Mobocertinib: Mechanism of action, clinical, and translational science

Abstract

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations represent ~6%–12% of all EGFR‐mutated non‐small cell lung cancer (NSCLC) cases. First‐, second‐, and third‐generation tyrosine kinase inhibitors (TKIs) have limited clinical activity against EGFR ex20ins mutations. Mobocertinib is a first‐in‐class oral EGFR TKI that selectively targets in‐frame EGFR ex20ins mutations in NSCLC; accelerated approval in the United States was granted for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum‐based chemotherapy. Accelerated approval was based on the results from the three‐part, open‐label, multicenter, pivotal phase I/II nonrandomized clinical trial (NCT02716116) that enrolled 114 patients with locally advanced or metastatic EGFR ex20ins mutation–positive NSCLC who were previously treated with platinum‐based chemotherapy and received mobocertinib at the recommended dosage of 160 mg once daily. At the November 1, 2021, data cutoff date, the confirmed objective response rate per independent review committee (IRC) was 28%, median duration of response was 15.8 months, median progression‐free survival per IRC was 7.3 months, and median overall survival was 20.2 months. The most common treatment‐emergent adverse events were gastrointestinal‐ and skin‐related. The phase III EXCLAIM‐2 study evaluated mobocertinib versus chemotherapy as first‐line therapy for locally advanced or metastatic EGFR ex20ins–positive NSCLC; however, the primary end point was not met, resulting in initiating voluntary withdrawal of mobocertinib worldwide. This mini‐review article summarizes the mechanism of action, pharmacokinetic characteristics, key clinical trials, and clinical efficacy and safety data for mobocertinib.

Clinical and Translational Card for Mobocertinib.

• Mechanism of action: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets in‐frame EGFR exon 20 insertion mutations in non‐small cell lung cancer (NSCLC).

• Indication(s): For the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by a US Food and Drug Administration (FDA)‐approved test, whose disease has progressed on or after platinum‐based chemotherapy. This indication was approved under accelerated approval based on overall response rate and duration of response. In October 2023, the sponsor announced the initiation of a voluntary withdrawal of mobocertinib worldwide based on results of the phase III EXCLAIM‐2 study, in which the primary end point was not met.

• Dosage and administration: 160 mg (4 × 40 mg capsules) orally once daily with or without food.

• Major metabolic pathway: Metabolism via cytochrome P450 3A (CYP3A).

• Key PK characteristics: Absolute bioavailability: 37%; mean apparent volume of distribution at steady‐state: 3509 L; median T _max: 4 h; geometric mean C _max at steady‐state: 70.4 ng/mL; geometric mean AUC₂₄ at steady‐state: 951 h*ng/mL; mean plasma elimination half‐life at steady‐state: 18 h.

INTRODUCTION

Activating mutations in the epidermal growth factor receptor (EGFR) kinase domain have been implicated in the oncogenesis of non‐small cell lung cancer (NSCLC). Most (~85%) EGFR‐mutated NSCLC cases arise from an exon 19 deletion or exon 21 L858R point substitution. ¹ The L858R and exon 19 deletion mutations cause a destabilization of the inactive conformation of EGFR, thereby resulting in increased receptor dimerization and activity compared with the wild‐type (WT) receptor. ¹ First‐generation EGFR tyrosine kinase inhibitors (TKIs; e.g., erlotinib and gefitinib) are reversible inhibitors that compete with adenosine triphosphate (ATP) for binding to EGFR mutants, whereas second‐generation EGFR TKIs (e.g., afatinib and dacomitinib) irreversibly bind to the C797 residue of EGFR and were designed to overcome the most common resistance mechanism (T790M mutation) to first‐generation TKIs. ¹ The third‐generation EGFR TKI osimertinib is also an irreversible inhibitor and has more selectivity for T790M mutations over WT EGFR compared with the second‐generation inhibitors. ¹ The third most common class of EGFR mutations in NSCLC are EGFR exon 20 insertion (ex20ins) mutations, which are characterized by in‐frame insertions or duplications between amino acids 762 and 774 of the EGFR protein. ² These mutations are diverse, with over 100 unique variants identified. ³ EGFR ex20ins mutations represent ~6%–12% of all EGFR NSCLC cases; however, due to their diversity and the challenges in identifying these mutations via standard polymerase chain reaction techniques, the frequency of EGFR ex20ins mutations in NSCLC is likely underestimated. ⁴ Compared with all patients with EGFR‐mutated NSCLC, patients with EGFR ex20ins–positive NSCLC are more likely to be nonsmokers, women, and of Asian descent. ⁵

