Zipalertinib + Chemotherapy for Non-Small Cell Lung Cancer

(REZILIENT3 Trial)

Recruiting at 160 trial locations

Overseen By Taiho Oncology, INC

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Taiho Oncology, Inc.

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Cardiac disease, Interstitial lung disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

272 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the new drug zipalertinib (also known as CLN-081, TAS-6417, or TPC-064), combined with standard chemotherapy, is more effective than chemotherapy alone for treating non-small cell lung cancer (NSCLC) that has spread or cannot be surgically removed. The focus is on patients whose cancer has a specific change in the EGFR gene known as an ex20ins mutation. Suitable candidates for this trial have NSCLC with the EGFR ex20ins mutation, have not received prior treatment for their advanced cancer, and have adequate organ function. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients access to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot take medications that strongly affect CYP3A4 enzymes within 7 days before starting the trial. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that zipalertinib in combination with chemotherapy is likely to be safe for humans?

Research has shown that zipalertinib is generally safe for patients with non-small cell lung cancer with EGFR ex20ins mutations. In earlier studies, patients who had tried other treatments experienced manageable side effects with zipalertinib. While side effects occurred, they were mostly mild and manageable with proper care.

The most common side effects included tiredness and nausea, typical of many cancer treatments. No unexpected or severe side effects emerged that would raise major safety concerns. This suggests that zipalertinib, when combined with chemotherapy, is considered safe for patients with this specific type of lung cancer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Zipalertinib is unique because it introduces a novel approach to treating non-small cell lung cancer by targeting specific molecular pathways that current chemotherapy options, like pemetrexed with carboplatin or cisplatin, do not address. Most standard treatments primarily work by damaging rapidly dividing cells, but zipalertinib is believed to target cancer cells more precisely, potentially improving effectiveness and reducing side effects. Researchers are excited about zipalertinib because it could enhance the efficacy of existing chemotherapy regimens and offer new hope for patients who might not respond well to current treatments.

What evidence suggests that zipalertinib combined with chemotherapy could be effective for non-small cell lung cancer?

Research shows that zipalertinib could help treat non-small cell lung cancer (NSCLC) with specific genetic changes known as EGFR ex20ins mutations. Studies have found that zipalertinib significantly benefits patients with this type of lung cancer. Importantly, it has a manageable safety profile, meaning the side effects are not too severe. Previous trials with patients already treated for NSCLC showed positive results. In this trial, some participants will receive zipalertinib with chemotherapy, while others will receive chemotherapy alone. This suggests that zipalertinib could be a valuable addition to current chemotherapy treatments. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

Adults with advanced non-small cell lung cancer (NSCLC) that have a specific mutation called EGFR exon 20 insertion. They must be over 18, have stable brain metastases if present, an ECOG performance status of 0 or 1, and a life expectancy of at least three months. Participants should not have had prior systemic treatment for their NSCLC except certain adjuvant/neoadjuvant therapies over six months ago.

Inclusion Criteria

I have at least one tumor that can be measured if I'm enrolling in Part B.

I haven't had systemic treatment for my advanced non-squamous NSCLC, but early-stage treatments over 6 months ago are okay.

I can provide a sample of my tumor for testing.

Exclusion Criteria

I had cancer before, but it's either been treated or stable for over 2 years.

I haven't had certain treatments or major surgery within the last month.

I have serious heart problems, including heart failure or irregular heartbeat.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-In

Determine the recommended dose of zipalertinib in combination with standard chemotherapy

21 days per cycle, until progressive disease or withdrawal

Rolling-6 design, multiple visits

Phase 3 Treatment

Randomized, controlled, open-label study to assess efficacy and safety of zipalertinib with chemotherapy

21 days per cycle, carboplatin or cisplatin for 4 cycles, until progressive disease or withdrawal

Multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Zipalertinib

Trial Overview The trial is testing the effectiveness and safety of a new drug named Zipalertinib in combination with standard platinum-based chemotherapy versus chemotherapy alone in patients with advanced NSCLC harboring the EGFR exon 20 insertion mutation.

How Is the Trial Designed?

Group I: Part B Experimental Treatment 1 Intervention

Enrollment into the Phase 3 portion of the study will begin following completion of Part A. Approximately 260 patients will be randomized on a 1:1 basis to receive pemetrexed and a platinum agent (either carboplatin or cisplatin) with or without zipalertinib on a 21-day cycle. Carboplatin or cisplatin will be administered for 4 cycles. Patients may continue to receive zipalertinib (experimental study arm) and pemetrexed (both study arms) until documentation of PD or until other withdrawal criteria are met, whichever comes first.

Group II: Part A (Safety Lead in) Experimental Treatment 1 Intervention

Part A: Safety Lead-In Approximately 6-12 patients will receive zipalertinib administered at an initial dose of zipalertinib PO BID (Dose Level 1) in combination with pemetrexed and carboplatin or cisplatin on a 21-day cycle. Patients may continue to receive study treatment until documentation of progressive disease (PD) or until other withdrawal criteria are met, whichever comes first.

Who Is Running the Clinical Trial?

Taiho Oncology, Inc.

Lead Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

Published Research Related to This Trial

Axitinib, when combined with standard chemotherapy regimens (paclitaxel/carboplatin or gemcitabine/cisplatin), showed a promising objective response rate of 37.0% in patients with advanced non-small cell lung cancer (NSCLC).

