Mobocertinib induces anticancer responses in advanced platinum + pretreated EGFR 20 insertion NSCLC
Class-leading EGFR tyrosine kinase (TKI) inhibitor mobocertinib elicited rapid, profound and long-lasting responses and demonstrated a tolerable safety profile in patients with pretreated platinum EGFR exon 20 metastatic insertion positive non-small cell lung cancer (mNSCLC), according to updated results from an ongoing phase 1/2 study (NCT02716116) presented virtually at the ASCO 2021 annual meeting.
In the cohort of platinum-pretreated patients (n = 114), the confirmed overall response rate (ORR) by Independent Review Committee (IRC) assessment was 28% (95% CI, 20% to 37 %); all responses were partial responses (PR). Based on the investigator’s assessment, the confirmed ORR was 35% (95% CI, 26% to 45%); the complete response rate (CR) was less than 1% and the PR rate was 34%.
The median duration of response (DOR) was 17.5 months (95% CI: 7.4 to 20.3) according to CRF and 11.2 months (95% CI, 5.6 – not evaluable ). [NE]) by the investigator’s assessment. The confirmed disease control rate (DCR) was 78% (95% CI, 69% to 85%) based on CRF 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 to 9.2) .
“Based on these data, we believe that mobocertinib is a potential treatment option for patients with EGFR 20 insertion mutations, ”said study lead author Suresh S. Ramalingam, MD, FASCO, Professor in the Department of Hematology and Medical Oncology, Roberto C. Goizueta Distinguished Chair for cancer research, associate dean for cancer research and director of the Division of Medical Oncology, Department of Hematology and Medical Oncology, Emory University School of Medicine in a virtual data presentation.
“Mobocertinib is an orally administered tyrosine kinase inhibitor that is specifically 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 at the Winship Cancer Institute at Emory University. “Among EGFR mutations, the 20 insertion mutations represent about 10%.
The first part of the three-part study used a 3 + 3 dose escalation Phase 1 design to assess mobocertinib in patients with advanced NSCLC. Part 2 of the study used a phase 2 dose extension schedule to assess daily mobocertinib at 160 mg.
In total, 7 cohorts and 1 extension cohort (EXCLAIM; part 3 of the study) will be evaluated.
The median duration of follow-up was 14.2 months (range 0.7-35.8) in the cohort of platinum-pretreated patients and 13.0 months (range 0.7-18.8) in the EXCLAIM cohort.
Cohort 1 evaluated patients who received previous platinum therapy and who had refractory patients EGFR mNSCLC positive on exon 20 insertion and no active or measurable central nervous system metastasis.
Patients had a median age of 60 years (range, 27-84); 66% of patients were women and the majority of patients were Asian (60%). Almost all patients had an adenocarcinoma histology (98%) and an ECOG performance index (PS) of 1 (75%).
In particular, the majority of patients had never smoked (71%).
The median number of previous cancer treatment regimens was 2; 100% of patients received platinum-based chemotherapy, 43% received immunotherapy, and 25% received EGFR TKIs.
Finally, 35% of patients had brain metastases on inclusion.
In addition, the results of a second cohort of extension patients (EXCLAIM; n = 96) were presented in the virtual poster. The patients included in the EXCLAIM cohort had previously treated EGFR NSCLC positive on insertion of exon 20. In this cohort, 86 patients had previously received platinum-based therapy.
Baseline patient characteristics were similar in this cohort compared to the cohort of platinum-pretreated patients. The median age of the patients was 59 years (range: 27-80), 65% of the patients were female, and most of the patients were of Asian descent (69%). The vast majority of patients had an adenocarcinoma histology (99%) and an ECOG PS of 1 (71%). Most of the patients had never smoked (73%).
The median number of prior lines of cancer treatment in the EXCLAIM cohort was 1; 90% of patients received platinum-based chemotherapy, 34% received immunotherapy and 31% received EGFR TKIs.
Finally, 34% of patients had brain metastases on inclusion.
