Clinical Activity Observed With Mobocertinib for Advanced EGFR Exon 20 Insertion+ NSCLC With or Without Prior Immunotherapy


Previously platinum-treated patients with EGFR exon 20 insertion mutation–positive non–small cell lung cancer saw clinical activity with mobocertinib regardless of prior PD-1/PD-L1 inhibitor history.

Previously platinum-treated patients (PPP) with EGFR exon 20 insertion mutation–positive non–small cell lung cancer (NSCLC) saw clinical activity with mobocertinib (TAK-788) regardless of prior PD-1/PD-L1 inhibitor history, according to results from a phase 1/2 trial (NCT02716116) presented during the 2021 World Conference on Lung Cancer.1

Results showed that in the overall previously PPP subset (n = 114), the confirmed overall response rate (ORR) via an independent review committee (IRC) was 28% (95% CI, 20%-37%) and the disease control rate (DCR) was 78% (95% CI, 69%-85%). Additionally, among patients in the PPP subset who received prior PD-1/PD-L1 therapy, the confirmed ORR via IRC was 25% (95% CI, 14%-40%) and was 30% (95% CI, 20%-43%) in those who did not receive prior checkpoint blockade.

The confirmed ORR via investigator assessment in the overall subset was 38% (95% CI, 24%-53%) and 33% (95% CI, 22%-46%), respectively.

“The safety profile of mobocertinib was consistent with the EGFR TKI class and manageable in both populations,” said lead study author Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology and director of Belfer Center for Applied Cancer Science at Dana-Farber Cancer Institute. “These results suggest that mobocertinib is effective in platinum-pretreated patients that have an EGFR exon 20 insertion mutation, regardless of the sequence of treatment with prior anti-PD(L)-1 therapies.”

Up to 12% of patients with EGFR-mutated NSCLCs have EGFR exon 20 insertion mutations, and there were no approved targeted agents for this specific patient population outside the United States as of August 1, 2021. Currently, the recommended standard of care is PD-1/PD-L1 inhibitors for those without activating mutations. However, in the EGFR exon 20 insertion mutation–positive subset, these outcomes are limited with a median progression-free survival (PFS) of approximately 2 to 3 months.

Mobocertinib is an oral, first-in-class, irreversible EGFR TKI targeting EGFR exon 20 insertion mutations in NSCLC. The FDA previously granted a priority review designation to a new drug application for mobocertinib in April 2021 for the treatment of patients with EGFR exon 20 insertion mutation–positive NSCLC who progressed on platinum-based chemotherapy.2 In China, the indication would be specific to those who received prior chemotherapy.

In the 3-part, phase 1/2 trial, investigators are exploring the efficacy and safety of mobocertinib in platinum-pretreated patients with locally advanced or metastatic NSCLC who have EGFR in-frame exon 20 insertion mutations in subsets with and without PD-1/PD-L1 inhibitors. The study also consists of dose-escalation, -expansion, and -extension (EXCLAIM) cohorts.

From all 3 parts, patients who previously received platinum-based chemotherapy were included and all had an ECOG performance status of 0 to 1 and received at least 1 prior line of therapy for locally advanced or metastatic disease. Mobocertinib was given at 160 mg daily.

The primary end point was confirmed ORR per RECIST v1.1 criteria as assessed by an IRC; secondary outcome measures were investigator-assessed ORR, IRC-assessed DCR, duration of response (DOR), and PFS. Overall survival (OS) was also assessed. All patients who received at least 1 dose of mobocertinib were evaluable for safety.

Part 1 of the trial, the dose-escalation phase, was a 3+3 design of patients with advanced NSCLC and had an ECOG performance score of 0 to 2; 6 patients had prior platinum-based therapy.

Part 2 comprised the expansion phase, where mobocertinib was given at 160 mg daily. Here, the primary end point was ORR via RECIST v1.1 criteria; secondary end points were safety, tolerability, pharmacokinetics, and efficacy.

Part 3 of the trial, the EXCLAIM extension cohort, included patients with previously treated EGFR exon 20 insertion mutation–positive disease (n = 96; prior platinum–treated patients = 86).