Due to modified structures in the EGFR kinase domain in the presence of ex20ins mutations, first‐, second‐, and third‐generation TKIs have limited clinical activity toward EGFR ex20ins mutations. ⁴ Accordingly, among patients with EGFR ex20ins–positive NSCLC, first‐ and second‐generation EGFR TKIs achieve response rates of ~10%, with estimated median progression‐free survival (PFS) of 1–3 months. ⁶ In a retrospective real‐world study among Chinese patients with advanced NSCLC with EGFR ex20ins mutations treated with first‐line platinum‐based chemotherapy, the overall response rate (ORR) was 19.2% and median PFS was 6.4 months, ⁷ and in a separate study of similar patients in the United States, confirmed ORR was 19.5% and PFS was 5.7 months. ⁸ In a recent systematic literature review and meta‐analysis, first‐line platinum‐based chemotherapy resulted in a pooled estimated ORR of 24.6% (pooled n = 122), median PFS of 5.6 months (pooled n = 237), and median overall survival (OS) of 19.6 months (pooled n = 198) among patients with EGFR ex20ins–positive NSCLC. ⁹

Mobocertinib is a first‐in‐class, orally administered, EGFR TKI that targets in‐frame EGFR ex20ins mutations in NSCLC and has shown better potency and selectivity for EGFR ex20ins mutations over WT EGFR in preclinical evaluations. ¹⁰ This mini‐review summarizes clinical data for mobocertinib in patients with NSCLC, including patients with EGFR ex20ins–positive NSCLC.

DRUG REGULATORY APPROVAL

Mobocertinib received accelerated approval in the United States in September 2021 as the first oral targeted therapy for patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum‐based chemotherapy. ¹¹ Approval was based on the results from a pivotal phase I/II study (NCT02716116) that demonstrated a favorable benefit‐risk profile for mobocertinib 160 mg once daily (q.d.) in patients with EGFR ex20ins–positive NSCLC previously treated with platinum‐based chemotherapy. ¹² In October 2023, the sponsor announced the initiation of a voluntary withdrawal of mobocertinib worldwide based on the results of the phase III EXCLAIM‐2 study. ¹³ , ¹⁴ EXCLAIM‐2 evaluated mobocertinib versus chemotherapy as first‐line therapy for locally advanced or metastatic EGFR ex20ins–positive NSCLC, and the primary end point was not met. ¹³

As of October 2023, only one other drug, amivantamab, had also received accelerated approval by the US Food and Drug Administration (FDA) for patients with EGFR ex20ins–positive NSCLC. Additional agents are in clinical development.

MECHANISM OF ACTION

Mobocertinib is a novel kinase inhibitor of EGFR designed to specifically target EGFR ex20ins mutations in NSCLC. ¹⁰ The insertion of in‐frame amino acids at the C‐terminal of the C‐helix seen in structural modeling of EGFR ex20ins mutations leads to conformational changes closely resembling the active form of WT EGFR. ¹⁰ This similarity in the ATP binding site between WT EGFR and EGFR ex20ins mutations makes these mutations difficult to treat because other currently approved TKIs may inhibit WT EGFR more potently than the mutated version containing EGFR ex20ins. Accordingly, the lack of selectivity for EGFR ex20ins mutations results in poor treatment outcomes due to the higher doses that would be needed for clinically meaningful efficacy and their associated dose limiting toxicities. ¹⁵

Mobocertinib was developed using a structure‐guided design that included both in vitro and in vivo nonclinical assay validations (Figure 1). ¹⁰ Its design also considered the limitations of other EGFR TKIs toward EGFR ex20ins mutations by targeting structural characteristics in the protein near the α C‐helix. ¹⁰ Preclinical studies have shown that mobocertinib irreversibly binds to cysteine 797 in EGFR and inhibits EGFR ex20ins mutations more potently than WT EGFR. ¹⁰ , ¹¹ Specifically, in the Ba/F3 screening assay, the half‐maximal inhibitory concentration (IC₅₀) values for mobocertinib toward the five variants containing EGFR ex20ins mutations (FQEA, NPG, ASV, NPH, and SVD) ranged from 4.3 to 22.5 nmol/L versus 34.5 nmol/L for WT EGFR. ¹⁰ Compared with reversible binding, the irreversible binding mechanism is thought to result in increased potency via higher affinity binding, more sustained EGFR kinase activity inhibition, and greater overall selectivity. ¹⁰

FIGURE 1.

Mobocertinib mechanism of action. The left panel shows a simplified diagram of WT EGFR and EGFR with an ex20ins mutation that results in ligand‐independent activation. The right panel shows the active site cleft (green surface) with binding interactions of the EGFR ex20ins mutation D770_N771insNPG/V948R (residues in yellow), EGFR T790M/V948R mutation (transparent gray ribbon with residues in dark green), and WT EGFR (residues in pink) with mobocertinib (light green) and another EGFR TKI, osimertinib (yellow). Of note, the C5‐carboxylate isopropyl ester of mobocertinib occupies a selectivity pocket (red dotted circle) that is not targeted by osimertinib. EGFR, epidermal growth factor receptor; ex20ins, exon 20 insertion mutation; TKI, tyrosine kinase inhibitor; WT, wild‐type. Adapted with permission from Wang et al. ³²

PHARMACOKINETIC CHARACTERISTICS

The recommended mobocertinib dosage is 160 mg q.d. (four 40‐mg immediate‐release capsules). ¹¹ , ¹⁶ The median time to peak concentration of mobocertinib is 4 h. ¹¹ , ¹⁶ The absolute bioavailability of mobocertinib is 37%, and the mean apparent volume of distribution at steady‐state is 3509 L. ¹¹ , ¹⁷ After multiple‐dose administration of 160 mg q.d., the steady‐state geometric mean mobocertinib maximum plasma concentration (C _max) and area under the plasma concentration‐time curve from time 0–24 h (AUC₂₄) were 70.4 ng/mL and 951 h*ng/mL, respectively ¹⁸ , ¹⁹ , ²⁰ ; thus, the mobocertinib C _max (120 nmol/L) and C _average (68.3 nmol/L) concentrations at the recommended dose (data on file, Takeda Development Center Americas, Inc.) exceed the IC₅₀ values for the five EGFR ex20ins mutations evaluated in vitro. ¹⁰

Mobocertinib is primarily metabolized by CYP3A to form two active metabolites, AP32960 and AP32914, ²¹ that are equipotent to mobocertinib. AP32960 and AP32914 comprise 36% and 4%, respectively, of the combined molar AUC of mobocertinib, AP32960, and AP32914. The combined molar C _max and AUC of mobocertinib, AP32960, and AP32914 is dose‐proportional after single‐ and multiple‐dose administration over the 5‐mg to 180‐mg q.d. dose range. However, no clinically meaningful accumulation in mobocertinib AUC was observed after administration of 160 mg q.d. due to autoinduction of CYP3A‐mediated metabolism. After administration of a single 160‐mg oral dose of ¹⁴C‐mobocertinib, ~76% of the dose was recovered in feces (~6% as unchanged mobocertinib) and ~4% was recovered in urine (~1% as unchanged mobocertinib). ¹¹ Approximately 12% and 1% of the administered dose was recovered as the metabolite AP32960 in feces and urine, respectively. The mean steady‐state plasma elimination half‐lives for mobocertinib, AP32960, and AP32914 were 18, 24, and 18 h, respectively. ¹¹

In a population pharmacokinetic (PK) analysis including data from 110 healthy volunteers and 317 patients with NSCLC enrolled across four clinical studies (including the pivotal phase I/II study), age (18–86 years), race, sex, body weight (37.3–132 kg), mild‐to‐moderate renal impairment, and mild hepatic impairment had no clinically meaningful effects on the PK of mobocertinib, AP32960, and AP32914. ¹⁷ Dedicated organ impairment studies evaluating the effects of severe renal impairment (NCT04056455) and moderate or severe hepatic impairment (NCT04056468) on mobocertinib PK have demonstrated that unbound combined molar AUC of mobocertinib and its active metabolites was increased in participants with severe renal impairment, while moderate and severe hepatic impairment had no clinically meaningful effect on mobocertinib PK. ¹¹ Two studies in healthy volunteers evaluating the effect of food on mobocertinib PK found that the combined molar C _max and AUC of mobocertinib, AP32960, and AP32914, were similar after administration with a high‐fat or low‐fat meal compared with administration in the fasted state. ¹¹ , ¹⁶ Therefore, mobocertinib can be administered with or without food.

