Emerging TKIs Drive Renewed Progress in EGFR Exon 20 Insertion–Positive NSCLC

Zosia Piotrowska, MD, MHS.

Few molecular subtypes in thoracic oncology have undergone as dramatic a therapeutic transformation in recent years as EGFR exon 20 insertion–positive non–small cell lung cancer (NSCLC), according to Zosia Piotrowska, MD, MHS. Once considered “undruggable,” this heterogeneous class of mutations, which accounts for approximately 10% of all EGFR mutations in NSCLC, has become the focus of an accelerating wave of targeted drug development.¹

At the 23rd Annual Winter Lung Cancer Conference^®, an event held by Physicians’ Education Resource, LCC, Piotrowska reviewed recent advances and ongoing challenges in managing this patient population, with particular focus on newly approved agents, 2 next-generation drugs in late-stage development, central nervous system (CNS) activity data, and upcoming first-line trials poised to reshape the treatment paradigm.

“When we get that next-generation sequencing report and see [the presence of an] EGFR [mutation], we get excited; then we see the exon 20 insertion, and we [feel disheartened],” Piotrowska stated in her presentation during the meeting. “I hope that will change in the future.”

Piotrowska is an associate professor of medicine at Harvard Medical School, a thoracic medical oncologist at Massachusetts General Hospital, and co-clinical director of the Massachusetts General Brigham Cancer Institute Thoracic Medical Oncology Program in Boston.

What is the current standard of care (SOC) for EGFR exon 20 insertion–mutant NSCLC?

The current first-line SOC for patients with locally advanced or metastatic NSCLC harboring an EGFR is the combination of amivantamab-vmjw (Rybrevant) plus carboplatin and pemetrexed.1 Amivantamab was first FDA approved as monotherapy in 2021 for adult patients with locally advanced or metastatic NSCLC displaying an EGFR exon 20 insertion mutation whose disease has progressed on or after platinum-based chemotherapy based on data from the phase 1 CHRYSALIS study (NCT02609776) and later received full approval in combination with carboplatin and pemetrexed in the confirmatory phase 3 PAPILLON study (NCT04538664) in March 2024.^2,3

The oral TKI mobocertinib (Exkivity) was also previously granted FDA accelerated approval in EGFR exon 20 insertion mutation–positive, locally advanced or metastatic NSCLC in September 2021 based on findings from a cohort of patients from a phase 1/2 trial (NCT02716116).⁴ However, mobocertinib was voluntarily pulled from the market in 2023 by Takeda, the drug’s developer, after data from the phase 3 EXCLAIM-2 trial (NCT04129502) failed to demonstrate superiority over chemotherapy in the frontline setting.⁵ This led to a dearth of effective new treatment options for patients with EGFR exon 20 insertion–positive disease outside of SOC amivantamab, Piotrowska stated.

“For many years, we really didn’t have therapy options for our patients outside of a clinical trial following the withdrawal of mobocertinib,” she noted.¹ “That changed, at least in theory, earlier over this last year…with the FDA approval of sunvozertinib.”

Sunvozertinib is FDA approved—so why can’t patients get it?

On July 2, 2025, the FDA granted accelerated approval to sunvozertinib (Zegfrovy) for adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.⁶ The approved United States (US) dose is 200 mg once daily.

The approval was supported by data from the global phase 2 WU-KONG1B study (NCT03974022).⁷ At the 200-mg dose level (n = 85), the confirmed ORR with sunvozertinib was 45.9% (95% CI, 33.6%-58.6%), the median duration of response (DOR) was 11.1 months (95% CI, 8.2–NE), and the median PFS was 8.4 months (95% CI, 6.8-13.9). In patients who had received prior amivantamab (n = 12), the ORR dropped to 25%, and in patients with baseline CNS metastases (n = 21), the systemic ORR was 29%.

Piotrowska noted that a key contextual limitation of the trial was that amivantamab plus chemotherapy had not yet become the dominant frontline SOC when most patients were enrolled onto WU-KONG1B. This patient population will be an important real-world consideration going forward.

Despite sunvozertinib’s FDA approval, critical access barriers persist. “Unfortunately, due to production and supply issues, [sunvozertinib] has not been available [in the US]. This is a big challenge for patients with EGFR exon 20 insertions looking for this drug,” Piotrowska said.¹

Which other next-generation agents could fill this therapeutic gap?

Zipalertinib (CLN-081/TAS6417) Zipalertinib is an orally available, irreversible, next-generation EGFR inhibitor designed to selectively target exon 20 insertion mutations while sparing wild-type EGFR. The agent received FDA breakthrough therapy designation (BTD) in January 2022 based on findings from the phase 1/2 REZILIENT1 trial (NCT04036682).⁸

Data presented at the 2025 ASCO Annual Meeting showed that the confirmed ORR with zipalertinib in the primary cohort of patients with prior exposure to platinum-based chemotherapy only (n = 125) was 40% (95% CI, 31.3%-49.1%).⁹ In patients who had received prior amivantamab without another exon 20 TKI (n = 30), the ORR was 30% (95% CI, 14.7%-49.4%). However, in the 21 patients who had received both prior amivantamab and a prior exon 20 insertion–directed TKI, the ORR was 14% (95% CI, 3.0%-36.3%). The safety profile of zipalertinib was notable for predominantly dermatologic toxicities, with a relatively low rate of grade 3 AEs and a 22% incidence of diarrhea of any grade.

