2024 Regulatory Approvals Across NSCLC Propel the Therapeutic Landscape Forward

Noman Ashraf, MD

Treatment options in the rapidly evolving non-small cell lung cancer (NSCLC) landscape are continuing to grow, including for those with certain genetic mutations, according to Noman Ashraf, MD, a hematologist-oncologist at Tampa General Hospital and an associate professor of medicine at the University of South Florida Health Morsani College of Medicine.

The therapeutic landscape for patients with NSCLC has expanded following the FDA approval of various regimens. For patients with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed, the regulatory agency approved amivantamab-vmjw (Rybrevant) in combination with chemotherapy in September 2024.¹ This approval came after the August 2024 approval of perioperative durvalumab (Imfinzi) and prior to the October 2024 approval of perioperative nivolumab (Opdivo), both for patients with resectable NSCLC and no known EGFR mutations or ALK rearrangements.^2,3

In an interview with OncLive® following an OncLive State of the Science Summit™ on lung cancer which he chaired, Ashraf highlighted ongoing investigations that spotlight these advancements and a case study that was discussed at the event. Additionally, Ashraf expanded on treatment with the HER2-directed antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in another article.

OncLive: At the OncLive Summit, you shared insights on a case study considering immunotherapy rechallenge for a patient with lung cancer. What were your key takeaways?

Ashraf: This was a patient who was receiving chemotherapy and immunotherapy, then developed autoimmune hemolytic anemia from the immunotherapy, which was life-threatening and required steroids for a long time. When they tried to taper down the steroids, [the patient experienced] a recurrence of adverse effects [AEs] and some hepatitis from the immunotherapy.

In those [types of] cases, I would probably not rechallenge the patient with immunotherapy unless they had no other alternatives. This patient had a HER2 mutation, [so] at the time of progression, I would opt for using the ADC T-XDd which is now approved for that indication.

What was the significance of the recent FDA approval of amivantamab plus carboplatin and pemetrexed for patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations?

The standard of care until recently for patients with advanced, EGFR-mutated NSCLC was third-generation TKIs—osimertinib [Tagrisso] was mostly given although you could use [other agents] as well. However, once patients progressed on osimertinib, they didn’t have a lot of options other than chemotherapy. The phase 3 MARIPOSA-2 trial [NCT04988295] showed that the combination of amivantamab with chemotherapy seems to benefit patients who have progressed on third-generation TKIs such as osimertinib. It is a great option because before this the only option we had was chemoimmunotherapy; we know from multiple studies now [that] immunotherapy doesn’t work for patients who have an EGFR mutation.

Immunotherapy is not a good option, but amivantamab which is a bispecific antibody targeting both EGFR and MET, is a great option for these patients. Approximately a third of patients who progress on osimertinib have MET amplifications or mutations in the MET pathway, so by addressing both the EGFR and the MET pathways, you’re blocking both [and] can overcome some of the resistance with amivantamab. This is a great option for our patients. At the same time, more recently the FDA approved amivantamab in the frontline setting in combination with lazertinib [Lazcluze], [which is] also a third-generation TKI. This would then not be an option for progression on that regimen.

What is key to note about treating patients with EGFR mutations in the current NSCLC treatment armamentarium?

As far as EGFR mutations, patients who have advanced NSCLC and even localized NSCLC, have multiple options and these options are increasing. We had earlier generation TKIs, then the third-generation TKI osimertinib, and now we’ve moved on to lazertinib with amivantamab [and] osimertinib with chemotherapy in the first line, and in the second line amivantamab combined with chemotherapy. There are a lot of options, and it’s an exciting time for patients who only had a few options in the past.

What questions remain to optimize the use of checkpoint inhibitors in the perioperative space?

Multiple regimens have now been approved in the perioperative or preoperative settings combining chemotherapy with immunotherapy. We have data from the phase 3 CheckMate 816 study [NCT02998528] of nivolumab with chemotherapy. Then we [evaluated] perioperative chemotherapy with the phase 3 KEYNOTE-671 trial [NCT03425643], and most recently the phase 3 AEGEAN trial [NCT03800134] with durvalumab [(Imfinzi) and chemotherapy] perioperatively.

There are still some questions that remain unanswered. I always worry about patients who have a complete pathologic response at surgery: Do they really need to go on to immunotherapy for approximately a year after their surgery? I don’t think we have the answer to that. CheckMate 816 only had a preoperative arm, the phase 3 CheckMate 77T study [NCT04025879] on the other hand had a perioperative arm, [and] the other trials all gave perioperative chemoimmunotherapy. None of them looked at whether patients who have a complete pathologic response, which is anywhere from approximately 18% to 25% of patients, benefit from more immunotherapy after their surgery.

At this time, I offer it to my patients. I discuss it with them. I don’t push it too much, so if the patient’s a bit reluctant or if they start having any AEs from post-operative immunotherapy, I’m liberal about discontinuing immunotherapy in patients who’ve had a complete pathologic response [following] surgery.

References

1. FDA approves amivantamab-vmjw with carboplatin and pemetrexed for non-small cell lung cancer with EGFR exon 19 deletions or L858R mutations. FDA. September 19, 2024. Accessed October 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-amivantamab-vmjw-carboplatin-and-pemetrexed-non-small-cell-lung-cancer-egfr-exon-19
2. FDA approves neoadjuvant/adjuvant durvalumab for resectable non-small cell lung cancer. FDA. August 15, 2024. Accessed October 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvantadjuvant-durvalumab-resectable-non-small-cell-lung-cancer
3. U.S. Food and Drug Administration approves perioperative treatment of neoadjuvant Opdivo (nivolumab) and chemotherapy followed by surgery and adjuvant single-agent Opdivo for resectable non-small cell lung cancer (NSCLC). News release. Bristol Myers Squibb. Oc-tober 3, 2024. Accessed October 23, 2024. bit.ly/4dY0WxN