There are 6 cohorts within part 2 of the study; those with prior platinum-based therapy refractory EGFR exon 20 insertion mutations with no active measurable central nervous system (CNS) metastases (n = 22; cohort 1); refractory HER2 exon 20 insertion or point mutations, and no active, measurable CNS metastases (cohort 2); refractory EGFR or HER2 exon 20 insertions or point mutations with measurable active CNS metastases (cohort 3); treatment-naïve or refractory other EGFR mutations with or without T790M mutations and uncommon EGFR mutations (cohort 4); refractory EGFR exon 20 insertion mutations with prior response to an EGFR TKI (cohort 5); treatment-naïve EGFR exon 20 insertion mutations (cohort 6); and refractory other tumor types (non-NSCLC) with EGFR/HER2 mutations (cohort 7).

The findings presented at the 2021 World Conference on Lung Cancer comprised all PPPs from all 3 parts in the trial (n = 114). The data cutoff date was November 1, 2020.

In the PPP population, 49 patients (43%) had received prior immunotherapy, either as monotherapy or in combination with chemotherapy. Among those who received prior PD-1/PD-L1 therapy (n = 48), 32 (67%) had received at least 28 (58%) had immunotherapy as their most recent treatment.

The median age was 60 years (range, 27-84), and 66% of patients were female; 60% of patients were Asian and the majority (98%) had adenocarcinoma. Most patients (75%) had an ECOG performance status of 1 and were never-smokers (71%). Patients had received 1 (41%), 2 (32%), or more than 3 (27%) prior systemic anticancer regimens. The median number of prior regimens was 2.

Thirty-five percent of patients had brain metastases at baseline.

Additional findings showed that, in the PPP subset of patients who did and did not receive PD-1/PD-L1 inhibition, the median DOR with mobocertinib was 17.5 months (95% CI, 3.7–not estimable [NE]) and 11.0 months (95% CI, 3.8-17.5), respectively; the DOR at 6 months or more via IRC was 58% and 60%, respectively. The confirmed DCR in this subset who previously received PD-1/PD-L1 inhibition (n = 48) was 77% (95% CI, 63%-88%) compared with 79% (95% CI, 67%-88%) for those who did not receive prior checkpoint inhibitors (n = 66).

The median PFS in each group was similar at 7.4 months (95% CI, 5.5-21.1) and 7.3 months (5.4-10.2), respectively. The respective median OS was 21.1 months (95% CI, 13.1-NE) and 24.0 months (95% CI, 13.1-NE).

Furthermore, there were no marked differences between the 2 cohorts regarding best change from baseline in target lesion volume, as well as duration of treatment in confirmed responders, both by IRC assessment, Jänne noted.

Regarding safety, treatment-related adverse events (TRAEs) occurred in 100% of both patients with (n = 48) and without (n = 66) prior PD-1/PD-L1 inhibitor therapy. Grade 3 or higher TRAEs occurred in 58% and 39% of patients, respectively, and serious treatment-emergent adverse events (TEAEs) were in 54% and 45% of patients, respectively.

Furthermore, drug discontinuations due to TEAEs occurred in 21% of patients on prior PD-1/PD-L1 inhibition and in 14% of those who did not receive the class of agents; TEAE-related dose modification rates were 77% and 55%, respectively.

Some of the TRAEs that occurred in 20% or more patients in either the prior and no PD-1/PD-L1 treatment cohorts included: diarrhea (94% vs 89%, respectively), rash (42% vs 47%), paronychia (27% vs 45%), decreased appetite (33% vs 36%), vomiting (35% vs 26%), increased blood creatinine (23% vs 27%), anemia (21% vs 15%), nausea (42% vs 29%), dry skin (35% vs 27%), stomatitis (21% vs 26%), pruritus (19% vs 23%), increased amylase (21% vs 17%), dermatitis acneiform (21% vs 17%), increase lipase (23% vs 17%), and fatigue (23% vs 8%).

Interstitial lung disease was reported in 1 patient in the PPP subset who did not receive prior PD-1/PD-L1 therapy.

The application for mobocertinib in this setting is expected to be decided on by October 26, 2021.


  1. Jänne PA, Ramalingam SS, Kim TN, et al. Mobocertinib in platinum-pretreated EGFR exon 20 insertion+ metastatic NSCLC patients with/without prior anti-PD(L)-1 therapy. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer; September 8-14, 2021; virtual. Abstract FP09.01.
  2. Takeda announces U.S. FDA grants priority review for new drug application for mobocertinib (TAK-788) as a treatment for EGFR exon20 insertion+ metastatic non-small cell lung cancer. News release. Takeda. April 27, 2021. Accessed April 28, 2021.
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