“This suggests that there’s cross-resistance between these different TKIs,” Piotrowska explained.¹ “If we are ever in the fortunate situation of having multiple of these agents, sequencing them will not be a particularly effective strategy.”

Based on these data, a rolling submission of a new drug application to the FDA seeking the accelerated approval of zipalertinib in chemotherapy-pretreated NSCLC harboring EGFR exon 20 insertion mutations was initiated in November 2025 and finalized in February 2026.¹⁰

“Hopefully this will be something that, over the next year, will become available for our patients,” Piotrowska said.¹

Furmonertinib (AST2818) Furmonertinib is an oral, third-generation, highly brain-penetrant, mutant-selective EGFR TKI.¹¹ It received FDA BTD in October 2023 for the first-line treatment of previously untreated locally advanced or metastatic nonsquamous NSCLC with EGFR exon 20 insertion mutations, based on data from the phase 1b FAVOUR trial (NCT04858958).

Notably, first-line data from the phase 1b FAVOUR trial showed a markedly higher confirmed ORR of 78.6% (95% CI, 59.05%-91.70%) by IRC in 28 treatment-naïve patients treated at 240 mg, with a median DOR of 15.2 months (95% CI, 8.74-28.84).¹² In previously treated patients, at 240 mg (n=26), the confirmed ORR was 46.2% (95% CI, 26.6%-66.6%) and the median DOR was 13.1 months (95% CI, 5.62-13.80).

“This does indicate that activity could be even better in that frontline setting,” Piotrowska said.¹

Furmonertinib was also evaluated after platinum–based chemotherapy in the pivotal phase 2 FURMO-003 trial (NCT05466149).¹³ Results presented at the 2025 ESMO Congress showed that the confirmed ORR by independent review committee among 70 patients was 44.3%, with a median PFS of 8.3 months (95% CI, 5.5-10.9). TRAEs leading to dose reduction occurred in 12.7% of patients, and only 5.6% discontinued treatment due to TRAEs. The most common TRAEs with the agent included diarrhea (64.8%), anemia (39.4%), elevated creatinine (33.8%), elevated AST (31.0%), decreased appetite (29.6%), rash (28.2%), and stomatitis (22.5%); no grade 5 events or deaths due to TRAEs were reported.

What do we know about the central nervous system (CNS) activity of these agents?

Brain metastases represent a particularly important unmet need in EGFR exon 20 insertion–positive NSCLC, and more active CNS-targeted therapies are needed, Piotrowska emphasized.¹

A dedicated CNS cohort in the REZILIENT1 trial provided the most robust prospective intracranial activity data to date for any EGFR exon 20 insertion–directed TKI.¹⁴ Among 16 patients with RANO-BM evaluable CNS metastases—9 of whom had EGFR exon 20 insertions and 6 who had other EGFR mutations—31.3% achieved a confirmed intracranial partial response by RANO-BM criteria. Two of the 5 intracranial responders also had leptomeningeal disease at baseline. The median intracranial duration of response was 8.1 months. The systemic ORR in the full cohort was 27.8%.

“There’s a hint that this drug does get into the CNS. The comparable intracranial and systemic ORR is a good sort of indicator that this drug is penetrating into the CNS,” Piotrowska said.¹ “[Although] we hope to see both the systemic and intracranial response rate improve with new agents in the future, it is encouraging to see a drug that is having comparable intracranial and systemic activity here—but these are small numbers. These dedicated CNS cohorts are really important to be able to robustly assess the CNS activity of new agents.”

FURVENT (NCT05607550): Comparing furmonertinib (firmonertinib) at 2 dose levels (160 mg and 240 mg once daily) with platinum-based chemotherapy in previously untreated patients with locally advanced or metastatic non-squamous EGFR exon 20 insertion–positive NSCLC.¹⁷ Of note, this trial completed enrollment in the first quarter of 2025, with topline PFS data projected in early 2026.

“The zipalertinib study is taking an approach more similar to [the phase 3] FLAURA2 [NCT04035486], combining zipalertinib with chemotherapy—taking more of a risk on the safety profile in the hopes of achieving better efficacy—whereas sunvozertinib and furmonertinib are both TKI monotherapy compared to chemotherapy,” Piotrowska pointed out.¹ That was the design of the EXCLAIM-2 trial. We’ll have to wait and see how these studies shake out in terms of efficacy and safety and see which ones [could] change our frontline SOC.”

The contrast between chemotherapy-combination and TKI-monotherapy approaches echoes broader debates in EGFR-mutant NSCLC and will be closely watched, Piotrowska concluded, noting that results from these trials will be the next major inflection point in the field.

