Zipalertinib (CLN-081/TAS6417): A Comprehensive Review of a Novel EGFR TKI Targeting Exon 20 Insertion Mutations in Non-Small Cell Lung Cancer

1. Introduction

1.1. Overview of Zipalertinib

Zipalertinib, also identified by the codes CLN-081 and TAS6417, represents an investigational therapeutic agent under development for specific oncological indications.[1] It is characterized as an orally available, small molecule belonging to the class of irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).[1] Chemically, its structure incorporates elements from acrylamides, amines, indolizines, pyrimidines, and quinolines.[4] The primary focus of Zipalertinib's clinical development is the treatment of non-small cell lung cancer (NSCLC) characterized by specific mutations in the EGFR gene, with a particular emphasis on exon 20 insertion (ex20ins) mutations.[1]

1.2. The Unmet Need in EGFR Exon 20 Insertion NSCLC

Mutations within the EGFR gene, typically located in exons 18 through 21, function as critical oncogenic drivers in a subset of NSCLC, predominantly adenocarcinoma. These mutations lead to constitutive activation of downstream signaling pathways, promoting cancer cell proliferation and survival.[1] While significant progress has been made with EGFR TKIs targeting common mutations (e.g., exon 19 deletions, L858R point mutation), the landscape is markedly different for patients whose tumors harbor EGFR exon 20 insertion mutations.[6]

EGFR ex20ins mutations constitute a heterogeneous group of in-frame insertions and/or duplications, accounting for approximately 4% to 10% of all identified EGFR mutations in NSCLC.[1] Historically, these mutations have conferred de novo resistance to first- and later-generation EGFR TKIs, limiting therapeutic options.[1] Consequently, platinum-based chemotherapy has remained a cornerstone of standard care for these patients.[1] However, outcomes with chemotherapy are often suboptimal compared to TKI efficacy in classical EGFR mutations, with real-world data indicating objective response rates (ORR) around 19.5% and median overall survival (OS) ranging from approximately 16 to 17 months.[1] While targeted therapies like the EGFR/MET bispecific antibody amivantamab have gained approval, challenges remain, including intravenous administration, infusion-related reactions, and specific toxicities such as rash and diarrhea.[6] The prior availability of mobocertinib, another oral TKI, was curtailed due to its withdrawal, further emphasizing the need for effective and well-tolerated oral agents specifically designed for this molecular subtype.[6]

1.3. Development and Collaboration

Zipalertinib (originally TAS6417) was originated by Taiho Pharmaceutical Co., Ltd..[4] Its clinical development is being actively pursued through a collaborative effort between Taiho Pharmaceutical (including its subsidiary Taiho Oncology, Inc.) and Cullinan Therapeutics, Inc. (also listed as Cullinan Oncology LLC).[2]

A significant strategic partnership was formalized between Cullinan and Taiho in 2022, outlining the terms for co-development and commercialization.[9] This agreement involved a substantial upfront payment of $275 million from Taiho to Cullinan, with potential for an additional $130 million in regulatory milestone payments. Furthermore, the terms stipulate a 50/50 profit-sharing arrangement within the United States market.[9] The magnitude of this financial commitment, particularly the upfront payment for an asset still undergoing Phase 2 evaluation at the time, signals strong confidence from both parties in Zipalertinib's potential clinical value and market prospects. Such substantial investment often reflects a shared belief in the drug's ability to address the significant unmet need in EGFR ex20ins NSCLC, where existing therapies face limitations.[1] The equal profit share in the key US market further reinforces the expectation of considerable therapeutic and commercial success.

While Zai Lab (Shanghai) Co., Ltd. is listed as an "Active Organization" associated with Zipalertinib in some databases [10], the specific nature of its involvement or any distinct licensing agreements pertaining to Zipalertinib were not detailed in the reviewed materials.

2. Mechanism of Action

2.1. EGFR Exon 20 Insertions as Therapeutic Targets

EGFR ex20ins mutations represent a diverse collection of genetic alterations within exon 20, leading to the insertion or duplication of amino acids in the EGFR protein.[1] These structural changes, particularly near the ATP-binding pocket, often result in conformational shifts that hinder the binding of many conventional EGFR TKIs, explaining the observed resistance.[1] This inherent resistance profile necessitates the development of inhibitors specifically engineered to accommodate or overcome these structural alterations.