In a clinical drug–drug interaction study in healthy volunteers, the strong CYP3A inhibitor itraconazole increased the combined molar exposure (AUC) of mobocertinib and its two active metabolites by 527% compared with a single dose of mobocertinib administered alone. In contrast, the strong CYP3A inducer rifampin reduced the combined molar exposure (AUC) of mobocertinib and its two active metabolites by 95% versus a single‐dose administered alone. ²¹ The results of physiologically‐based pharmacokinetic (PBPK) analyses demonstrated that strong CYP3A inhibitors are predicted to increase the combined molar steady‐state AUC of mobocertinib, AP32960, and AP32914 by ~400%, and moderate CYP3A inhibitors are predicted to increase the combined molar steady‐state AUC of mobocertinib and its active metabolites by ~100%–200%. ¹¹ The PBPK analyses also indicated that strong CYP3A inducers and moderate CYP3A inducers are predicted to decrease the combined molar steady‐state AUC of mobocertinib and its active metabolites by ~90% and 60%, respectively. ¹⁸ Based on these results, co‐administration of mobocertinib with moderate or strong CYP3A inhibitors or inducers should be avoided. If concomitant use of a moderate CYP3A inhibitor is unavoidable, the dose of mobocertinib should be reduced by ~50% (i.e., from 160 to 80 mg, 120 to 40 mg, or 80 to 40 mg) and the QT interval corrected for heart rate (QTc) monitored more frequently as increased exposures have been associated with an increase in the QTc interval. Mobocertinib is a weak inducer of CYP3A in vivo as co‐administration of 160 mg mobocertinib q.d. with oral or i.v. midazolam (a sensitive CYP3A substrate) reduced midazolam AUC by ~30% and 20%, respectively. ²²

Exposure–response analyses were performed using efficacy and safety data from platinum‐pretreated patients with EGFR ex20ins–positive NSCLC who were enrolled in the pivotal phase I/II clinical trial (NCT02716116), and received the recommended mobocertinib dosage of 160 mg q.d. ²³ These analyses demonstrated that combined molar exposure of mobocertinib, AP32960, and AP32914 was not a statistically significant predictor of independent review committee (IRC)–assessed objective response rate, thereby indicating that the efficacy benefit of mobocertinib was consistent across the observed range of exposures achieved after administration of the 160‐mg q.d. dose. ²³ Exposure–safety analyses found a statistically significant relationship between combined molar exposure and the probability of grade ≥ 3 treatment‐emergent adverse events (TEAEs), with higher exposures associated with an increased probability of experiencing these events (odds ratio associated with a decrease in systemic exposure corresponding to a dose reduction from 160 to 120 mg q.d.: 0.701, 95% confidence interval [CI]: 0.534–0.92, p = 0.004). ²³ In addition, concentration‐QTc analyses showed a concentration‐dependent increase in the QTc interval. ¹¹

KEY CLINICAL TRIALS

Several clinical trials were conducted to evaluate the efficacy, safety, and clinical pharmacology of mobocertinib (Table 1). Clinical efficacy and safety studies include the pivotal phase I/II dose‐escalation, expansion, and extension study (NCT02716116) in patients with advanced EGFR ex20ins mutation–positive NSCLC and other EGFR/HER2 mutation–positive solid tumors, ¹⁹ , ²⁰ a phase I/II study (NCT0387778) in Japanese patients with NSCLC, and the phase III, randomized study (NCT04129502) comparing first‐line mobocertinib with platinum‐based chemotherapy in previously untreated, locally advanced or metastatic EGFR ex20ins–positive NSCLC. Dedicated studies were also performed to comprehensively evaluate the clinical pharmacology of mobocertinib and its active metabolites during development. ¹⁶ , ²¹ , ²² , ²⁴

TABLE 1.

Key mobocertinib clinical studies.

