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Cullinan, Taiho show six-month progression-free survival benefit in phase 3 lung cancer trial

Cullinan, Taiho show six-month progression-free survival benefit in phase 3 lung cancer trial

New Capabilities

Zipalertinib plus chemo delayed tumor progression six months beyond chemotherapy alone, setting up a first-line challenge to Johnson & Johnson's Rybrevant.

Yesterday: Full results presented at IASLC World Conference on Lung Cancer

Overview

Updated Yesterday

Patients with EGFR exon 20 insertion lung cancer have had almost no targeted options in the front-line setting. A phase 3 trial presented Sept. 13 in Seoul changed that. Adding the oral drug zipalertinib to chemotherapy delayed tumor progression by six months compared with chemotherapy alone.

The REZILIENT3 result, from Taiho and Cullinan Therapeutics, positions the pair to challenge Johnson & Johnson's Rybrevant, the only FDA-approved first-line treatment for this lung cancer subgroup. The companies plan to seek U.S. approval for the combination.

Why it matters

For EGFR exon 20 insertion lung cancer patients, zipalertinib plus chemo could add six months without progression and bring an oral option to first-line care.

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Key Indicators

14.5 months
Median progression-free survival with zipalertinib plus chemo
Versus 8.5 months with chemotherapy alone, per blinded independent review at the interim analysis.
6.0 months
Median progression-free survival improvement
The gain from adding zipalertinib to platinum-pemetrexed chemotherapy.
0.50
Hazard ratio for progression or death
A 50% risk reduction; the result was statistically significant (P = 0.00015).
65.0%
Objective response rate with the combination
Versus 40.3% with chemotherapy alone in the 279-patient trial.

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People Involved

Daniel Tan
Daniel Tan
Principal investigator of REZILIENT3; professor of medical oncology
Presented the results at the IASLC 2026 World Conference on Lung Cancer in Seoul

Organizations Involved

Cullinan Therapeutics
Cullinan Therapeutics
Biopharmaceutical company (Nasdaq: CGEM)
Co-developing zipalertinib and planning a U.S. filing for the first-line combination

Biotech co-developing zipalertinib with Taiho after licensing the drug in earlier-stage deals.
Taiho Pharmaceutical
Taiho Pharmaceutical
Pharmaceutical company (Taiho Oncology in the U.S.)
Leads REZILIENT3 and global zipalertinib development with Cullinan

Japanese drugmaker running phase 3 development for zipalertinib in EGFR-mutant lung cancer.
Johnson & Johnson
Johnson & Johnson
Pharmaceutical company
Current first-line standard via Rybrevant plus chemotherapy

Markets Rybrevant (amivantamab), the only FDA-approved first-line therapy for EGFR exon 20 insertion NSCLC.
AstraZeneca
AstraZeneca
Pharmaceutical company
Competitor via Zegfrovy, an oral EGFR inhibitor it licensed from Dizal

Holds global rights to Zegfrovy (sunvozertinib), an oral EGFR inhibitor approved in second-line and moving into first-line trials.

Timeline

2022 September 2026

4 events Latest: Yesterday
Tap a bar to jump to that date

  1. Full results presented at IASLC World Conference on Lung Cancer

    Latest Conference presentation

    Presidential symposium in Seoul showed median progression-free survival of 14.5 months with the combination versus 8.5 with chemo alone.

  2. REZILIENT3 meets progression-free survival endpoint

    Clinical trial

    Interim analysis showed zipalertinib plus chemo cut progression or death risk by 50%; the data monitoring committee recommended unblinding.

  3. Zegfrovy approved in second-line setting

    Regulatory

    Dizal's oral EGFR inhibitor won FDA approval for previously treated exon 20 insertion lung cancer, later licensed to AstraZeneca.

  4. Taiho buys back partial zipalertinib rights

    Deal

    Taiho paid Cullinan up to $405 million to reacquire rights as it accelerated development of the oral EGFR inhibitor.

Scenarios

1

FDA approves zipalertinib-chemo as first-line EGFR exon 20 treatment

Likely Resolves by End of 2028

Discussed by: Leerink Partners, TD Cowen, William Blair analysts

Cullinan and Taiho plan to submit after discussions with the FDA. Approval would give the field its first oral first-line option. Oral dosing and the absence of infusion premedication could drive adoption over Rybrevant, though the added chemotherapy may temper enthusiasm versus the all-oral Zegfrovy.

2

Final overall survival analysis confirms a survival benefit

Uncertain Resolves by Q2 2028

Discussed by: REZILIENT3 investigators and Leerink Partners

The interim overall survival hazard ratio of 0.72 is immature, at 30% of events, and not significant. If benefit fails to hold at final analysis, the case rests on progression-free survival and response. A confirmed overall survival gain would solidify the drug's first-line position.

3

Zipalertinib-chemo becomes the preferred first-line regimen

Possible Resolves by Q2 2029

Discussed by: William Blair, Leerink Partners

The 14.5-month median progression-free survival exceeds the benchmarks of both current options: Rybrevant at 11.4 months and Zegfrovy at 10.3 months. If the NCCN names it a preferred regimen and clinicians favor oral dosing, zipalertinib-chemo could become the standard, despite the added chemotherapy toxicity.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

2017 - 2018

Tagrisso (osimertinib) overtakes first-generation EGFR drugs (2017-2018)

In the FLAURA trial, AstraZeneca's osimertinib beat erlotinib and gefitinib as front-line therapy for EGFR-mutant lung cancer, with better brain-penetration and fewer severe side effects.

Then

Osimertinib displaced the first-generation drugs and became the global standard of care, passing $7 billion in annual sales.

Now

It became the model for an oral targeted therapy overtaking an established option on efficacy and tolerability.

Why this matters now

Zipalertinib-chemo aims to run the same playbook against Rybrevant: comparable or better efficacy in an easier-to-administer oral form.

September 2021 - October 2023

Exkivity (mobocertinib) withdrawal (2021-2023)

Takeda's oral kinase inhibitor won accelerated FDA approval for EGFR exon 20 insertion lung cancer in 2021 based on response rates. A required confirmatory phase 3 trial then failed to meet its endpoint.

Then

Takeda voluntarily withdrew Exkivity from the market in 2023, leaving the mutation without an oral targeted option in second-line.

Now

The episode reinforced the FDA's expectation that accelerated approvals produce confirmatory data, and it underscored how hard this tumor type is to treat.

Why this matters now

Zipalertinib is an oral drug for the same mutation that Exkivity targeted. REZILIENT3 is the confirmatory, phase 3 evidence that Exkivity never delivered.

2024

FLAURA2: osimertinib plus chemotherapy (2024)

AstraZeneca's FLAURA2 trial showed that adding chemotherapy to osimertinib improved progression-free survival in front-line EGFR-mutant NSCLC, mirroring the zipalertinib-chemo design.

Then

FLAURA2 extended progression-free survival but left the overall survival benefit unproven at the first readout, fueling debate about whether chemotherapy adds durable value.

Now

It set the precedent that EGFR inhibitors plus chemo can beat the inhibitor alone, while raising questions about added toxicity.

Why this matters now

REZILIENT3 faces the same question: whether the six-month progression-free gain translates into an overall survival benefit once final data mature.

Sources

(9)
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Fierce Biotech Medical Xpress Endpoints News BioPharma Dive BioSpace Taiho Pharmaceutical U.S. Securities and Exchange Commission Market Newsdesk Taiho Oncology