In this cohort, the ORR confirmed by CRI was 25% (95% CI, 17% to 35%); all responses were PRs. The ORR confirmed by the investigator’s assessment was 32%; 1% of patients achieved CR and 31% RP.
The median DOR was NE (95% CI, 5.6-NE) according to CRF and 11.2 months (95% CI, 7.0-NE) according to the investigator’s assessment. The confirmed DCRs were 76% (95% CI, 66% to 84%) and 75% (95% CI, 65% to 83%), respectively.
In the EXCLAIM cohort, 60% (n = 58) of patients presented with progressive disease according to the investigator’s assessment. The brain was the primary site of disease progression in 38% (n = 22) of patients. Of these patients, 23% (n = 5) continued treatment with mobocertinib for at least 3 months after initial disease progression. The median duration of treatment beyond initial disease progression was 1.6 months (95% CI, -0.2-6.7).
Additionally, in the remaining 62% of patients (n = 36) who had progressive disease in initial sites other than the brain, 6% (n = 2) continued mobocertinib for at least 3 months after progressive disease. initial. The median duration of treatment beyond initial disease progression was 0.1 months (95% CI, -1.0-10.0).
In the EXCLAIM cohort, 33 patients presented with brain metastases at baseline. Of these patients, 76% (n = 25) developed progressive disease according to the investigator’s assessment, of which 68% reported the brain as the primary 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 were still on mobocertinib at the time of data closure. The median duration of treatment was 7.4 months (range, 0.0-34.0) and 6.8 months (range, 0.0-18.8), respectively.
“Almost 85% of the patients in this study had some level of tumor shrinkage. [with mobocertinib]… And almost 50% of patients with an objective response still have an ongoing response at the time of data close for this presentation, ”said Ramalingam.
Notably, in the cohort of platinum-pretreated patients, responses were observed in all subgroups evaluated, regardless of prior treatment with TKI EGFR, prior immunotherapy, or EGFR variant of the insertion mutation of exon 20.
In addition, the safety profile observed with mobocertinib was consistent with the known profiles of EGFR TKIs.
Regarding safety in the cohort of platinum-pretreated patients, all patients (100%) reported adverse reactions (AEs) of any grade and 99% of patients reported treatment-related AEs (TRAE) of any grade. Of these, any AEs of grade 3 or greater were seen in 69% of patients and any AEs of grade 3 or greater were seen in 47% of patients.
Serious AEs were noted in 49% of patients; 46% of them were grade 3 or higher. A quarter of patients (25%) experienced an AE that resulted in dose reduction and 17% an AE that resulted in discontinuation of treatment.
The most frequently reported AEs leading to discontinuation of treatment in this cohort included diarrhea (4%), nausea (4%), vomiting (2%), decreased appetite (2%) and stomatitis (2%). Other common AEs of all grades included rash, paronychia, dry skin, increased creatinine, and pruritus.
In the EXCLAIM cohort, any adverse reaction of any grade was reported in 100% of patients, 66% of which were grade 3 or higher. Almost all of the patients (99%) reported adverse reactions of any grade, 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 presented with an AE requiring dose reduction, and 10% of patients presented with an AE requiring discontinuation.
Nausea and diarrhea were the most frequently reported AEs that required discontinuation of treatment in the EXCLAIM cohort. Other AEs included rash, paronychia, decreased appetite, dry skin, increased creatinine, stomatitis, vomiting, acneiform dermatitis, pruritus, and increased amylase.
It should be noted that one treatment-related death from heart failure occurred in the EXCLAIM cohort in a patient previously treated with platinum.
In the EXCLAIM cohort, patient-reported outcome data demonstrated average improvements over baseline in European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 scores for dyspnea, cough and chest pain. Despite the worsening of the gastrointestinal symptom scores, the 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 the EXCLAIM cohort of the phase 1/2 study. J Clin Oncol. 2021; 39 (suppl 15): 9014. doi: 10.1200 / JCO.2021.39.15_suppl.9014