Study phase (NCT)	Key inclusion criteria/patient population	No. of patients	Key end points	Status	Key findings
Efficacy and safety studies
Pivotal Phase I/II study (NCT02716116) 12 , 19 , 20	Previously treated NSCLC	Dose‐escalation phase (5 mg to 180 mg q.d.): n = 73	DLTs, MTD, RP2D	Completed	MTD/RP2D: 160 mg q.d.
	NSCLC; seven histologically/ molecularly defined cohorts (including EGFR ex20ins+)	Dose‐expansion phase (160 mg q.d.): safety evaluable n = 136; efficacy evaluable n = 70	Safety, tolerability, and antitumor activity	Analysis ongoing	Previously treated EGFR ex20ins + NSCLC (n = 28): ORR 43%; median DoR 14 mo; median PFS 7 mo; all cohorts: AE profile manageable and consistent with other EGFR TKIs
	Previously treated EGFR ex20ins + NSCLC	Dose‐extension phase (EXCLAIM; 160 mg q.d.): n = 96	Safety, tolerability, and antitumor activity	Analysis ongoing	ORR by IRC: 26%; median DoR 13.8 mo; median PFS 7.3 mo; median OS 19.8 mo (November 1, 2021, data cutoff; data on file, Takeda Development Centers, Inc.)
	Prior platinum‐based therapy; refractory EGFR ex20ins + NSCLC	PPP cohort (160 mg q.d.): n = 114 (dose escalation: n = 6; dose expansion: n = 22; extension: n = 86)	ORR by IRC, safety, tolerability, efficacy	Analysis ongoing	ORR by IRC: 28%; mDoR 15.8 mo; mPFS 7.3 mo; OS 20.2 mo (November 1, 2021, data cutoff)
Phase I/II study in Japanese patients (NCT03807778)	Japanese patients with NSCLC	Phase I: Dose‐escalation phase (40 mg to 160 mg q.d.): n = 20	DLTs, MTD, safety	Analysis ongoing	DLTs at 120 mg q.d. (grade 3 diarrhea; n = 1) and 160 mg q.d. (grade 3 ILD; n = 1 and grade 2/3 transaminase elevations/grade 2 diarrhea; n = 1); MTD/RP2D: 160 mg q.d.
	Treatment naïve Japanese patients with EGFR ex20ins + NSCLC	Phase II: 160 mg q.d.: n = 33	Efficacy and safety	Analysis ongoing	NA
Phase III study as first‐line treatment (NCT04129502) 13	Previously untreated, locally advanced, or metastatic EGFR ex20ins + NSCLC	354 patients randomized 1:1 to mobocertinib 160 mg q.d. or platinum‐based chemotherapy	PFS, ORR, OS	Study stopped for futility	Study did not meet its primary efficacy end point; no new safety signals were observed
Clinical pharmacology studies
Phase I absolute bioavailability and human ADME study (NCT03811834) 24	Healthy participants	n = 7	Absolute bioavailability, mass balance, metabolism, routes of excretion, and PK	Completed	Mobocertinib has an absolute bioavailability of ~37% and is eliminated mainly in feces as metabolites
Single‐dose PK/low‐fat meal/relative bioavailability study (NCT03482453) 16	Healthy participants	Dose escalation: n = 40 Low‐fat food effect: n = 16 Relative bioavailability: n = 13	Safety, tolerability, and PK, including low‐fat meal effect and relative bioavailability of two capsule products	Completed	Mobocertinib was well tolerated at single oral doses from 20 mg to 160 mg; a low‐fat meal had no clinically meaningful effect on combined molar exposures of mobocertinib and its active metabolites, and the two capsule products were bioequivalent
Phase I high‐fat meal effect study (NCT04441255)	Healthy participants	n = 14	PK	Completed	A high‐fat meal had no clinically meaningful effect on combined molar exposures of mobocertinib and its active metabolites 11
Phase I DDI study with midazolam (NCT04051827) 22	Refractory locally advanced or metastatic NSCLC	n = 26	PK, safety, and tolerability	Completed	Coadministration of mobocertinib 160 mg q.d. reduced the AUC∞ of oral and i.v. midazolam by ~32% and 16%, respectively, which is consistent with mobocertinib being a weak inducer of CYP3A; AEs were consistent with the known safety profile of mobocertinib
Phase I DDI study with rifampin and itraconazole (NCT03928327) 21	Healthy participants	Itraconazole DDI: n = 12 Rifampin DDI: n = 12	PK	Completed	Itraconazole increased combined molar AUC∞ of mobocertinib and its two active metabolites by 527%; rifampin decreased combined molar AUC∞ of mobocertinib and its two active metabolites by 95%
Phase I severe renal impairment study (NCT04056455)	Healthy participants with normal renal function or participants with severe renal impairment	n = 26	PK	Completed	Unbound combined molar AUC of mobocertinib and its two active metabolites was increased by 112% in the severe renal impairment group as compared to the normal renal function group 11
Phase I moderate or severe hepatic impairment study (NCT04056468)	Healthy participants with normal hepatic function or participants with moderate (Child‐Pugh B) or severe (Child‐Pugh C) hepatic impairment	n = 24	PK	Completed	Moderate and severe hepatic impairment have no clinically meaningful effect on mobocertinib PK 11

Abbreviations: ADME, absorption, distribution, metabolism, and excretion; AE, adverse event; AUC_∞, area under the plasma concentration‐time curve from time 0 to infinity; DDI, drug–drug interaction; DLT, dose‐limiting toxicity; DoR, duration of response; EGFR, epidermal growth factor receptor; ex20ins, exon 20 insertion mutation; ILD, interstitial lung disease; IRC, independent review committee; mo, month; MTD, maximum tolerated dose; NA, not available; NSCLC, non‐small cell lung cancer; ORR, objective response rate; OS, overall survival; PK, pharmacokinetics; PFS, progression‐free survival; PPP, platinum‐pretreated patients; QD, once daily; RP2D, recommended phase II dose; TKI, tyrosine kinase inhibitor.

