Mobocertinib Shows Encouraging ORR in EGFR Exon 20–Mutant Advanced NSCLC

Pasi A. Jänne, MD, PhD

Mobocertinib (formerly TAK-788) demonstrated clinically meaningful benefit and a manageable safety profile in previously treated patients with metastatic non–small cell lung cancer (NSCLC) who have EGFR exon 20 insertion mutations, according to phase 1/2 data that were presented during the International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer.¹

In patients who were previously treated with platinum-based chemotherapy, the confirmed objective response rate (ORR) was 26% (95% CI, 19%-35%) per an independent review committee (IRC), and 35% (95% CI, 26%-45%) per investigator assessment. The median progression-free survival (PFS), via both IRC and investigator assessment, was 7.3 months.

In a second cohort of patients who were received a prior EGFR TKI, the confirmed ORR was 23% (95% CI, 15%-33%) per IRC, and 32% (95% CI, 23%-43%) per investigator assessment; the median PFS was 7.3 months. By investigator assessment, it was 7.1 months.

Additionally, the safety profile of mobocertinib was consistent with the known profiles of other EGFR TKIs. Given that this is a patient population for which no other approved targeted therapies exist, results from this study represent encouraging progress, stated Takeda, the manufacturer of mobocertinib.²

“Results show mobocertinib demonstrated clinically meaningful responses and a noteworthy duration of response in patients with EGFR exon 20 insertion–positive metastatic NSCLC who received prior platinum-based therapy,” said Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute. “These data are promising and provide further evidence for mobocertinib as a potential oral treatment for patients with EGFR exon 20 insertion–mutant metastatic NSCLC, who are in critical need of targeted treatment options.”

Mobocertinib is a potent, small-molecule TKI specifically designed to selectively target EGFR exon 20 insertion mutations. Mobocertinib received breakthrough therapy designation from the FDA in April 2020 for patients with EGFR exon20 insertion–mutant metastatic NSCLC, whose disease has progressed on or after platinum-based chemotherapy. Most recently, in October 2020, mobocertinib was designated as a breakthrough therapy in China by the Drug Review Center for the same indication.

The study was comprised of a phase 1 dose-escalation portion, which is evaluating mobocertinib alone and in combination with chemotherapy, and a phase 2 expansion, which included 7 different cohorts, plus an extension cohort, aimed at investigating the antitumor activity of mobocertinib.

The platinum-pretreated population (PPP) cohort analysis investigated 114 patients with EGFR exon 20 insertion–mutant metastatic NSCLC who received prior platinum-based therapy from the dose-escalation and -expansion phases of the phase 1/2 trial and were treated with mobocertinib at a 160-mg, once-daily dose.

The phase 2 extension cohort, known as EXCLAIM, investigated 96 previously treated patients with EGFR exon 20 insertion–mutant metastatic NSCLC who were treated with mobocertinib at the 160-mg dose.

The primary endpoint for the study was confirmed ORR, as assessed by IRC, while secondary endpoints included safety, tolerability, and efficacy.

In the analysis of the PPP cohort (n = 114), the median age was 60 years (range, 27-84), 66% were female, and 60% were of Asian descent. Thirty-two percent of patients had received at least 2 prior systemic lines of anticancer therapy (range, 1-7). Moreover, the median time on treatment was 7.0 months (range, 0-31).

In EXCLAIM (n = 96), the median age of patients was 59 years (range, 27-80). Sixty-five percent of patients were female, 69% were of Asian descent, and 31% had more than 2 prior systemic lines of therapy (range, 1-4). The median time on treatment was 6.5 months (range, 0-14). The median duration of response, per Kaplan-Meier estimates, was not estimable.

Amongst the PPP cohort, mobocertinib resulted in reductions of target lesions volume, with 82% of patients (n = 94) experiencing a reduction from baseline in the sum of target lesion diameter. Results were similar in the EXCLAIM cohort, with 80% of patients (n = 77) also experiencing a reduction from baseline in the sum of target lesion diameter.

Additionally, confirmed ORRs with mobocertinib were similar among all prespecified subgroups. In Asian versus non-Asian patients in the PPP cohort, the ORRs were 28% and 22%, respectively, while in the EXCLAIM cohort the ORRs were 24% and 20%, respectively.

In those who received prior immunotherapy versus those without in the PPP cohort, the ORRs were 25% and 28%, respectively, while this subgroup in the EXCLAIM cohort had ORRs of 21% and 24%, respectively.

Finally, those who received a prior EGFR TKI versus those who did not in the PPP cohort had ORRs of 21% and 28%, respectively. In the EXCLAIM cohort, these rates were 15% and 26%, respectively.

The safety profile observed in the analysis demonstrated that mobocertinib was manageable. Some of the most common treatment-related adverse events (TRAEs; ≥20%) in platinum-pretreated patients were diarrhea (90%), rash (45%), paronychia (34%), nausea (32%), decreased appetite (32%), dry skin (30%) and vomiting (30%). Grade 3 or higher TRAEs (≥5%) included diarrhea (21%). Nineteen patients (17%) discontinued due to AEs, most commonly due to diarrhea (4%), nausea (4%), vomiting (2%), decreased appetite (2%), and stomatitis (2%). The safety profile observed in EXCLAIM was largely consistent with that observed in the platinum-pretreated population.

“The importance of advancing research for people living with EGFR exon 20 insertion–mutant metastatic NSCLC—a complex and devastating disease with no approved targeted therapies— cannot be overstated, as existing treatment options provide limited benefit and patients often have poor survival outcomes,” said Christopher Arendt, head, Oncology Therapeutic Area Unit, Takeda. “We’re proud of these positive results from mobocertinib, the first oral therapy designed to selectively target their disease, and we look forward to submitting data from the platinum-pretreated population analysis to the FDA and other regulatory agencies around the globe.”

References

1. Zhou C, Ramalingam S, Li B, et al. Mobocertinib in NSCLC with EGFR exon 20 insertions: results from EXCLAIM and pooled platinum-pretreated patient populations. Presented at: International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual.
2. Takeda presents positive results for mobocertinib in patients with EGFR exon20 insertion+ mNSCLC who received prior platinum-based chemotherapy. News release. Takeda. January 28, 2021. Accessed January 29, 2021. https://bit.ly/36oWCHT