Despite Limitations, Oral Mobocertinib Offers Ongoing Benefits for Lung Cancer Subset, Says Expert

Vamsidhar Velcheti, MD
Medical Oncologist
Director, Thoracic Medical Oncology
Perlmutter Cancer Center
NYU Langone Health
New York, New York

The oral tyrosine kinase inhibitor mobocertinib (Exkivity) improved clinical outcomes in patients with platinum-pretreated EGFR exon 20 insertion+ metastatic non­–small cell lung cancer (NSCLC), according to recent results from a phase 1/2 study¹ (NCT02716116).

Vamsidhar Velcheti, MD, a medical oncologist and director of thoracic medical oncology at the Perlmutter Cancer Center of NYU Langone, spoke with CancerNetwork^® about these data, which were presented in a poster at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

Among the study population of platinum-pretreated patients with EGFR exon 20 insertion+ metastatic NSCLC (n = 114, median age 60 years, 66% female, 60% Asian), treatment with oral mobocertinib elicited a confirmed objective response rate (ORR) of 28% per independent review committee (IRC) and showed a median duration of response of 17.5 months.

However, the high frequency of progressive disease in the brain (25%) and lower IRC-assessed confirmed ORR in patients with baseline brain metastases suggested that mobocertinib may have limited intercranial activity. Investigators nonetheless concluded that this treatment could offer ongoing systemic benefits to this patient population.

CancerNetwork^®: What was the rationale for assessing mobocertinib in this patient population?

There are several different agents targeting patients with activating EGFR mutations, but not all mutations are created equal, and certain EGFR mutations are not responsive to any currently available second- and third-generation inhibitors. This is an area of unmet need, and [so we assessed] mobocertinib [because it] seemed to show activity in patients with EGFR exon 20 mutations.

There was no approved drug for EGFR exon 20 mutations until the recent approvals of mobocertinib² and amivantamab [Rybrevant].³ These drugs are both clinically active in patients with EGFR exon 20 insertion+ metastatic NSCLC.

How did patients perform on this regimen?

Drugs targeting the EGFR pathway display some common on-target adverse events [AEs] because of the effects they have on wild-type EGFR-mutated disease. We tend to see a lot of skin and gastrointestinal [GI] toxicity with these agents…but these are often manageable with aggressive supportive care.

The AEs with mobocertinib didn’t surprise us. [As expected,] we saw significant GI toxicity from wild-type EGFR inhibition with this drug. In most patients, these toxicities were managed without a dose reduction, but in some cases a dose reduction was needed to control symptoms.

How do you see this treatment potentially affecting clinical practice?

Presently, there are limited treatment options for these patients. The FDA has so far approved two drugs for EGFR exon 20 mutations. The first of these, the EGFR-MET bispecific antibody amivantamab, demonstrated clinical activity similar to mobocertinib, [the second approval]. The key difference [between them] is that mobocertinib is an oral agent while amivantamab is an infusional agent, and…some patients prefer oral therapies [because they minimize] visits to the doctor’s office. The choice between them [comes down to] patient preference.

Amivantamab is also very well tolerated aside from some infusion reactions on the first day of administration. Patients [tend to] tolerate the drug very well after those initial reactions, and while some patients also suffer skin toxicity, it tends to be easily managed. GI toxicities also tend to be substantially less severe with amivantamab vs mobocertinib.

What should your colleagues take away from the from this research?

Both mobocertinib and amivantamab are good treatment options for patients with EGFR exon 20 mutations. There are differences [between them] regarding patient quality of life, AE profiles, and route of administration, and so, [for example], patients [may prefer] oral mobocertinib to avoid frequent trips to the physician's office.

We don’t yet know if we could use these treatments in sequence. We don’t have [sufficient] clinical data. One treatment may work well after patients progress on the other treatment, [but we can’t yet say]. Although responses to these two drugs have been promising, patients still progress at some point, and so [we need to know] if we can we sequence to a different EGFR exon 20 inhibitor upon progression. We’ll see more data on that question published very soon.

[Additionally], there are many promising EGFR exon 20 inhibitors [currently] in development. We’re looking forward to more data on drugs like CLN-081, as well as other agents still in early preclinical development. There are many promising potential treatment options for this patient population.

References

1. Janne PA, Ramalingam SS, Yang CHY, et al. Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic non–small cell lung cancer (mNSCLC): Treatment (tx) beyond progressive disease (PD) in platinum-pretreated patients (pts) with and without intracranial PD. J Clin Oncol. 2022;40(16):9099. doi:10.1200/JCO.2022.40.16_suppl.9099
2. FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. News release. FDA. September 16, 2021. Accessed September 19, 2022. https://bit.ly/3dq2CXH
3. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed September 19, 2022. https://bit.ly/3BSO6Bc