are intravenous and oral, respectively, and are used in a post first-line setting, so a refractory setting in patients with EGFR exon 20 insertions, kind of like sotorasib’s approval in KRAS G12C mutations.

These drugs are different; they aren’t the easiest to get used to administering. Amivantamab requires a stepped-up infusion, and specifically awareness of dealing with infusion-related reactions, which occur in just about everybody, so we are adjusting to that experience, including [that with] some pulmonary toxicity. Mobocertinib also has some unusual tolerability awareness that doctors need to get used to whether it’s gastrointestinal or pulmonary in nature. The big take-home [message] is now we have 2 alterations, KRAS G12C and EGFR exon 20 insertions, for which a year ago we had no options. In terms of standards, now we have 3 and probably a forthcoming option, which is exciting.