SUMMARY OF CLINICAL EFFICACY AND SAFETY

Mobocertinib efficacy and safety were evaluated in a three‐part, open‐label, multicenter, nonrandomized, pivotal phase I/II clinical trial (NCT02716116), which consisted of a dose‐escalation phase in patients with advanced refractory NSCLC, an expansion phase in seven molecularly and histologically defined expansion cohorts, and an extension cohort (EXCLAIM) in patients with previously treated EGFR ex20ins–positive NSCLC. An initial efficacy evaluation for patients enrolled in the dose‐escalation portion of the study demonstrated an investigator‐assessed confirmed ORR of 19% for mobocertinib 120 mg q.d. (based on 21 evaluable patients) and 43% for 160 mg q.d. (based on 28 evaluable patients), ²⁰ which supported the selection of 160 mg q.d. for subsequent evaluation in the expansion phase and extension cohort. The patient population that supported the accelerated approval of mobocertinib was the cohort of patients with locally advanced or metastatic EGFR ex20ins–positive NSCLC who were previously treated with platinum‐based chemotherapy and received the recommended dosage of 160 mg q.d. (N = 114; referred to as the platinum‐pretreated patients [PPP]). This population included 28 patients from the dose‐escalation and expansion cohorts and 86 patients from the EXCLAIM extension cohort. Patients received mobocertinib q.d. until disease progression, intolerable adverse events (AEs), or another protocol‐specified criterion was met. ¹² The primary end point was the confirmed ORR by IRC assessment, and secondary end points included the ORR by investigator assessment, duration of response (DoR), time to response, disease control rate, PFS, OS, and safety (i.e., AEs).

At the November 1, 2021, data cutoff date for the study, median duration of follow‐up was 25.8 months (range: 0.7–48.0) for the PPP. ¹⁹ The median age was 60 years, and most patients (66%) were women. All patients received prior platinum‐based chemotherapy, 43% received prior immunotherapy, and 25% received prior EGFR TKI therapy. Median time on treatment was 7.4 months (range: 0.0–48.0). The confirmed ORR was 28% (95% CI: 20%–37%) per IRC assessment and 35% (95% CI: 26%–45%) per investigator assessment. Median DoR was 15.8 months (95% CI: 7.4–19.4) per IRC assessment and 13.9 months (95% CI: 5.6–19.4) per investigator assessment. ¹⁹ Ninety‐six patients (84%) had a reduction from baseline in sum of target lesion diameters per IRC (Figure 2). Median PFS per IRC was 7.3 months (95% CI: 5.5–9.2 months), and median OS was 20.2 months (95% CI: 14.9–25.3 months).

FIGURE 2.

Waterfall plot of IRC‐assessed best percentage change from baseline in the sum of target lesion diameters in platinum‐pretreated patients from the phase I/II study of mobocertinib.^{a, 19} Blue bars indicate near loop insertions. Pink bars indicate far loop insertions. Purple bars indicate helical insertions. Green bars indicate insertions that are not established. ^aIncludes patients with measurable disease who had at least one post‐baseline assessment. The dotted lines at −30% and +20% indicate the threshold for partial response and progressive disease, respectively, according to RECIST, version 1.1. IRC, independent review committee; RECIST, Response Evaluation Criteria in Solid Tumors.

Available data suggest that mobocertinib may have limited intracranial activity. ¹² From the EXCLAIM cohort (n = 96) at the November 1, 2020, data cutoff date, the brain was the first site of investigator‐assessed progression in 38% of all patients (22/58) with progressive disease and in 68% of patients (17/25) with baseline brain metastases who had progressive disease. Approximately 23% of patients remained on mobocertinib for greater than or equal to 3 months after initial progressive disease in the brain; thus, patients may have systemic benefit with mobocertinib treatment after intracranial progression. ¹²

Overall, the safety profile of mobocertinib was largely characterized by WT EGFR–related toxicities. The incidence of any‐grade and grade ≥ 3 serious treatment‐related adverse events (TRAEs) was infrequent (19% and 18%, respectively; Table 2). The percentage of patients who experienced an AE leading to a dose reduction or treatment discontinuation was 27% and 18%, respectively. The most common AEs leading to discontinuation were diarrhea (4%) and nausea (2%). ¹⁹ The most frequent any‐grade TRAEs were diarrhea (92%), rash (46%), paronychia (38%), and decreased appetite (37%), and the most frequent grade ≥ 3 TRAEs were diarrhea (23%), nausea (4%), stomatitis (4%), and vomiting (3%).

TABLE 2.