2.2. Zipalertinib's Molecular Interaction

Zipalertinib functions as a covalently binding, irreversible EGFR-TKI.[1] Its design incorporates a unique chemical scaffold intended to effectively fit into the ATP-binding site located in the EGFR hinge region, even in the presence of ex20ins-induced conformational changes.[1] Upon binding, Zipalertinib forms a covalent bond with a conserved cysteine residue (Cys797) within the ATP pocket, leading to irreversible inhibition of the receptor's kinase activity.[1] This targeted inhibition blocks the constitutive downstream signaling cascades that drive tumor proliferation and survival in EGFR-mutant NSCLC.[1] This mechanism, tailored to the specific structural challenge posed by ex20ins mutations, represents a rational drug design strategy aimed directly at circumventing a primary mode of resistance to earlier TKIs.

2.3. Selectivity Profile

A key characteristic highlighted in preclinical evaluations is Zipalertinib's selectivity profile. It demonstrates potent inhibition of various mutant EGFR forms, including those with ex20ins mutations (IC50 values reported between 1.1-8.0 nM), while exhibiting significantly less activity against wild-type (WT) EGFR.[1] Preclinical assessments also suggest minimal inhibitory activity against the human epidermal growth factor receptor 2 (HER2).[6]

The preferential targeting of mutant EGFR over WT EGFR is clinically significant. Inhibition of WT EGFR is the primary driver of common EGFR TKI-associated toxicities, namely dermatologic reactions (rash) and gastrointestinal disturbances (diarrhea).[6] By sparing WT EGFR, Zipalertinib is hypothesized to possess a wider therapeutic window. This implies that clinically effective doses, capable of inhibiting the target mutant EGFR, may be achievable with a lower burden of these mechanism-based side effects compared to less selective inhibitors.[1] Early clinical data reporting lower rates of high-grade rash and diarrhea appear to support this premise.[1]

3. Clinical Development Program: The REZILIENT Trials

3.1. Overview

The clinical evaluation of Zipalertinib is primarily anchored in the REZILIENT series of clinical trials. This program encompasses studies ranging from initial dose-finding and safety assessments (Phase 1/2) to larger efficacy evaluations (Phase 2b) and a pivotal registrational study (Phase 3).[1]

3.2. REZILIENT1 (NCT04036682): Phase 1/2b Dose Escalation and Expansion in Pretreated Patients

REZILIENT1 served as the foundational study for Zipalertinib, designed as a Phase 1/2a/b trial.[5] Its objectives were to assess the safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of Zipalertinib administered as monotherapy.[1] The study enrolled patients with locally advanced or metastatic NSCLC confirmed to harbor EGFR ex20ins mutations who had experienced disease progression following prior systemic therapies.[1] Various dose levels, ranging from 30 mg to 150 mg administered twice daily (BID), were investigated during the dose-escalation phase, ultimately establishing 100 mg BID as the Recommended Phase 2 Dose (RP2D).[1] The trial, initiated in 2019, enrolled a substantial number of patients (approximately 284 reported across the full study).[9] Crucially, the Phase 2b portion of REZILIENT1 successfully met its primary endpoint, demonstrating a significant overall response rate (ORR) in the targeted patient population.[2]

3.3. REZILIENT2 (NCT05967689): Phase 2b Multi-Cohort Evaluation

Building upon the findings from REZILIENT1, the REZILIENT2 study was initiated in July 2023 as a global, open-label, multi-cohort Phase 2b trial.[11] This study aims to further evaluate the efficacy and safety of Zipalertinib at the established 100 mg BID dose across distinct, clinically relevant patient populations.[12] Enrollment targets are approximately 40 patients per cohort, with potential for expansion based on meeting predefined efficacy thresholds.[12] The defined cohorts are:

• Cohort A: Patients with EGFR ex20ins NSCLC who have progressed on or after prior treatment specifically targeting ex20ins mutations (e.g., amivantamab, sunvozertinib) used either alone or in combination with chemotherapy.[12] This cohort directly investigates the activity of Zipalertinib in the post-amivantamab resistance setting, a growing clinical need as amivantamab usage increases in earlier lines of therapy.[9] Success here could establish Zipalertinib as a valuable sequential treatment option.
• Cohort B: Patients with EGFR ex20ins NSCLC who are treatment-naïve for advanced/metastatic disease and are considered unsuitable for, or have refused, standard first-line platinum-based chemotherapy.[12] This explores the potential of Zipalertinib monotherapy in a specific first-line niche.
• Cohort C: Patients with EGFR ex20ins or other uncommon EGFR mutations who present with active central nervous system (CNS) metastases, including leptomeningeal disease (LMD). This cohort allows enrollment of both treatment-naïve and previously treated patients.[12] The inclusion of patients with active CNS disease is particularly noteworthy, as this population is often excluded from clinical trials, and effective CNS penetration is a critical attribute for NSCLC therapies.[6] This cohort aims to formally assess intracranial efficacy using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria [12], moving beyond the anecdotal CNS responses seen in REZILIENT1.[1]
• Cohort D: Treatment-naïve patients with locally advanced or metastatic NSCLC harboring other uncommon single or compound EGFR mutations (specifically excluding the C797S resistance mutation).[12] This expands the investigation beyond ex20ins mutations.

The primary endpoint for REZILIENT2 is investigator-assessed ORR according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Secondary endpoints encompass disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), OS, intracranial efficacy endpoints for Cohort C, safety and tolerability assessments, and PK analyses.[12]

3.4. REZILIENT3 (NCT05973773): Phase 3 First-Line Combination Therapy

REZILIENT3 is an ongoing, global, randomized Phase 3 trial initiated in mid-2023, designed as a potential registrational study.[1] It evaluates the efficacy and safety of Zipalertinib administered in combination with standard first-line platinum-based chemotherapy (pemetrexed plus investigator's choice of carboplatin or cisplatin) compared against chemotherapy alone.[1] The target population is previously untreated patients with locally advanced or metastatic nonsquamous NSCLC harboring EGFR ex20ins mutations.[1]

The study employs a two-part structure: Part A involves a safety lead-in phase enrolling 6-12 patients to confirm the safety and tolerability of the Zipalertinib combination regimen before proceeding to the randomized phase.[1] Part B plans to randomize approximately 260 patients on a 1:1 basis to either the Zipalertinib-chemotherapy combination arm or the chemotherapy-alone arm.[1] An important design feature is the allowance for optional crossover: patients randomized to the chemotherapy-only arm may receive Zipalertinib monotherapy upon documented disease progression as assessed by blinded independent central review (BICR).[19]

The primary endpoint of REZILIENT3 is PFS, assessed by BICR.[1] Key secondary endpoints include OS, ORR, DOR, and safety.[1] The decision to evaluate Zipalertinib in combination with chemotherapy in the first-line setting within this pivotal trial, rather than pursuing monotherapy registration initially, may reflect a strategic assessment that combination therapy could offer superior efficacy and potentially establish a new standard of care, aligning with trends observed for other targeted agents in NSCLC. This contrasts with the first-line monotherapy evaluation in REZILIENT2 Cohort B, which is restricted to patients unsuitable for chemotherapy.[17]

Table 1: Overview of Key Zipalertinib Clinical Trials

Trial Name (NCT ID)	Phase	Status	Key Patient Population	Intervention(s)	Primary Endpoint
REZILIENT1 (NCT04036682)	1/2b	Completed	Pretreated locally advanced/metastatic NSCLC with EGFR ex20ins mutations	Zipalertinib Monotherapy (Dose Escalation & Expansion)	Phase 2b: ORR
REZILIENT2 (NCT05967689)	2b	Recruiting	Multiple cohorts: Pretreated/Naive EGFR ex20ins, Active CNS mets (ex20ins/uncommon), Naive uncommon EGFR mutations	Zipalertinib Monotherapy (100 mg BID)	Investigator-Assessed ORR
REZILIENT3 (NCT05973773)	3	Recruiting	Treatment-naïve locally advanced/metastatic nonsquamous NSCLC with EGFR ex20ins mutations	Zipalertinib (100 mg BID) + Chemo vs. Chemo alone (Optional Crossover)	BICR-Assessed PFS

Abbreviations: BID, twice daily; BICR, Blinded Independent Central Review; CNS, Central Nervous System; EGFR, Epidermal Growth Factor Receptor; ex20ins, exon 20 insertion; NSCLC, Non-Small Cell Lung Cancer; ORR, Overall Response Rate; PFS, Progression-Free Survival.

