Emerging TKIs Shake Up the Treatment Landscape for EGFR Exon 20 Insertion+ NSCLC

Lyudmila Bazhenova, MD

Chemotherapy with or without immunotherapy continues to be the preferred frontline choice for patients with non–small cell lung cancer (NSCLC) who harbor EGFR exon 20 insertion mutations, according to Lyudmila Bazhenova, MD, who added novel options like amivantamab-vmjw (Rybrevant) and mobocertinib (Exkivity) have become available for use in the second-line setting, but the optimal sequence of these agents remains largely unknown.

“EGFR exon 20 insertion mutations are distinct from classical and atypical EGFR mutations. Remember, they do not respond to first- and third-generation EGFR TKIs. We currently have 2 drugs approved, amivantamab and mobocertinib, for the second-line, platinum-platinum setting,” Bazhenova said in a presentation during the 19th Annual Winter Lung Cancer Conference^®, an event hosted by Physicians’ Education Resource^®, LLC.¹ “The optimal sequence of these agents in this setting is unknown…Central nervous system [CNS] penetration remains the major issue for both of those compounds, as those with active brain metastases were excluded from both of those clinical trials.”

In her presentation, Bazhenova, a professor of medicine, director of the Hematology Oncology Training Program, and leader of the Lung Cancer Unit at UC San Diego Moores Cancer Center, discussed key challenges faced with diagnosing and appropriately treating those with tumors that harbor EGFR exon 20 insertion mutations, and provided insight into the second-line options that have recently garnered regulatory approval.

EGFR Exon 20 Insertion Mutations: Historically Untargetable and Underdiagnosed

EGFR insertion 20 mutations are detected in approximately 10% of all EGFR-mutated NSCLCs, and they are mutually exclusive from other mutations, according to Bazhenova. She added that these mutations are very heterogeneous and can happen at any point of the EGFR exon, with the majority occurring at near loop.^2,3

“The challenge with EGFR exon 20 insertions is that if you are using commercially available polymerase chain reaction [PCR] kits, you are going to miss a lot of [these] mutations,” Bazhenova noted.⁴ “If you compare [the use of] single-gene PCR via an available PCR kit with [that of] next-generation sequencing, you are missing about 50% of mutations.”

Historically, these mutations have been considered untargetable, Bazhenova added, and they are known to be generally refractory to first- and second-generation EGFR TKIs. Data have demonstrated that treatment with erlotinib (Tarceva) or gefitinib (Iressa) has resulted in a median progression-free survival (PFS) ranging from 1.5 months to 2 months; the median PFS achieved with afatinib in these patients is just 2.9 months.^3,5-7 The A763_Y764insFQEA mutation is an exception in that this has been found to be sensitive to these kinds of agents, according to Bazhenova.

“Despite the fact that EGFR exon 20 insertions are generally not sensitive to EGFR TKIs, these agents are still commonly used in our patients. Real-world data from the Flatiron database, presented during the 2021 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer,⁸ showed that approximately 20% of patient with these mutations receive an EGFR TKI in the first-line setting,” Bazhenova said. “Fifteen percent of these patients receive EGFR TKIs in the second-line setting, and about 10% receive them in the third-line setting. Another surprising finding was that many patients who have an EGFR mutation will receive single-agent immunotherapy in the first-line setting, which I would note is the wrong option.”

The retrospective comparative analysis of real-world outcomes in those with EGFR exon 20 insertion–positive NSCLC (n = 181) compared with those who had common EGFR mutations like L858R or exon 19 deletion (n = 2833) also revealed a 75% increased risk of death in the former population. The median real-world OS was 16.2 months (95% CI, 11.04-19.38) in the subset with EGFR exon 20 insertions vs 25.5 months (95% CI, 24.48-27.04) in those with common EGFR mutations; the 5-year overall survival (OS) rates these populations were 8% vs 19%, respectively.

The median real-world PFS was also worse for those with EGFR exon 20 insertion mutations vs common EGFR mutations, at 2.9 months (95% CI, 2.14-3.91) and 10.5 months (95% CI, 10.05-10.94), respectively. The 5-year PFS rates were 9% and 17%, respectively.

Novel Second-Line Options Join the Treatment Armamentarium

Amivantamab

In March 2021, the FDA approved the EGFR/MET bispecific antibody amivantamab as the first treatment for adult patients with NSCLC whose tumors harbor EGFR exon 20 insertion mutations.⁹

The decision was supported by findings from the open-label, dose-escalation and -expansion phase 1/2 CHRYSALIS trial (NCT02609776), which showed that the agent elicited an overall response rate (ORR) of 40% (95% CI, 29%-51%), a median duration of response (DOR) of 11.1 months (95% CI, 6.9–not reached), and a median PFS of 8.3 months (95% CI, 6.5-10.9) among 81 patients who were previously treated with platinum-based chemotherapy.¹⁰

“A key point of that study was that those with active brain metastases were not included,” Bazhenova noted. “Emerging data [suggest that] maybe the location of the mutation actually matters in [terms of] response. The numbers here are small, but [it appears] that if a patient has a mutation in the near loop, they tend to [do] a little bit better than those with mutations in the far loop. That [finding] still needs to be confirmed with more patient samples.”

