Mobocertinib Does Not Improve PFS Vs Chemotherapy in EGFR Exon 20+ NSCLC

“The efficacy of mobocertinib was not superior to platinum-based chemotherapy as first-line treatment of EGFR [exon 20 insertion–positive] NSCLC,” according to the study authors.

Frontline mobocertinib (Exkivity) did not meet the primary end point of progression-free survival (PFS) compared with platinum-based chemotherapy among those with advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, according to data from the phase 3 EXCLAIM-2 trial (NCT04129502) published in the Journal of Clinical Oncology.¹

Based on blinded independent central review (BICR), the median PFS was 9.6 months (95% CI, 7.1-11.1) with mobocertinib vs 9.6 months (95% CI, 7.2-11.4) with chemotherapy (HR, 1.04; 95% CI, 0.77-1.39; P = .803). Additionally, the median PFS per investigator evaluation was 8.6 months (95% CI, 6.9-9.9) and 8.4 months (95% CI, 7.1-11.1) in each respective arm. Data showed no differences in PFS outcomes with mobocertinib vs chemotherapy across prespecified subgroups.

Mobocertinib yielded a confirmed objective response rate (ORR) of 32% (95% CI, 26%-40%) vs 30% (95% CI, 24%-38%) with chemotherapy per BICR; the respective rates were 37% (95% CI, 30%-45%) vs 30% (95% CI, 24%-38%) per investigator assessment. Additionally, the median time to response in each arm was 1.5 months vs 2.8 months per BICR. The median duration of response (DOR) was 12.0 months (95% CI, 8.5-23.6) vs 8.4 months (95% CI, 5.7-11.0) based on BICR, respectively.

Data highlighted that the median overall survival (OS) was not estimable (NE; 95% CI, 22.6-NE) with mobocertinib vs 30.0 months (95% CI, 29.0-NE) with chemotherapy (HR, 0.98; 95% CI, 0.62-1.54). In each respective arm, the OS rates were 61% (95% CI, 49%-71%) vs 62% (95% CI, 50%-73%) at 2 years and 51% (95% CI, 36%-64%) vs 47% (95% CI, 30%-63%) at 3 years.

“The efficacy of mobocertinib was not superior to platinum-based chemotherapy as first-line treatment of EGFR [exon 20 insertion–positive] NSCLC,” Pasi A. Jänne, MD, PhD, wrote with study coauthors.¹ “The primary end point [of PFS] crossed the prespecified futility boundary, and the trial was discontinued prematurely.”

Jänne is senior vice president for Translational Medicine, director of the Belfer Center for Applied Cancer Science, director of the Chen-Huang Center for EGFR Mutant Lung Cancers, and David M. Livingston, MD, chair at Dana-Farber Cancer Institute as well as a professor of Medicine at Harvard Medical School.

In the open-label phase 3 EXCLAIM-2 trial, a total of 354 patients were randomly assigned to receive mobocertinib at 160 mg once daily (n = 179) or pemetrexed in combination with cisplatin or carboplatin every 3 weeks for 4 cycles followed by maintenance pemetrexed (n = 175).

The trial’s primary end point was PFS per BICR based on RECIST v1.1 criteria. Secondary end points included confirmed ORR, OS, DOR, time to response, time to deterioration (TTD), and health-related quality of life.

Patients 18 years and older with histologically or cytologically confirmed nonsquamous cell locally advanced, recurrent, or metastatic NSCLC and documented EGFR exon 20 insertion mutations were eligible for enrollment on the study.² Other eligibility criteria included having 1 or more measurable lesions per RECIST v1.1 guidelines, a life expectancy of 3 months or longer, an ECOG performance status of 0 or 1, and adequate organ and hematologic function.

The median age was 64 years (range, 25-87) in the mobocertinib arm and 62 years (range, 31-88) in the chemotherapy arm. Additionally, most patients in each respective arm were female (60% vs 66%), Asian (55% vs 56%), and had adenocarcinoma histology (99% vs 98%). Most of the study population had an ECOG performance status of 1 (53% vs 58%), no history of smoking (54% vs 61%), and stage IVB disease (55% vs 60%).

Based on EORTC QLQ-LC13 composite lung cancer symptoms scores, the median TTD was 9.4 months with mobocertinib vs 5.0 months with chemotherapy, with event rates of 46% and 56% in each arm (HR, 0.68; 95% CI, 0.50-0.93). Additionally, diarrhea events occurred in 84% vs 12% of patients (HR, 16.73; 95% CI, 10.21-27.41), appetite loss events affected 52% vs 34% (HR, 1.90; 95% CI, 1.35-2.68), and constipation events were reported in 9% vs 38% (HR, 0.185; 95% CI, 0.105-0.328).

At least 1 treatment-emergent adverse effect (AE) of any grade occurred in 99% of the mobocertinib arm and 98% of the chemotherapy arm, with grade 3 or higher events affecting 62% and 53% of patients in each arm. Serious TEAEs were highlighted in 36% and 25% of patients in each respective arm, with TEAEs resulting in dose modification in 77% vs 63%, dose interruption in 70% vs 6%, dose reduction in 45% vs 20%, and treatment discontinuation in 18% vs 20%.

The most common any-grade TEAEs in the mobocertinib and chemotherapy arms, respectively, included diarrhea (96% vs 18%), paronychia (47% vs 1%), decreased appetite (43% vs 29%), stomatitis (40% vs 14%), nausea (37% vs 47%), and dermatitis acneiform (35% vs 2%). Additionally, the most common grade 3 or higher TEAE was diarrhea in the mobocertinib arm (20%) and anemia in the chemotherapy arm (10%).

References

1. Jänne PA, Wang BC, Cho BC, et al. First-line mobocertinib versus platinum-based chemotherapy in patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer in the phase III EXCLAIM-2 trial. J Clin Oncol. 2025:JCO2401269. doi:10.1200/JCO-24-01269.
2. TAK-788 as first-line treatment versus platinum-based chemotherapy for non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. ClinialTrials.gov. Updated November 29, 2024. Accessed February 13, 2025. https://tinyurl.com/fzzxwmvn