Sources: 1

4. Clinical Efficacy

4.1. Efficacy in Pretreated Patients (REZILIENT1)

Initial results from the REZILIENT1 study demonstrated encouraging anti-tumor activity for Zipalertinib monotherapy in patients with heavily pretreated EGFR ex20ins NSCLC. Objective responses were observed across the various dose levels tested.[1] At the established RP2D of 100 mg BID, a confirmed ORR of 41% was reported among response-evaluable patients in the Phase 1/2a portion.[1] Across all dose levels evaluated in the initial cohort presented (n=73), the confirmed ORR was 38.4%.[6] The demonstration of consistent responses in approximately 40% of patients within this refractory population, who often have limited effective therapeutic options after failing standard chemotherapy, underscores the significant biological activity of Zipalertinib.[1]

4.2. Efficacy Post-Amivantamab (REZILIENT1 Phase 2b / REZILIENT2 Cohort A)

Data specifically focusing on patients who had progressed on or after prior therapy with the EGFR/MET bispecific antibody amivantamab were presented from the Phase 2b part of REZILIENT1 at the European Society for Medical Oncology (ESMO) Congress in 2024.[5] In this cohort of 30 evaluable patients, Zipalertinib (100 mg BID) achieved a confirmed ORR of 40.0% (95% CI, 22.7%-59.4%). This included one patient (3.3%) achieving a complete response (CR) and 11 patients (36.7%) achieving partial responses (PR).[5] The median DOR in this post-amivantamab setting was not reached (NE) at the time of the data cutoff, suggesting potential durability, while the median PFS was reported as 9.7 months (90% CI, 4.1-NE).[5] Achieving this level of response and disease control after failure of another targeted agent specifically directed against EGFR ex20ins mutations provides strong evidence for Zipalertinib's distinct activity and its potential utility in sequential therapy strategies.

4.3. Central Nervous System (CNS) Activity

Preliminary evidence suggesting potential CNS activity emerged from the REZILIENT1 study. Intracranial partial responses were observed in two patients who had previously treated, stable CNS metastases at the time of enrollment.[1] However, these findings are considered anecdotal due to the small number of patients with CNS lesions evaluated, the fact that these metastases were stable at baseline, and the lack of uniform CNS assessment protocols within the initial study design.[6] While encouraging, this preliminary signal requires rigorous confirmation. The dedicated Cohort C within the ongoing REZILIENT2 trial [12], which specifically enrolls patients with active CNS metastases (including LMD) and employs formal RANO-BM criteria for response assessment [12], is essential to definitively establish the extent and reliability of Zipalertinib's CNS efficacy. Confirmation of meaningful CNS activity would represent a significant advantage, given the prevalence of brain metastases in NSCLC and the limitations of many systemic therapies in crossing the blood-brain barrier.[6]

4.4. Efficacy in Other Settings (Ongoing Trials)

Efficacy data for Zipalertinib in other important clinical contexts are currently being generated through ongoing trials. This includes its performance as a first-line agent, both as monotherapy (in chemotherapy-ineligible/refusing patients in REZILIENT2 Cohort B) and in combination with chemotherapy (REZILIENT3), as well as its activity against other uncommon EGFR mutations (REZILIENT2 Cohort D).[1] Results from these studies will be critical in defining the broader applicability of Zipalertinib across the NSCLC treatment spectrum.

Table 2: Key Efficacy Outcomes for Zipalertinib Monotherapy (REZILIENT1)

Patient Population	Zipalertinib Dose	N (Evaluable)	Confirmed ORR (%) (95% CI)	Median DOR (months) (95% CI)	Median PFS (months) (90% CI)
Overall Pretreated (Phase 1/2a RP2D Cohort)	100 mg BID	-	41	-	-
Pretreated Post-Amivantamab (Phase 2b Cohort)	100 mg BID	30	40.0 (22.7-59.4)	NE	9.7 (4.1-NE)

Abbreviations: BID, twice daily; CI, Confidence Interval; DOR, Duration of Response; EGFR, Epidermal Growth Factor Receptor; ex20ins, exon 20 insertion; N, Number of patients; NE, Not Estimable; NSCLC, Non-Small Cell Lung Cancer; ORR, Overall Response Rate; PFS, Progression-Free Survival; RP2D, Recommended Phase 2 Dose.

