FDA Approves EXKIVITY® for Metastatic Non Small Cell Lung Cancer with EGFR exon 20 Insertion Mutations

SUMMARY: The FDA on September 15, 2021, granted accelerated approval to EXKIVITY® (Mobocertinib), for adult patients with locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after Platinum-based chemotherapy. The FDA also approved the Oncomine Dx Target Test as a companion diagnostic device to select patients with the above mutations for EXKIVITY® treatment.

The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions, and occur in about 2-3% patients with NSCLC, and are insensitive to EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5 year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. There is therefore a clinically unmet need for this patient group, as there are no approved targeted therapies available and platinum-doublet chemotherapy remains the standard of care for these patients.

EXKIVITY® is a novel oral EGFR TKI, that was designed to address the unmet need in patients with EGFR exon 20 insertion mutant positive NSCLC. EXKIVITY® was designed to potently inhibit oncogenic variants containing activating mutations in exon 20, with selectivity over Wild Type EGFR.

The present FDA approval of EXKIVITY® was based on an international, non-randomized, open-label, multicohort clinical trial (NCT02716116) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. This trial was conducted in three parts- Dose escalation or Part 1, to determine the safety profile of EXKIVITY®, Expansion phase or Part 2, to evaluate the antitumor activity of EXKIVITY® in seven histologically and molecularly defined cohorts, and Extension phase or Part 3, to evaluate efficacy of EXKIVITY® in patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations, and who have been previously treated.

So, this 3-part, multicenter study has dose-escalation/expansion and extension (EXCLAIM) cohorts. Patients with EGFR exon 20 insertion positive metastatic NSCLC, with ECOG status 0-1, and one or more prior lines of therapy for locally advanced/metastatic disease, received EXKIVITY® 160 mg orally daily, until disease progression or intolerable toxicity. Efficacy was evaluated in 114 patients whose disease had progressed on or after Platinum-based chemotherapy. Among these platinum pretreated patients, the median age was 60 years, 66% were female, 60% were Asian, and 59% had 2 or more prior systemic therapies. The main efficacy outcome measures were confirmed Objective Response Rate (ORR) assessed by blinded Independent Review Committee (IRC) and Duration of Response.

At a median follow up of 14.2 months, the ORR was 28%, with a median Duration of Response of 17.5 months. The median Progression Free Survival was 7.3 months and the median Overall Survival was 24 months. Clinically meaningful improvements were observed for dyspnea, coughing, chest pain, and these benefits were evident by cycle 2, and maintained throughout treatment. The most common adverse reactions were rash, nausea, stomatitis, vomiting, diarrhea, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain.

It was concluded that EXKIVITY® is the first and only oral therapy specifically designed to target EGFR exon 20 insertions, and the present FDA approval is an important addition, designed for this patient population.

Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study. Ramalingam SS, Zhou C, Kim TM, et al. J Clin Oncol. 2021;39(suppl 15):9014. DOI:10.1200/JCO.2021.39.15_suppl.9014.