Joshua K. Sabari, MD

Joshua K. Sabari, MD, assistant professor of the department of medicine at NYU Grossman School of Medicine and medical director at NYU Langone Health, discusses the significance of 

 exon 20 insertion mutations in patients with non–small cell lung cancer.

 mutation that does not respond well to the standard treatment of osimertinib (Tagrisso) for 

 exon 19 and 21 mutations, though Sabari says that a higher dose of osimertinib does have a 20% to 25% response rate for patients with exon 20 insertions.

The standard of care in the first line is platinum-based doublet therapy with pemetrexed plus either cisplatin or carboplatin. Immunotherapy has been investigated, but according to Sabari, the median progression-free survival (PFS) for patients receiving pembrolizumab (Keytruda) is only about 2 to 2.5 months. In addition, immune-related adverse events (irAEs) associated with immunotherapy when combined or followed by EGFR tyrosine kinase inhibitors (TKIs) can be especially dangerous.

Two targeted therapies have been approved in the second line specifically for patients with an 

 exon 20 insertion. Amivantamab (Rybrevant) is an intravenous EGFR/cMET bispecific antibody. Mobocertinib (Exkivity) is an oral therapy with a different mechanism of action, and is an EGFR HER2 exon 20 TKI. 

 exon 20 insertion mutations is that patients do not respond to standard therapies. So osimertinib at 80 mg, which is a standard FDA-approved dose, is ineffective in this population. We've looked at 160-mg dosage, and we see about a 20% [to] 25% response rate in the population. So it's important that in the 

 exon 20 insertion population, we're using agents that have activity in that specific setting. The standard of care in the frontline setting remains chemotherapy with a platinum doublet, carboplatin and pemetrexed or cisplatin and pemetrexed.

The utilization of immunotherapy remains controversial. The median PFS for single-agent immunotherapy in this setting—pembrolizumab—is about 2 to 2 and a half months. So not only is it not effective, but we know that there's increased risk of irAEs or toxicities when we then think about using 

-directed therapy subsequently. So in my clinical practice, I'm using chemotherapy alone in the frontline setting.

In the second line setting, we now have 2 FDA-approved therapies for patients so if you identify an 

 exon 20 insertion mutation, you can match your patient to either amivantamab, an EGFR/cMET bispecific antibody, or mobocertinib, an EGFR/HER2 exon 20 TKI, a tyrosine kinase inhibitor.

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Joshua K. Sabari, MD, discusses the significance of EGFR exon 20 insertion mutations in patients with non–small cell lung cancer. 

EGFR Therapies Fail to Benefit Patients With NSCLC and Exon 20 Insertions

Joshua K. Sabari, MD, medical director of Kimmel Pavilion 12 at NYU Langone Health’s Perlmutter Cancer Center and assistant professor of medicine at NYU Grossman School of Medicine, discusses the trials that showed efficacy for durvalumab (Imfinzi) and atezolizumab (Tencentriq) in patients with extensive-stage small cell lung cancer (ES-SCLC).

The phase 3 CASPIAN trial (NCT03043872) investigated whether durvalumab with or without tremelimumab given alongside carboplatin or cisplatin and etoposide would improve overall survival (OS) and progression-free survival (PFS) in patients with ES-SCLC versus carboplatin or cisplatin and etoposide alone. The phase 3 IMpower133 trial (NCT02763579) investigated the OS and PFS benefit of atezolizumab with carboplatin and etoposide versus carboplatin and etoposide alone.

According to Sabari, the study designs were similar, though in the CASPIAN trial, up to 6 cycles of platinum-based chemotherapy could be used compared with 4 cycles in the IMpower133 trial. The IMpower133 trial also did not allow enrollment of patients who had received prophylactic cranial irradiation (PCI). Both studies did not allow patients with untreated brain metastases due to the high rate of recurrence and death in patients with central nervous system (CNS) involvement.

The studies had similar positive results, with durvalumab showing an objective response rate (ORR) of 68% in the CASPIAN trial, while atezolizumab had an ORR of 60% in the IMpower133 trial. The hazard ratio for death was nearly identical according to Sabari.

Both trials met their primary end point of OS and PFS, leading to approval by the FDA for use in this setting.

 I think both of these studies were very similar to each other in their design. The major differences here being that the CASPIAN study using durvalumab allowed for 6 cycles of cisplatin [or carboplatin] use. The ORR in the CASPIAN study appeared to be slightly higher at 68% than in the IMpower133 study, [which was] about 60%. And when you look across both of these studies, though, the rate of CNS recurrence and the rate of mortality in patients who had CNS disease upfront was quite high. So both of these studies did not allow any untreated patients with brain metastases, but did allow for patients with treated metastasis.

 One other thing that you need to consider is in the CASPIAN study, it did allow for PCI, whereas the IMpower133 study did not. Again, that being said, when you look at the hazard ratio of both of these studies, it’s…0.76 [in IMpower133] and 0.75 [in CASPIAN], being very similar. It's really hard to distinguish. I think one thing that will be interesting in the future is looking at the tail of the [Kaplan-Meier] curve. Are there a substantial number of patients alive and doing well on 1 agent versus the other? That might differentiate these 2 combinations, but in 2022, I don't think there's any major difference between the 2 regimens.

Joshua K. Sabari, MD, discusses the trials that showed efficacy for durvalumab and atezolizumab in patients with extensive-stage small cell lung cancer. 

Joshua K. Sabari, MD | Authors

Articles

EGFR Therapies Fail to Benefit Patients With NSCLC and Exon 20 Insertions

Atezolizumab and Durvalumab Show Similar Benefit for ES-SCLC