Note: Data for the "Overall Pretreated (Phase 1/2a RP2D Cohort)" ORR is from 1; specific N, DOR, and PFS for this exact cohort were not detailed in provided snippets. Data for the "Pretreated Post-Amivantamab" cohort is from the ESMO 2024 presentation.5

5. Safety and Tolerability

5.1. Overall Safety Profile

Based on data accumulated primarily from the REZILIENT1 trial, Zipalertinib has demonstrated a generally manageable safety profile.[1] Treatment-related adverse events (TRAEs) of any grade were reported in the vast majority of patients (~99%).[14] The incidence of Grade 3 or higher TRAEs varied somewhat across different reports and patient cohorts, ranging from approximately 23% in the initial publication cohort to 38% in the later post-amivantamab cohort analysis.[5]

5.2. Common Treatment-Related Adverse Events (TRAEs)

The most frequently observed TRAEs (any grade) associated with Zipalertinib treatment in REZILIENT1 included dermatologic toxicities such as rash (reported rates varying from 38% to 80% across different analyses), paronychia (nail fold inflammation, ~32-36%), and dry skin (~18-20%). Other common events included anemia (~24%), stomatitis (mouth inflammation, ~11%), fatigue (~21%), nausea (~16%), and diarrhea (~30%).[5] While severe toxicities may be less common, the high frequency of these any-grade events suggests that management of persistent, lower-grade side effects like rash, nail changes, or diarrhea will be important for maintaining quality of life and treatment adherence during potentially long-term therapy.[6]

5.3. Notable and Serious TRAEs

Among the more severe (Grade 3 or higher) TRAEs, anemia was reported in approximately 9-10% of patients, and Grade 3 rash occurred in about 7%.[5] A significant safety concern identified is the potential for pneumonitis or interstitial lung disease (ILD), which occurred as a Grade 3 or higher event in 7% of patients in the post-amivantamab cohort analysis.[5] This aligns with a known class effect for EGFR TKIs and necessitates careful monitoring and prompt intervention if suspected. Pneumonitis/ILD represents a critical risk requiring vigilance and patient education, similar to other inhibitors in this class.

Notably, consistent with the drug's preclinical selectivity profile [1], the incidence of high-grade (Grade ≥3) rash and diarrhea associated with Zipalertinib 100 mg BID appears relatively low compared to historical data for less selective EGFR TKIs.[1] In the ESMO 2024 data presentation for the post-amivantamab cohort, no Grade 4 or 5 TRAEs were reported.[9] This potentially favorable profile regarding severe skin and gastrointestinal toxicity supports the hypothesis of improved tolerability stemming from WT EGFR sparing and could represent a significant clinical advantage.[6]

5.4. Dose Modifications and Discontinuations

The need for dose adjustments or cessation of therapy due to adverse events provides insight into treatment tolerability. In the post-amivantamab cohort from REZILIENT1, 7% of patients required dose reduction or discontinued Zipalertinib due to TRAEs.[5]

5.5. Comparison and Context

When contextualizing Zipalertinib's safety, the lower rates of severe rash and diarrhea are a potential point of differentiation compared to some other EGFR inhibitors, including those targeting ex20ins mutations.[6] However, it is important to acknowledge that even chronic Grade 1 or 2 toxicities can impose a significant burden on patients over time, affecting quality of life and potentially adherence.[6] Therefore, proactive management strategies for common lower-grade events will likely be necessary.

Table 3: Common Treatment-Related Adverse Events (TRAEs) with Zipalertinib (100 mg BID, REZILIENT1 Post-Amivantamab Cohort, N=45)

Adverse Event	Any Grade (%)	Grade ≥3 (%)
Rash	38	7
Paronychia	36	0
Anemia	24	9
Dry Skin	20	0
Dermatitis Acneiform	16	0
Nausea	16	0
Stomatitis	11	0
Diarrhea	*	*
Fatigue	*	*
Pneumonitis/ILD	-	7

Abbreviations: BID, twice daily; ILD, Interstitial Lung Disease; N, Number of patients; TRAE, Treatment-Related Adverse Event.

Note: Data primarily based on ESMO 2024 presentation (n=45 overall safety population in that cohort).5 () Diarrhea and Fatigue were reported as common TRAEs in earlier/broader REZILIENT1 analyses 14 but specific percentages for this cohort were not listed in.5 Pneumonitis/ILD Grade 3+ rate from.5*

6. Regulatory Status and Future Directions

6.1. FDA Breakthrough Therapy Designation

In recognition of its promising early clinical data in a setting of unmet need, Zipalertinib was granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) in January 2022.[2] This designation was specifically for the treatment of patients with EGFR ex20ins mutant NSCLC whose disease had progressed on or after platinum-based chemotherapy.[14] BTD is intended to expedite the development and regulatory review process for drugs targeting serious conditions where preliminary evidence suggests a substantial improvement over existing therapies.

