Dr Joshua Sabari Looks to the Future of Targeted Treatment for NSCLC

The American Journal of Managed Care^® spoke with Joshua K. Sabari, MD, oncologist, NYU Langone Perlmutter Cancer Center, and PAPILLON study investigator, about the March 1 approval of first-line amivantamab plus chemotherapy for non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations and the potential impact of these phase 3 data both in the lung cancer space and for targeted therapies in general.

“I think targeted therapies really have revolutionized the care in non–small cell lung cancer,” Sabari states. “I'm really hoping that the approval of amivantamab and chemotherapy in the front line will lay tracks for the development of future therapeutic strategies for patients with EGFR exon 20.”

To learn more about this approval, please click here.

Transcript

How might your PAPILLON study discoveries influence future research for targeted therapies in lung cancer?

We know that non–small cell lung cancer is a difficult diagnosis. It's critical in 2024 to profile patients genomically to understand whether they have a driver mutation, an actual alteration, that we can then match patients to targeted therapy so that they live longer and have better quality of life. Anytime we identify a driver mutation, that potentially improves the opportunities for therapeutic options for our patients. Understanding that a patient had an exon 20 insertion mutation, 3 to 5 years ago, did not change prognosis; chemotherapy or chemotherapy and immunotherapy were the only approved regimens in that patient population.

Fast forward to 2024, you now have an FDA-approved matched targeted therapy, amivantamab, in combination with chemotherapy, which clearly improves progression-free survival [PFS], clearly improves the objective response rate—objective response rate of 73% when using amivantamab plus chemo vs only 47% when using chemotherapy alone. The survival data, which I think is king, is still immature, but we hope to see a survival benefit even despite the robust crossover in this trial, meaning the control arm moving on to receive amivantamab in the second line.

Are there also implications for targeted therapies in general?

I think targeted therapies really have revolutionized the care in non–small cell lung cancer. You have some targeted therapies that as a single agent have 80% or 85% response rates, durability, PFS in that 20- to 25-month range. I think this is the first iteration of targeted therapeutics for EGFR exon 20. Sure, we still have a long way to go, but this is clearly a significant sort of benefit for patients, particularly in response rate, PFS, and, hopefully, overall survival as well. I'm really hoping that the approval of amivantamab and chemotherapy in the front line will lay tracks for the development of future therapeutic strategies for patients with EGFR exon 20. Specifically focusing on improving CNS [central nervous system] response, specifically focusing on improving tolerability and toxicity for these agents.

What are some other top priorities in the lung cancer space at present?

The EGFR exon 20 space is quite an exciting area for patients, as well as clinicians studying in this space. Again, go back 3 to 5 years, we didn't have any therapies that we could utilize in this patient population. Now there are over 15 or 20 therapeutics in development. What we need, I think, in this setting, in this space, is better targeted therapies. We need to effectively be able to target the tyrosine kinase. We know in exon 20, there's a lot of steric hindrance, preventing classical first-, second-, third-generation EGFR TKIs [tyrosine kinase inhibitors] from binding. Amivantamab has clearly shown that with a different mechanism of action, we can see clinical efficacy and durability in this patient population.

I think the future and the significant unmet need includes CNS. So active, untreated CNS metastases is an active area of investigation. We are seeing some other small molecules start to enter this space. ORIC-114, for example, is potentially going to have CNS penetration. There are other now frontline studies ongoing, with agents such as sunvozertinib, zipalertinib, as well as furmonertinib in the front line. So again, I think amivantamab has paved the way to allow us to study this space.

What I would hope to see in the future is a bispecific antibody, potentially amivantamab, in combination with an exon 20–specific TKI that had CNS activity or potentially novel combination strategies, as you can imagine; trispecifics, ADCs [antibody-drug conjugates] in the future as well.

I think one of the exciting things about this trial is we enrolled during COVID-19. I was fortunate to be on the steering committee, and to rapidly enroll over 300 patients within a 1-year period shows you how significant this unmet need is in this patient population. Patients need these therapies. Even when this regimen of the PAPILLON study was NCCN [National Comprehensive Cancer Network] recommended, a few months ago, patients were showing up in the office needing this therapy. So I think we now have a frontline targeted opportunity for our patients. It doesn't mean that we stop studying newer options into the future. But it really does change the landscape for a subset of patients who you see in the clinic who for many, many years did not have any targeted approaches.