Disclosures: Piotrowska disclosed serving in a consulting role and receiving honoraria from AbbVie, AstraZeneca, Bayer, Black Diamond, Blossom Hill, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Genentech, Genmab, Gilead, Janssen, Merck, Natera, Revolution Medicines, Sanofi, Summit, Taiho, Takeda, Tubulis; and receiving institutional research support from AbbVie, AstraZeneca, Blossom Hill Therapeutics, Blueprint Medicines, Cullinan Oncology, Daiichi Sankyo, Janssen, Novartis, Nuvalent, Spectrum, SystImmune, Takeda, and Tesaro/GSK.

References

1. Piotrowska, Z. Targeting EGFR exon 20: advances and challenges. Presented at: 23rd Annual Winter Lung Cancer Conference; January 23-January 25, 2026; Hollywood, FL.

2. FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed April 10, 2026.

3. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-amivantamab-vmjw-metastatic-non-small-cell-lung-cancer

4. 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 April 10, 2026. https://www.takeda.com/newsroom/newsreleases/2021/takeda-exkivity-mobocertinib-approved-by-us-fda/

5. Takeda provides update on Exkivity (mobocertinib). News release. Takeda. October 2, 2023. Accessed April 10, 2026.https://www.takeda.com/newsroom/newsreleases/2023/Takeda-Provides-Update-on-EXKIVITY-mobocertinib/

6. FDA grants accelerated approval to sunvozertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. FDA. July 2, 2025. Accessed April 10, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sunvozertinib-metastatic-non-small-cell-lung-cancer-egfr-exon-20

7. Yang JC, Wang M, Doucet L, et al. Phase II dose-randomized study of sunvozertinib in platinum-pretreated non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations (WU-KONG1B). J Clin Oncol. 2025;43(29):3198-3208. doi:10.1200/JCO-25-00788

8. FDA grants breakthrough therapy designation for Cullinan Oncology’s CLN-081 in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer. News release. Cullinan Oncology, Inc.; January 4, 2022. Accessed April 10, 2026. https://investors.cullinanoncology.com/news-releases/news-release-details/fda-grants-breakthrough-therapy-designation-cullinan-oncologys

9. Piotrowska Z, Passaro A, Nguyen D, et al. Zipalertinib in patients with epidermal growth factor receptor exon 20 insertion-positive non-small cell lung cancer previously treated with platinum-based chemotherapy with or without amivantamab. J Clin Oncol. 2025;43(21):2387-2397. doi:10.1200/JCO-25-00763

10. Cullinan Therapeutics provides corporate update and reports fourth quarter and full year 2025 financial results. News release. Cullinan Therapeutics Inc. March 10, 2026. Accessed April 10, 2026. https://investors.cullinantherapeutics.com/news-releases/news-release-details/cullinan-therapeutics-provides-corporate-update-and-reports-6

11. Arrivent receives FDA breakthrough therapy designation for furmonertinib for first-line treatment of advanced or metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. News release. ArriVent Biopharma, Inc. October 30, 2023. Accessed April 10, 2026. https://arrivent.com/arrivent-receives-fda-breakthrough-therapy-designation-for-furmonertinib-for-first-line-treatment-of-advanced-or-metastatic-non-small-cell-lung-cancer-with-egfr-exon-20-insertion-mutations/

12. Han B, Zhou C, Zheng W, et al. A phase 1b study of furmonertinib, an oral, brain penetrant, selective EGFR inhibitor, in patients with advanced NSCLC with EGFR exon 20 insertions. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract OA03.04.

13. Cheng Y, et al. Furmonertinib in EGFR exon 20 insertion NSCLC post-chemotherapy: FURMO-003 pivotal phase 2 results. Presented at: European Society for Medical Oncology (ESMO) Annual Congress 2025. Abstract 1848MO.

14. Efficacy of zipalertinib in NSCLC patients with EGFR exon 20 insertion mutations who received prior platinum-based chemotherapy with or without amivantamab. J Clin Oncol. 2025;43(16):8503. doi:10.1200/JCO.2025.43.16_suppl.8503

15. REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (REZILIENT3). Clinicaltrials.gov Updated March 10, 2026. Accessed April 10, 2026. https://clinicaltrials.gov/study/NCT05973773

16. A study of DZD9008 versus platinum-based doublet chemotherapy in local advanced or metastatic non-small cell lung cancer (WU-KONG28). Clinicaltrials.gov. Updated February 17, 2026. Accessed April 10, 2026. https://clinicaltrials.gov/study/NCT05668988

17. ArriVent’s topline pivotal phase 3 FURVENT data for firmonertinib in first-line NSCLC EGFR exon20 insertion mutations is projected to be early 2026. News release. ArriVent. July 12, 2025. Accessed April 10, 2026. https://ir.arrivent.com/news-releases/news-release-details/arrivents-topline-pivotal-phase-3-furvent-data-firmonertinib