Mobocertinib Suggests Benefit for Patients With NSCLC Harboring EGFR Exon 20 Insertions

Pasi A. Jänne, MD, PhD

Mobocertinib (TAK-788), a small molecule tyrosine kinase inhibitor (TKI), provides promise for a new potential option for the treatment of patients with metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, following a Breakthrough Therapy designation granted by the FDA in April 2020. Findings from a dose-escalation study were presented during the 2020 European Society of Medical Oncology (ESMO) Congress, indicating a 43% objective response rate (ORR) and an 86% disease control rate for mobocertinib in patients with NSCLC and EGFR exon 20 insertions.

Both the partial response and stable disease rates were 43% among those who received the recommended phase 2 dose of 160 mg. Two patients had progressive disease among the 28 patients treated in this phase 1/2 clinical trial (NCT02716116). The median duration of response was 13.9 months (96% CI, 5.0-not reached), and the median progression-free survival was 7.3 months.

The safety profile was found to be manageable and consistent with that of other EGFR TKIs. All-grade and grade 3 or higher treatment-related adverse events included, respectively, diarrhea in 82% and 32%, nausea in 39% and 11%, rash in 46% and 0%, vomiting in 36% and 7%, decreased appetite in 39% and 0%, dry skin in 18% and 0%, and fatigue in 14% and 4%.

Unlike other EGFR TKIs, mobocertinib is specifically designed to target EGFR exon 20 insertions rather than only the EGFR mutation. Overall, these findings are encouraging for patients with NSCLC harboring an EGFRexon 20 insertions.

In an interview with Targeted Oncology, Pasi A. Jänne, MD, PhD, director, Lowe Center for Thoracic Oncology, director Belfer Center for Applied Cancer Science, director, Chen-Huang Center for EGFR Mutant Lung Cancers; senior physician, Dana-Farber Cancer Institute, and professor, Medicine, Harvard Medical School, discussed the updated findings from the phase 1/2 study of mobocertinib as treatment of patients with NSCLC who harbor an EGFR exon 20 insertions.

TARGETED ONCOLOGY: What are the current unmet needs for patients with NSCLC who harbor EGFR exon 20 insertions?

Jänne: This is a subset of about 8% to 10% of EGFR-mutant lung cancers, and unlike the other subtypes of EGFR-mutant lung cancer where we have, in some cases, multiple approved therapies, we don't have an approved or effective therapy for the EGFR exon 20 patients. It's been a challenge and a struggle in the field to try to find an effective therapy that would have the same kind of benefit as we see now for the other approved agents.

TARGETED ONCOLOGY: What was the rationale for mobocertinib in this patient population?

Jänne: Mobocertinib is a next-generation EGFR inhibitor, and it was specifically designed preclinically to try to be more effective against the exon 20 insertions. I will say that in prior iterations, several EGFR inhibitors had been tried for this patient population, which were repurposed for this patient population, unlike mobocertinib, which is specifically designed to be more effective against the exon 20 insertions.

This trial then decided to test that hypothesis in phase 1/2 study, and the data that were presented at ESMO included the escalation and expansion doses of the patient population at 160 milligram, which is the dose moving forward.

TARGETED ONCOLOGY: What were the methods of design for this study?

Jänne: This was a typical dose-escalation trial, and a typical phase 1 that started at doses as low as 5 mg and went all the way up to 180 mg. Ultimately, the 160 mg dose was felt to be the maximum tolerated dose, and was the dose used in the expansion cohort for this patient population. Patients were those who had been previously treated with agents that we commonly use to treat NSCLC, and, in general, patients had received several prior lines of anti-cancer therapy, so it's a relatively heavily-pretreated patient population enrolled into this particular trial.

TARGETED ONCOLOGY: What were the results that were presented at this year's meeting?

Jänne: In this patient population, which includes 28 patients, at that recommended 160 mg dose, there was a 43% confirmed ORR, and the duration of response was 13.9 months. The median progression-free survival in this patient population was 7.3 months. One of the things that we also noted was that the responses were not necessarily localized to 1 particular exon 20 insertion. These exon 20 insertions are not 1 mutation; it's a series of mutations across a spectrum that happens in EGFR. So far, at least, we think that responses can be seen across the board and can be seen in patients who have or have not had prior chemotherapy, or prior immune checkpoint inhibitor therapy.

TARGETED ONCOLOGY: What did the safety profile of mobocertinib look like?

Jänne: In terms of the safety profile, the most common side effects that are seen with mobocertinib are gastrointestinal (GI) side effects, so they include things like diarrhea, nausea, and vomiting. We do see some evidence of skin toxicity, which is a common feature of EGFR-related toxicities, and we're developing strategies to try to manage, for example, the GI toxicities, with food or with other strategies as we want patients to be able to stay on therapy for a long period of time if it's an effective therapy against their cancer, but that therapy, of course, needs to be tolerable.

TARGETED ONCOLOGY: What do you think the clinical impact of these results will be, although it is still early?

Jänne: This has led to subsequent studies. There is a greater expansion cohort that has completed enrollment, and we'll hopefully find the data from that early next year. There's also now been a randomized phase 3 clinical trial that has begun enrolling patients who have never received previous anti-cancer therapy who have an exon 20 insertion. These patients are randomized to mobocertinib or to first-line chemotherapy.

I think the signals here are sufficient enough that it warrants further testing. The agent has also received the Breakthrough Therapy designation from the FDA. We hope that ultimately it will be an approved therapy and something that we can treat our patients with in the future.

TARGETED ONCOLOGY: What is your key takeaway?

Jänne: The general take-home message is that this is a potential targeted therapy for patients with this subtype of EGFR-mutant lung cancer with the exon 20 insertion. We hope that the data we've seen so far will be reproduced in subsequent trials and in greater numbers of patients, but I think patients and doctors alike should remain optimistic that we're finally at a point where we're starting to have effective therapies for this population of patients where we really have not been able to have effective therapies in the past.

_Reference

_{Riely GJ, Neal JW, Camidge DR, et al. Updated results from a phase 1/2 study of mobocertinib (TAK-788) in NSCLC with EGFR exon 20 insertions. Presented at: 2020 ESMO Congress; September 19-21, 2020; virtual. Abstract 1261M0.}