Summary of AEs in platinum‐pretreated patients (N = 114) from the pivotal phase I/II study of mobocertinib. ¹⁹

AE overview, n (%)	Any grade	Grade ≥ 3
Any AE	114 (100)	86 (75)
Any TRAE	113 (99)	59 (52)
Serious AE	60 (53)	55 (48)
Serious TRAE	22 (19)	20 (18)
AE leading to dose reduction	31 (27)	–
AE leading to treatment discontinuation	21 (18)	–
TRAEs in >20% of patients, %
Diarrhea	92	23
Rash	46	0
Paronychia	38	0.9
Decreased appetite	37	0.9
Nausea	34	4
Vomiting	32	3
Dry skin	31	0
Increased creatinine	27	2
Stomatitis	25	4
Pruritus	22	0.9

Abbreviations: AE, adverse event; TRAE, treatment‐related adverse event.

An analysis of patient‐reported outcomes was conducted using available data from 90 patients enrolled in the EXCLAIM extension cohort (November 1, 2020, data cutoff). ²⁵ Secondary measures included the European Organization for Research and Treatment of Cancer (EORTC) Core Quality‐of‐Life Questionnaire (QLQ‐C30) version 3.0 and a 13‐item EORTC lung cancer module (QLQ‐LC13) version 1.0. Prespecified symptoms of interest were dyspnea, cough, and chest pain. Over 50% of patients had stable or improved symptoms of dyspnea, cough, and chest pain through the study in the EORTC QLQ‐LC13 scores. For EORTC QLQ‐C30, baseline scores were maintained during the study for most (n = 86) patients. Overall, the analysis showed improvements in core lung cancer symptoms and maintenance of overall health‐related quality of life and functions, despite AEs, which included diarrhea, dry skin, rash, and decreased appetite.

A phase III study (EXCLAIM‐2) compared the efficacy and safety of mobocertinib versus platinum‐based chemotherapy as first‐line treatment in patients with locally advanced or metastatic EGFR ex20ins–positive NSCLC (NCT04129502). At the interim analysis, mobocertinib did not meet its primary efficacy end point (blinded IRC–assessed PFS) ¹³ ; thus, a voluntary withdrawal of mobocertinib was initiated worldwide. ¹⁴ No new safety signals were observed in the study. ¹³ Full publication of EXCLAIM‐2 data is forthcoming.

MOBOCERTINIB DOSING AND ADMINISTRATION

The recommended dosage of mobocertinib is 160 mg q.d. (4 × 40 mg capsules), with or without food. ¹¹ , ¹⁶ For patients experiencing AEs that require a dose reduction, the first recommended dose reduction is to 120 mg q.d., followed by a second dose reduction (if needed) to 80 mg q.d. ¹¹ There are no contraindications for the use of mobocertinib. The mobocertinib prescribing information contains warnings and precautions for QTc interval prolongation and Torsades de Pointes, interstitial lung disease/pneumonitis, cardiac toxicity, diarrhea, and embryo‐fetal toxicity. ¹¹ Because mobocertinib treatment can cause QTc interval prolongation, it is advised to assess the QTc interval and electrolytes at baseline, correct any electrolyte abnormalities prior to mobocertinib administration, monitor the QTc interval and electrolytes during treatment, and avoid concomitant use of drugs known to prolong the QTc interval. Strong or moderate CYP3A inhibitors should also be avoided as they may further prolong the QTc interval by increasing plasma concentrations of mobocertinib. As discussed previously, the mobocertinib dose should be reduced by ~50% and the QTc interval monitored more frequently if concomitant use with a moderate CYP3A inhibitor is unavoidable. Similarly, the dose of mobocertinib should be reduced by ~50% and the QTc interval monitored more frequently for patients with severe renal impairment. ¹¹

OTHER AGENTS TARGETING PATIENTS WITH NSCLC WITH EGFR ex20ins MUTATIONS

Amivantamab is an anti‐EGFR/c‐MET bispecific antibody indicated for patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum‐based chemotherapy. ²⁶ Results from the pivotal study for amivantamab included an ORR of 40%, a median DoR of 11.1 months, PFS of 8.3 months, and an OS of 22.8 months. ²⁶ The median follow‐up was 9.7 months (range: 1.1–29.3). The safety profile of amivantamab was consistent with toxicities associated with EGFR and MET inhibition. Infusion‐related reactions were common but low grade. ²⁶ Serious TEAEs were reported in 9% of patients and included infusion‐related reactions and diarrhea. Results from the confirmatory phase III trial for amivantamab (PAPILLON) have recently been reported. ²⁷ In this study, in the first‐line setting for patients with advanced EGFR ex20ins–positive NSCLC, amivantamab plus chemotherapy treatment resulted in longer median PFS (11.4 months) versus chemotherapy alone (6.7 months; hazard ratio: 0.40, p < 0.001). ²⁷

