Mobocertinib, elicited rapid, deep, and durable responses and demonstrated a tolerable safety profile in patients with platinum-pretreated EGFR exon 20 insertion–positive metastatic non–small cell lung cancer in a phase 1/2 study.
The first-in-class, oral, EGFR tyrosine kinase inhibitor (TKI), mobocertinib, elicited rapid, deep, and durable responses and demonstrated a tolerable safety profile in patients with platinum-pretreated EGFR exon 20 insertion–positive metastatic non–small cell lung cancer (mNSCLC), according to updated findings from an ongoing phase 1/2 study (NCT02716116) presented virtually during the 2021 ASCO Annual Meeting.
In the platinum-pretreated patient cohort (n = 114), the confirmed overall response rate (ORR) by independent review committee (IRC) assessment was 28% (95% CI, 20%-37%); all responses were partial responses (PRs). By investigator assessment, the confirmed ORR was 35% (95% CI, 26%-45%); the complete response (CR) rate was less than 1%, and the PR rate was 34%.
The median duration of response (DOR) was 17.5 months (95% CI, 7.4-20.3) by IRC and 11.2 months (95% CI, 5.6-not evaluable [NE]) by investigator assessment. The confirmed disease control rate (DCR) was 78% (95% CI, 69%-85%) by IRC and investigator assessment.
The median overall survival was 24.0 months (95% CI, 14.6-28.8), and the median progression-free survival was 7.3 months (95% CI, 5.5-9.2).
“Based on these data, we believe that mobocertinib is a potential treatment option for patients with EGFR 20 insertion mutations,” said lead study author Suresh S. Ramalingam, MD, FASCO, a professor in the Department of Hematology and Medical Oncology, the Roberto C. Goizueta Distinguished Chair for Cancer Research, assistant dean for Cancer Research, and director of the Division of Medical Oncology in the Department of Hematology and Medical Oncology at Emory University School of Medicine during a virtual presentation of the data.
“Mobocertinib is an orally administered tyrosine kinase inhibitor that is specifically being developed for the treatment of [patients with] EGFR [exon] 20 insertion mutations,” added Ramalingam, who is also deputy director and director of the Lung Cancer Program of Winship Cancer Institute of Emory University. “Among EGFR mutations, the insertion 20 mutations account for approximately 10%.”
Part 1 of the 3-part study utilized a 3+3 dose-escalation, phase 1 design to evaluate mobocertinib in patients with advanced NSCLC. Part 2 of the study utilized a phase 2 dose-expansion schema to evaluate daily mobocertinib at 160 mg.
In total, 7 cohorts and 1 extension cohort (EXCLAIM; part 3 of the study) will be evaluated.
The median follow-up time was 14.2 months (range, 0.7-35.8) in the platinum-pretreated patient cohort and 13.0 months (range, 0.7-18.8) in the EXCLAIM cohort.
Cohort 1 evaluated patients who received prior platinum-based therapy and had refractory EGFR exon 20 insertion–positive mNSCLC and no active or measurable central nervous system metastases.
Patients were a median age of 60 years (range, 27-84); 66% of patients were female, and the majority of patients were Asian (60%). Nearly all patients had adenocarcinoma histology (98%) and an ECOG performance status (PS) of 1 (75%).
Notably, the majority of patients were never smokers (71%).
The median number of prior anticancer regimens was 2; 100% of patients received prior platinum-based chemotherapy, 43% received prior immunotherapy, and 25% received prior EGFR TKIs.
Finally, 35% of patients had baseline brain metastases.
Additionally, findings from a second, extension cohort of patients (EXCLAIM; n = 96) were presented in the virtual poster. Patients included in the EXCLAIM cohort had previously treated EGFR exon 20 insertion–positive mNSCLC. In this cohort, 86 patients had received prior platinum-based therapy.
Baseline patient characteristics were similar in this cohort vs the platinum-pretreated patient cohort. The median patient age was 59 years (range, 27-80), 65% of patients were female, and most patients were of Asian descent (69%). The vast majority of patients had adenocarcinoma histology (99%) and an ECOG PS of 1 (71%). Most patients were never smokers (73%).
The median number of prior lines of anticancer therapy in the EXCLAIM cohort was 1; 90% of patients received prior platinum-based chemotherapy, 34% received prior immunotherapy, and 31% received prior EGFR TKIs.
Finally, 34% of patients had baseline brain metastases.
