FDA Greenlights Companion Diagnostic for Mobocertinib in EGFR Exon 20 Insertion+ NSCLC

The FDA has granted premarket approval to the Oncomine Dx Target Test for use as a companion diagnostic to identify patients with non–small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 20 insertion mutations who may be eligible to receive the newly approved small molecule TKI mobocertinib (Exkivity).¹

The test, which was developed by Thermo Fisher Scientific, can examine 23 genes linked with NSCLC at the same time. In the United States, the Oncomine Dx Target Test is now approved as a companion diagnostic for 5 targeted therapies in this disease and 1 targeted option in cholangiocarcinoma. In Japan, the test is greenlit for 5 biomarkers linked with 10 targeted therapies in NSCLC: EGFR, ALK, ROS1, BRAF, and RET.

On September 15, 2021, the FDA granted an accelerated approval to mobocertinib for use in adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on, or after, platinum-based chemotherapy.² The decision was supported by findings from a cohort of a phase 1/2 trial (NCT02716116).

Mobocertinib elicited an independent review committee (IRC)–assessed overall response rate (ORR) of 28% (95% CI, 20%-37%) in the cohort of 114 patients with EGFR exon 20 insertion–positive disease who previously received platinum-based chemotherapy.³ The median duration of response (DOR) with the TKI was 17.5 months (95% CI, 7.4-20.3). Additionally, the median progression-free survival in this cohort was 7.3 months (95% CI, 5.5-9.2) and the median overall survival was 24.0 months (95% CI, 14.6-28.8%).

Continued approval for the indication could be contingent upon verification and description of clinical benefit in a confirmatory trial.

“Without proper and timely diagnoses, patients with EGFR exon 20 insertion mutations don’t have access to therapies that can most effectively treat their disease,” Dion Warren, vice president and head of the US Oncology Business Unit at Takeda Oncology, stated in a press release. “We’re pleased to partner with Thermo Fisher to identify and address the unmet needs of patients with this rare cancer.”

The first part of the early-phase trial had a dose-escalation, 3+3 design and was comprised of patients with advanced NSCLC who had an ECOG performance status of less than 2. Six of the patients included in this portion of the research had received prior platinum-based chemotherapy. In the expansion phase of the trial, the TKI was examined at a daily dose of 160 mg in 7 cohorts.

The first cohort (cohort 1; n = 22) were the patients who received prior platinum therapy and had refractory EGFR exon 20 insertion–positive disease. These patients did not have active, measurable central nervous system metastases.

For the phase 2 portion of the trial, the primary end point was ORR per RECIST v1.1 criteria and secondary end points comprised safety and tolerability, pharmacokinetics, as well as efficacy.

Part 3 of the trial included an EXCLAIM extension cohort, which was comprised of 96 patients with EGFR exon 20 insertion–positive NSCLC, some of whom (n = 86) had received prior platinum-based chemotherapy.

In cohort 1, the median age of participants was 60 years (range, 27-84), 66% were female, 60% were Asian, 98% had adenocarcinoma histology, 75% had an ECOG performance status of 1, and 71% were never smokers. Thirty-five percent of patients had brain metastases at baseline.

Regarding prior systemic regimens, 41% received 1 prior regimen, 32% received 2, and 27% received 3 or more. All patients received prior platinum-based chemotherapy, 43% had previously received immunotherapy, and 25% had prior EGFR TKIs.

Additional findings from the trial presented during the 2021 ASCO Annual Meeting showed that the investigator-assessed confirmed ORR achieved with mobocertinib in cohort 1 was 35% (95% CI, 26%-45%), with a median DOR of 11.2 months (95% CI, 5.6–not evaluable [NE]). In this cohort, the investigator-assessed disease control rate (DCR) was 78% (95% CI, 69%-85%).

In the EXCLAIM cohort, the IRC-assessed confirmed ORR was 25% (95% CI, 17%-35%) with mobocertinib. The median DOR was NE (95% CI, 5.6–NE), the confirmed DCR was 76% (95% CI, 66%-84%). The investigator-assessed confirmed ORR in this cohort with the TKI was 32% (95% CI, 23%-43%), with a median DOR of 11.2 months (95% CI, 7.0–NE) and a DCR of 75% (95% CI, 65%-83%).

In terms of safety, the most frequent toxicities experienced with mobocertinib were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. The prescribing information for the TKI includes a boxed warning for QTc prolongation and Torsades de Pointes, and warnings and precautions regarding interstitial lung disease or pneumonitis, cardiac toxicity, and diarrhea.

“[Mobocertinib] offers new hope to previously treated patients with metastatic NSCLC and EGFR exon 20 insertion mutations, who usually do not respond well to other available treatments,” Garret Hampton, president of clinical next-generation sequencing and oncology at Thermo Fisher Scientific, stated in a press release. “FDA approval of the Oncomine Dx Target Test as a companion diagnostic for [mobocertinib] will allow clinicians to identify key biomarkers in patients who could benefit from this targeted therapy.”

References

1. FDA Approves tissue-based NGS companion diagnostic for Takeda’s targeted therapy for NSCLC patients with EGFR exon20 insertion mutations. News release. Thermo Fisher Scientific. September 15, 2021. Accessed September 16, 2021. https://prn.to/3CntcHX
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 September 16, 2021. https://bit.ly/2Xm3WSY
3. Ramalingam SS, Zhou C, Kim TM, et al. 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. J Clin Oncol. 2021;39(suppl 15):9014. doi:10.1200/JCO.2021.39.15_suppl.9014