Other EGFR TKIs are in development for patients with EGFR ex20ins–positive NSCLC. Newer agents may try to improve upon the efficacy and safety profile of mobocertinib, particularly with regard to central nervous system (CNS) activity. Agents in development include sunvozertinib (DZD9008), zipalertinib (CLN‐081), and BLU‐451. Sunvozertinib is an oral, potent, irreversible, and selective EGFR TKI targeting EGFR ex20ins mutations as well as the EGFR sensitizing mutation, T790M, and uncommon mutations. ²⁸ Preliminary efficacy from a phase I/II study (NCT03974022) in the first‐line setting reported 14 of 26 patients with a confirmed response (54%); median DoR was not reached. The most common TEAEs were diarrhea, creatine phosphokinase increase, and skin rash. ²⁸ In a phase II study in Chinese patients with advanced NSCLC with EGFR ex20ins mutations and whose disease had progressed on or after platinum‐based chemotherapy, the confirmed ORR by blinded independent central review was 60% overall and 49% in patients with baseline metastases. ²⁹ A phase III study comparing the efficacy and safety of sunvozertinib to that of platinum‐based doublet chemotherapy in patients with previously untreated advanced EGFR ex20ins–positive NSCLC is currently ongoing (NCT05668988). Zipalertinib is an oral irreversible EGFR inhibitor that, based on preclinical data, selectively targets cells expressing EGFR ex20ins mutations while sparing cells expressing WT EGFR. ³⁰ In a phase I/II study in patients with recurrent or metastatic NSCLC harboring EGFR ex20ins mutations (NCT04036682), 38.4% had a confirmed objective response with a median DoR of 10 months. The most common TRAEs were rash, paronychia, and diarrhea. ³⁰ A phase III study comparing the efficacy and safety of zipalertinib in combination with platinum‐based chemotherapy to that of chemotherapy alone in patients with previously untreated advanced EGFR ex20ins–positive NSCLC is currently ongoing (NCT05973773). BLU‐451 is a potent and selective inhibitor of EGFR ex20ins mutations that is also being evaluated in a phase I/II clinical trial (NCT05241873). ³¹ Preliminary data indicated that partial responses were observed (data not reported); the most common AEs were diarrhea and cough. ³¹

CONCLUSIONS

Mobocertinib was the first TKI to receive accelerated approval specifically for treating patients with EGFR ex20ins–positive NSCLC. At more than 2 years of follow‐up in the pivotal phase I/II trial, mobocertinib continued to demonstrate clinically meaningful benefit for patients with EGFR ex20ins–positive metastatic NSCLC whose disease has progressed on or after platinum‐based chemotherapy, with a manageable safety profile. Voluntary withdrawal of mobocertinib was initiated worldwide based on the results of the phase III EXCLAIM‐2 study, which demonstrated that mobocertinib efficacy was not superior to platinum‐based chemotherapy in patients with locally advanced or metastatic EGFR ex20ins–positive NSCLC in the first‐line setting. ¹³ , ¹⁴

A high unmet medical need for patients with EGFR ex20ins–positive NSCLC remains, especially for those with CNS metastases. Future agents should seek to improve upon the benefit–risk profile observed for these approved drugs to further provide physicians and patients with additional treatment options.

AUTHOR CONTRIBUTIONS

M.J.H., D.R.C., R.J.F., and N.G. wrote the manuscript. M.J.H. and N.G. designed the research and analyzed the data.

FUNDING INFORMATION

This review article was supported by Takeda Development Center Americas, Inc., Lexington, MA, USA.

CONFLICT OF INTEREST STATEMENT

M.J.H. is an employee of Takeda Development Center Americas, Inc. D.R.C. receives research funding from Inivata and has partaken in company‐sponsored trials (PI role) with AbbVie, AstraZeneca, Dizal, Inhibrx, Karyopharm, Pfizer, Phosplatin, Psioxus, Rain, Roche/Genentech, Seattle Genetics, Takeda, and Turning Point. R.J.F. is an employee of Takeda Development Center Americas, Inc. and reports stock ownership in Baxter, Bristol Myers Squibb, Gilead, Johnson and Johnson, Medtronics, Pfizer, Takeda, Teva, Viatriz, Simmer Biomet, and Zimvie. N.G. is an employee of Takeda Development Center Americas, Inc.

Hanley MJ, Camidge DR, Fram RJ, Gupta N. Mobocertinib: Mechanism of action, clinical, and translational science. Clin Transl Sci. 2024;17:e13766. doi: 10.1111/cts.13766