Mobocertinib only as good as platinum chemo in first-line NSCLC treatment

In the first-line treatment of locally advanced or metastatic nonsmall cell lung cancer (NSCLC) patients with EGFR exon 20 insertion (ex20ins) mutations, the investigational mobocertinib is safe and efficacious but not necessarily better than platinum-based chemotherapy, according to the phase III EXCLAIM-2 trial.

Results of the interim analysis showed that the primary endpoint of blinded independent centralized review (BICR)-assessed progression-free survival (PFS) was 9.6 months in both the mobocertinib and chemotherapy arms (hazard ratio [HR], 1.04, 95 percent confidence interval [CI], 0.77–1.39; p=0.803). [ESMO Asia 2023, abstract 507O]

“The primary endpoint crossed the prespecified futility boundary, and the trial hence is being discontinued,” reported lead investigator Dr Pasi Jänne of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute in Boston, Massachusetts, US.

“No benefit in PFS was observed in any of the prespecified patient subgroups,” Jänne added.

The overall response rate (ORR) was 32 percent with mobocertinib and 30 percent with chemotherapy. The respective disease control rates were 87 percent and 80 percent, and all the responses were partial responses, except for one complete response with chemotherapy.

Median time to response was shorter with mobocertinib at 1.5 months as opposed to 2.8 months with chemotherapy, which Jänne noted was typical for tyrosine kinase inhibitor (TKI) type of responses. Moreover, the duration of response was longer among mobocertinib-treated patients than among those who received chemotherapy (median, 12.0 vs 8.4 months; HR, 0.48, 95 percent CI, 0.26–0.88).

The overall survival (OS) was similar between the two treatment arms (not evaluable with mobocertinib vs 30.0 months with chemotherapy; HR, 0.98, 95 percent CI, 0.62–1.54).

“At the time of the analysis, 34 percent of the patients [in] the mobocertinib arm and 23 percent [of those] in the chemotherapy arm remained on the assigned treatment,” with a median follow-up duration of 13.1 and 13.8 months, respectively, Jänne said.

Giving an overview of safety, Jänne noted that treatment-emergent adverse events (TEAEs) leading to dose interruption and dose reduction occurred more frequently in the mobocertinib than in the chemotherapy arm (interruption: 70 percent vs 6 percent; reduction: 45 percent vs 20 percent). Diarrhoea was by far the most common side effect in the mobocertinib arm, with 20 percent of patients having grade ≥3 diarrhoea, whereas only 1 percent of patients in the chemotherapy arm had.

A few on-study deaths were recorded in the mobocertinib and chemotherapy arms due to progressive disease (6 percent and 2 percent, respectively). One case of treatment-related death occurred, and this was a patient in the chemotherapy arm who had sepsis.

Mobocertinib delayed time to deterioration in lung cancer symptoms, as well as cognitive function (HR, 0.60, 95 percent CI, 0.42–0.86) and constipation (HR, 0.19, 95 percent CI, 0.11–0.33), but shortened time to deterioration in symptoms such as diarrhoea (HR, 16.73, 95 percent CI, 10.21–27.41) and appetite loss (HR, 1.90, 95 percent CI, 1.35–2.68) compared with chemotherapy.

“Based on the results of this phase III clinical trial, [the sponsor] is working towards voluntary withdrawal of the marketing authorizations for mobocertinib globally,” Jänne said.

EXCLAIM-2 included 179 patients in the mobocertinib arm (median age 64 years, 60 percent women) and 175 patients in the chemotherapy arm (median age 62 years, 66 percent women). Mobocertinib was administered orally at 160 mg per day with or without food. Meanwhile, the chemotherapy regimen consisted of pemetrexed 500 mg/m² plus either cisplatin 75 mg/m² or carboplatin AUC 5.

A first-in-class, oral EGFR TKI that targets in-frame EGFRex20ins mutations, mobocertinib demonstrated better potency and selectivity for EGFRex20ins over wild-type EGFR in preclinical and phase I/II studies. [Cancer Discov 2021;11:1672-1699; ESMO Congress 2022, poster 988P]