The toxicity observed with amivantamab was as expected with EGFR monoclonal antibodies, Bazhenova added. In a safety population of 114 patients, the most common toxicity experienced with the agent was rash, and this occurred in 86% of patients; this event was grade 1 in 38% of these patients, grade 2 in 45% of patients, and grade 3 or higher in 4% of patients.

Notably, infusion-related reactions were experienced by 66% of patients; this event was grade 1 in 8% of patients, grade 2 in 55% of patients, and grade 3 or higher in 3% of patients.

“An important thing to be aware of is that this drug has infusion-related reactions. The first dose of the medication must be split between day 1 and 2, and the first 2 doses must be predosed with glucocorticoids,” Bazhenova explained. “The incidence of infusion-related reactions was 61% on day 1 and then about 5% on day 2; that [rate] decreases as you go further with additional administration of the drug. Starting on day 8, you do not have to give steroids. In my practice, I tend to keep steroids for the first months and then discontinue it with cycle 2.”

Mobocertinib

In September 2021, the FDA granted an accelerated approval to the novel irreversible EGFR TKI mobocertinib for use in adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on, or after, platinum-based chemotherapy.¹¹

The regulatory decision was supported by findings from a phase 1/2 trial (NCT02716116), which showed that when the agent was given at a dose of 160 mg, it induced an ORR of 28% (95% CI, 20%-37%) per blinded independent review committee assessment in a cohort of 114 patients with EGFR exon 20 insertion–positive NSCLC who received prior platinum-based therapy.¹² Moreover, the median DOR with the agent was 17.5 months (95% CI, 7.4-20.3), the median PFS was 7.3 months (95% CI, 5.5-9.2), and the median OS was 24.0 months (95% CI, 14.6-28.8).

“Remember, I said that EGFR exon 20 insertion mutations are not traditionally sensitive to EGFR TKIs. However, with the way that mobocertinib is designed, it can fit into the ATP-binding pocket,” Bazhenova explained. “Similar to amivantamab, those with active brain metastases were excluded [from the trial that supported the approval].”

Toxicity with mobocertinib was as expected with EGFR TKIs, according to Bazhenova, in that patients experienced treatment-related diarrhea (any grade, 91%; grade 3 or higher, 21%), nausea (34% and 4%, respectively), stomatitis (24% and 4%), and lipase increased (19% and 4%).

Emerging EGFR TKIs Under Exploration¹³

Osimertinib (Tagrisso) has been evaluated in 21 patients with EGFR exon 20 insertion mutations who have previously received 1 line of treatment and has been shown to elicit an ORR of 24% and a median PFS of 9.6 months. Treatment-related toxicities included diarrhea (76%), fatigue (67%), thrombocytopenia (67%), anemia (43%), leukopenia (43%), anorexia (43%), mucositis (38%), and rash (38%).

Another EGFR TKI, CLN-081 (TAS6417), has been assessed in 43 patients with EGFR exon 20 insertion mutations who previously received platinum chemotherapy.14 Eighteen percent of patients previously received a first- or second-generation EGFR TKI, 20% previously received osimertinib, and 9% previously received poziotinib/mobocertinib. Moreover, 56% of these patients previously received immunotherapy.

At all dose levels examined, the agent was found to produce an ORR of 31%; when given at a twice-daily dose of 100 mg, the CLN-081 elicited an ORR of 46%. Notably, efficacy was observed across all EGFR exon 20 insertion subtypes examined. A key treatment-related toxicity was rash, and that was reported in 73% of patients.

Lastly, poziotinib has also been investigated as a potential therapeutic option in 87 patients with EGFR exon 20 insertion mutations who previously received chemotherapy. Twenty-five percent of these patients also previously received an EGFR TKI.

Findings showed that poziotinib resulted in a median PFS of 4.2 months and a median DOR of 7.4 months, with efficacy observed across all EGFR exon 20 insertion subtypes. The most common treatment-related toxicities included diarrhea (79%), rash (60%), stomatitis (52%), paronychia (45%), nausea (38%), and anorexia (31%).

References

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9. FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA; May 21, 2021. Accessed February 7, 2022. https://prn.to/3hOrU1t
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11. 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 February 7, 2022. https://bit.ly/2Xm3WSY
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