6.2. Planned Regulatory Submissions

Following the positive outcome of the REZILIENT1 Phase 2b portion, which met its primary ORR endpoint, the developers, Cullinan Therapeutics and Taiho Pharmaceutical, have stated their intention to engage with the FDA.[9] Pending these discussions, they anticipate submitting Zipalertinib for regulatory approval in the United States during the second half of 2025.[9] The combination of BTD status and positive Phase 2b data in a refractory population raises the possibility that Zipalertinib could be considered for an accelerated approval pathway based on the single-arm REZILIENT1 results, contingent upon FDA agreement.

6.3. Positioning in the Treatment Landscape

Based on the currently available data, Zipalertinib appears poised to potentially fill a role as a therapeutic option for patients with EGFR ex20ins NSCLC following progression on prior systemic therapies.[6] Its demonstrated activity after both platinum-based chemotherapy and, significantly, after amivantamab failure, positions it favorably for second-line or later use.[5] The ongoing REZILIENT3 trial will be pivotal in determining its potential utility in the first-line setting, specifically in combination with chemotherapy.[1] The competitive landscape for EGFR ex20ins NSCLC includes other approved and investigational agents [6], and Zipalertinib's ultimate placement will depend heavily on comparative efficacy and safety data, particularly relative to the evolving standard of care which now includes amivantamab plus chemotherapy in the first line.[9] The outcome of the head-to-head REZILIENT3 comparison will strongly influence first-line positioning, while the REZILIENT2 Cohort A data remains critical for defining its role in later lines.

6.4. Ongoing Research and Future Potential

The comprehensive clinical development program continues with the REZILIENT2 and REZILIENT3 trials actively recruiting.[1] These studies are crucial for definitively evaluating Zipalertinib's efficacy and safety in various patient subgroups (treatment-naïve, active CNS metastases, uncommon EGFR mutations) and treatment strategies (monotherapy vs. combination).[1] Furthermore, longer-term follow-up from all trials will be necessary to ascertain mature overall survival data and the durability of responses, as well as to fully characterize the long-term safety profile.

7. Conclusion

7.1. Summary of Zipalertinib Profile

Zipalertinib (CLN-081/TAS6417) is an orally administered, irreversible EGFR TKI specifically designed to target the challenging EGFR exon 20 insertion mutations found in a subset of NSCLC patients. Clinical studies, primarily REZILIENT1, have demonstrated clinically meaningful anti-tumor activity, with objective response rates around 40% in heavily pretreated patient populations, including those who have progressed after prior amivantamab therapy.[1] Key potential advantages include its oral route of administration, a manageable safety profile characterized by relatively low rates of high-grade rash and diarrhea compared to less selective EGFR inhibitors, and preliminary indications of CNS activity that warrant further investigation.[1]

7.2. Limitations and Unanswered Questions

Despite the promising results, the current understanding of Zipalertinib is based predominantly on single-arm clinical trial data. Randomized, comparative data, particularly from the ongoing REZILIENT3 trial, are needed to definitively establish its efficacy relative to standard chemotherapy in the first-line setting.[1] Confirmation of the preliminary CNS activity signals requires robust data from dedicated cohorts like REZILIENT2 Cohort C.[12] Furthermore, mature data on long-term outcomes, including overall survival and the cumulative impact of chronic low-grade toxicities, are still pending.[6]

7.3. Overall Therapeutic Potential

Zipalertinib holds significant potential to address the unmet medical need for effective and well-tolerated treatments for patients diagnosed with EGFR exon 20 insertion-mutant NSCLC. Its demonstrated efficacy in refractory settings, including post-amivantamab failure, suggests it could become a valuable component of the treatment armamentarium, particularly in later lines of therapy. Its potential for improved tolerability regarding certain EGFR-mediated side effects and the possibility of CNS activity further enhance its profile. The outcomes of the ongoing Phase 2b (REZILIENT2) and Phase 3 (REZILIENT3) trials will be instrumental in fully elucidating Zipalertinib's role across different patient populations and treatment lines, ultimately defining its place within the dynamic therapeutic landscape for this specific molecular subtype of NSCLC.

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