FDA and Takeda to Withdraw Mobocertinib for EGFR Exon20+ NSCLC

• The FDA and Takeda are working on a voluntary withdrawal plan for mobocertinib (Exkivity) in patients with EGFR exon20 insertion mutation-positive locally advanced or metastatic non–small cell lung cancer (NSCLC) in the United States and globally.

• Although no new safety concerns arose in the phase 3 EXCLAIM-2 trial (NCT04129502), the study's primary end point was not achieved.

• Takeda is committed to ensuring that patients already on mobocertinib can continue treatment under appropriate conditions and healthcare provider consultation.

The FDA and Takeda have announced plans working towards a voluntary withdrawal of mobocertinib (Exkivity) for adult patients with EGFR exon20 insertion mutation-positive locally advanced or metastatic NSCLC whose disease has progressed on or after platinum-based chemotherapy in the United States.¹

In September 2021, accelerated approval was granted to mobocertinib by the FDA for use in this patient population based on findings from a phase 1/2 trial (NCT02716116).² In the study, from a cohort of patients who had received the agent at a dose of 160 mg had a confirmed objective response rate (ORR) of 28% (95% CI, 20%-37%) by independent review committee (IRC) assessment, along with a median duration of response (DOR) of 17.5 months (95% CI, 7.4-20.3). Additionally, the median progression-free survival (PFS) with mobocertinib was 7.3 months (95% CI, 5.5-9.2) and the median overall survival (OS) was 24.0 months (95% CI, 14.6-28.8). Experts like Liza C. Villaruz, MD considered mobocertinib to be a contributor to growth of effective therapy in the field.

“I think that the greatest area of growth within the recent, past years has been within areas of oncogene-driven non–small cell lung cancer in particular and specific subsets. There have been a lot of developments in the last couple of years in the smaller subsets of EGFR-mutant disease, such as the EGFR exon 20 insertions, where we now have 2 approved agents, mobocertinib and amivantamab [Rybrevant], which are very promising agents in previously treated patients with EGFR exon 20 insertion-positive tumors," said Villaruz, assistant professor of medicine, Division of Hematology/Oncology, University of Pittsburgh Medical Center, in an earlier interview.

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This decision to withdraw mobocertinib from the market is based on results from the phase 3 EXCLAIM-2 confirmatory trial (NCT04129502) in which the primary end point of IRC-assessed PFS was not met. These findings did not meet the confirmatory data requirements of the accelerated approval granted by the FDA nor the conditional marketing approvals granted in other countries.1

The company plans to voluntarily withdraw mobocertinib in a similar fashion in locations across the globe where it is approved, and they are working on next steps with regulators in other countries.

“Our steadfast commitment to pursue solutions for people with high unmet needs led us to develop and launch [mobocertinib] as the first oral therapy designed for patients with EGFR exon20 insertion-positive metastatic NSCLC,” said Awny Farajallah, MD, head of global medical affairs oncology at Takeda, in a press release. “We have been fortunate to witness the impact [mobocertinib] has had on this previously underserved population and are encouraged to see the advancements made since its approval to introduce new therapies for these patients. We hope that findings from the EXCLAIM-2 study will inform future research and development for this disease.”

In the phase 3, multicenter, open-label EXCLAIM-2 trial, investigators sought to assess the safety and efficacy of mobocertinib given alone vs platinum-based chemotherapy in the first-line for patients with EGFR exon20 insertion-positive locally advanced or metastatic NSCLC. Patients were required to be 18 years or older with at least 1 measurable lesion by RECIST v1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and acceptable organ and hematologic function.³

Patients were randomized in a 1:1 fashion to receive oral mobocertinib at a daily dose of 160 mg in arm A or chemotherapy given as intravenous pemetrexed at 500 mg/m² plus cisplatin at 75 mg/m² or carboplatin at an area under the curve of 5 mg x min/mL for 4 cycles, followed by pemetrexed maintenance, on day 1 every 21 days in arm B. Patients continued to receive treatment until disease progression, toxicity, or other discontinuation criteria were met. Further, patients were able to crossover from the control arm to the investigative arm.

The primary end point was IRC-assessed PFS, and secondary end points included IRC-assessed ORR, investigator-assessed ORR, DOR, time to response, disease control rate, PFS, OS, safety/tolerability, patient-reported outcomes, and health-related quality of life.

While no new safety signals were observed in the trial, the primary end point was not met, and full data from the study are expected to be presented at an upcoming medical meeting or published in a peer-reviewed journal.¹

Takeda has expressed their commitment to ensure that patients who are receiving mobocertinib can continue accessing the agent under appropriate circumstances and in consultation with healthcare providers. The company will continue to evaluate the impact of the withdrawal of mobocertinib.

REFERENCES:

1. Takeda provides update on EXKIVITY® (mobocertinib). Takeda. News release. October 2, 2023. Accessed October 3, 2023. https://tinyurl.com/yuac4z8a

2. Takeda's EXKIVITY (mobocertinib) approved by US FDA as the first oral therapy specifically designed for patients with EGFR exon20 insertion+ NSCLC. News release. Takeda Pharmaceutical Company. September 15, 2021. Accessed October 3, 2023. https://tinyurl.com/4r68t6yp

3. TAK-788 as first-line treatment versus platinum-based chemotherapy for non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. ClinicalTrials.gov. Updated April 7, 2023. Accessed October 3, 2023. https://tinyurl.com/2s49urnt