In this cohort, the confirmed ORR by IRC was 25% (95% CI, 17%-35%); all responses were PRs. The confirmed ORR by investigator assessment was 32%; 1% of patients achieved a CR and 31% achieved PRs.
The median DOR was NE (95% CI, 5.6-NE) by IRC and 11.2 months (95% CI, 7.0-NE) by investigator assessment. The confirmed DCRs were 76% (95% CI, 66%-84%) and 75% (95% CI, 65%-83%), respectively.
In the EXCLAIM cohort, 60% (n = 58) of patients experienced progressive disease by investigator assessment. The brain was the first site of progressive disease in 38% (n = 22) of patients. Of these patients, 23% (n = 5) continued on mobocertinib for at least 3 months after initial progressive disease. The median time on treatment beyond initial progressive disease was 1.6 months (95% CI, -0.2-6.7).
Additionally, in the remaining 62% of patients (n = 36) who experienced progressive disease in initial sites other than the brain, 6% (n = 2) continued on mobocertinib for at least 3 months after initial progressive disease. The median time on treatment beyond initial progressive disease was 0.1 months (95% CI, -1.0-10.0).
In the EXCLAIM cohort, 33 patients had brain metastases at baseline. Of these patients, 76% (n = 25) developed progressive disease by investigator assessment, 68% of which reported the brain as the first site of progressive disease.
Additional results indicated that 23% of patients (n = 26) in the platinum-pretreated patient cohort and 26% of patients (n = 25) in the EXCLAIM cohort remained on mobocertinib at the time of the data cut-off. The median time on treatment was 7.4 months (range, 0.0-34.0) and 6.8 months (range, 0.0-18.8), respectively.
“Nearly 85% of patients in this study had some level of tumor shrinkage [with mobocertinib]…and nearly 50% of patients with an objective response still have an ongoing response at the time of data cut-off for this presentation,” said Ramalingam.
Notably, in the platinum-pretreated patient cohort, responses were observed in all evaluated subgroups irrespective of prior EGFR TKI treatment, prior immunotherapy, or EGFR exon 20 insertion mutation variant.
Additionally, the safety profile observed with mobocertinib was consistent with the known profiles of EGFR TKIs.
Regarding safety in the platinum-pretreated patient cohort, all patients (100%) reported any-grade adverse effects (AEs), and 99% of patients reported any-grade treatment-related AEs (TRAEs). Of these, any grade 3 or greater AEs were observed in 69% of patients and any grade 3 or greater TRAEs were observed in 47% of patients.
Serious AEs were noted in 49% of patients; 46% of these were grade 3 or greater. A quarter of patients (25%) experienced an AE that led to dose reduction and 17% experienced an AE that led to treatment discontinuation.
The most commonly reported AEs that led to treatment discontinuation in this cohort included diarrhea (4%), nausea (4%), vomiting (2%), decreased appetite (2%), and stomatitis (2%). Other common any-grade AEs included rash, paronychia, dry skin, increased creatinine, and pruritus.
In the EXCLAIM cohort, any any-grade AEs were reported in 100% of patients, 66% of which were grade 3 or greater. Nearly all patients (99%) reported any-grade TRAEs, 42% of which were grade 3 or greater. Serious AEs were observed in 47% of patients, of which 44% were grade 3 or greater. Additionally, 22% of patients experienced an AE that required dose reduction, and 10% of patients experienced an AE that required treatment discontinuation.
Nausea and diarrhea were the most frequently reported AEs that required treatment discontinuation in the EXCLAIM cohort. Other AEs included rash, paronychia, decreased appetite, dry skin, increased creatinine, stomatitis, vomiting, dermatitis acneiform, pruritus, and increased amylase.
Of note, one treatment-related death from cardiac failure occurred in the EXCLAIM cohort in a platinum-pretreated patient.
In the EXCLAIM cohort, patient-reported outcome data demonstrated mean improvements from baseline in European Organisation for Research and Treatment of Cancer (EORTC) QLQ-LC13 scores for dyspnea, cough, and pain in chest. Despite worsening gastrointestinal symptom scores, mean EORTC QLQ-C30 Global Health Status/Quality of Life scores were preserved with mobocertinib.
Ramalingam SS, Zhou C, Kim TM, et al. Mobocertinib (TAK-788) in EGFR exon 20 insertion+ metastatic NSCLC: additional results from platinum-pretreated patients and EXCLAIM cohort of phase 1/2 study. J Clin Oncol. 2021;39(suppl 15):9014. doi:10.1200/JCO.2021.39.15_suppl.9014