The treatment was generally well tolerated, with manageable side effects such as hypertension and fatigue, and no severe bleeding events were reported, indicating a favorable safety profile for axitinib at a dose of 5 mg twice daily.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours. Kozloff, MF., Martin, LP., Krzakowski, M., et al.[2021]

Mobocertinib (TAK-788) is specifically designed to target exon 20 insertion mutations of EGFR in non-small cell lung cancer (NSCLC) and has shown a 28% objective response rate in a phase I/II trial involving platinum-pretreated patients.

The treatment demonstrated a median progression-free survival of 7.3 months and a duration of response of 17.5 months, leading to its accelerated approval by the FDA in 2021 as the first TKI for this specific mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mobocertinib in non-small cell lung cancer. Liu, S., Lowder, KE.[2022]

In the FLAURA China study involving 136 patients with EGFR mutation-positive advanced non-small-cell lung cancer, first-line treatment with osimertinib significantly improved progression-free survival (PFS) by 8 months compared to comparator EGFR TKIs, with median PFS of 17.8 months versus 9.8 months.

Osimertinib also showed a trend towards improved overall survival (OS) with a median of 33.1 months compared to 25.7 months for the comparator group, while the safety profile was consistent with previous findings, with no new safety signals identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study. Cheng, Y., He, Y., Li, W., et al.[2022]

In a study of 170 patients with advanced non-squamous non-small-cell lung cancer, axitinib combined with pemetrexed and cisplatin showed a higher objective response rate (45.5% and 39.7%) compared to chemotherapy alone (26.3%).

While the combination therapy did not significantly improve progression-free survival compared to chemotherapy alone, it was generally well tolerated, with hypertension being the most common serious side effect in the axitinib groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer. Belani, CP., Yamamoto, N., Bondarenko, IM., et al.[2021]

The combination of osimertinib and platinum-based chemotherapy (OPP) demonstrated a high objective response rate of 90.9% in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer, indicating strong efficacy.

The treatment was well-tolerated, with no treatment-related deaths and an acceptable safety profile, as only 14.9% of patients discontinued due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study. Saito, R., Sugawara, S., Ko, R., et al.[2023]

In a phase 2 study involving 36 previously untreated patients with BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC), the combination of dabrafenib and trametinib showed a significant overall response rate of 64%, indicating substantial antitumor activity.

While the treatment was effective, it was associated with a high incidence of adverse events, with 69% of patients experiencing grade 3 or 4 side effects, including pyrexia and liver enzyme increases, suggesting that while the therapy is promising, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Planchard, D., Smit, EF., Groen, HJM., et al.[2022]

In the AZENT study involving 22 patients with advanced non-small-cell lung cancer (NSCLC) and a specific EGFR mutation, first-line treatment with osimertinib resulted in a high objective response rate of 77.3%, indicating its efficacy in this patient population.

The median progression-free survival (PFS) was 23.1 months, suggesting that osimertinib can provide significant disease control for patients with coexisting low allelic fraction of the EGFR Thr790Met mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line osimertinib in patients with epidermal growth factor receptor-mutant non-small-cell lung cancer and with a coexisting low allelic fraction of Thr790Met. Majem, M., Sullivan, I., Viteri, S., et al.[2022]

In a study using a lung adenocarcinoma patient-derived xenograft model, the BRAFG469V mutation was identified as the only oncogenic mutation, and the model showed sensitivity to multiple EGFR tyrosine kinase inhibitors (TKIs).

The research suggests that clinically approved EGFR TKIs, such as gefitinib and osimertinib, can be repurposed to effectively target and treat non-small cell lung cancer patients with the BRAFG469V mutation, expanding treatment options for this specific genetic alteration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lung Cancer Driven by BRAFG469V Mutation Is Targetable by EGFR Kinase Inhibitors. Huo, KG., Notsuda, H., Fang, Z., et al.[2022]

Citations

1. taihooncology.com taihooncology.com/us/news/taiho-oncology-and-cullinan-therapeutics-present-data-on-zipalertinib-at-the-iaslc-2025-world-conference-on-lung-cancer/

Taiho Oncology and Cullinan Therapeutics Present Data ... Updated efficacy and safety data to be presented from the REZILIENT1 trial of zipalertinib from the cohort of patients with non-small cell ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00763

Zipalertinib in Patients With Epidermal Growth Factor ... Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in patients with EGFR ex20ins-mutant NSCLC who received prior ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40450572/

Zipalertinib in Patients With Epidermal Growth Factor ... Conclusion: Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in patients with EGFR ex20ins-mutant NSCLC ...

4. prnewswire.com prnewswire.com/news-releases/taiho-oncology-and-cullinan-therapeutics-present-data-on-zipalertinib-at-the-iaslc-2025-world-conference-on-lung-cancer-302549926.html

Taiho Oncology and Cullinan Therapeutics Present Data ... Updated efficacy and safety data to be presented from the REZILIENT1 trial of zipalertinib from the cohort of patients with non-small cell ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05967689

NCT05967689 | A Study of Zipalertinib in Patients With ... This study will evaluate the safety and efficacy of zipalertinib in participants with locally advanced or metastatic NSCLC harboring EGFR ex20ins mutations.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37384848/

Safety, Tolerability, and Antitumor Activity of Zipalertinib ... Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile.