Zipalertinib + Chemotherapy for Non-Small Cell Lung Cancer

(REZILIENT3 Trial)

Recruiting at 113 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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the safety and efficacy of zipalertinib in combination with standard first-line platinum-based chemotherapy compared to chemotherapy alone, in patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations.

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.

What data supports the effectiveness of the drug Zipalertinib + Chemotherapy for Non-Small Cell Lung Cancer?

Research on similar drugs like osimertinib, which is used for non-small cell lung cancer with specific mutations, shows that combining it with chemotherapy can improve survival rates. This suggests that combining Zipalertinib with chemotherapy might also be effective. ^{1 2 3 4 5}

What makes the drug Zipalertinib unique for treating non-small cell lung cancer?

Zipalertinib is a novel treatment option for non-small cell lung cancer that targets specific genetic mutations in cancer cells, potentially offering a more personalized approach compared to traditional chemotherapy. This drug is designed to inhibit certain proteins that help cancer cells grow, making it different from standard treatments that do not target these specific mutations. ^{1 4 6 7 8}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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 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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer. [2021]

2. England 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. [2022]

3. England 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. [2023]

4. England 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. [2021]

5. France pubmed.ncbi.nlm.nih.gov

Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Lung Cancer Driven by BRAFG469V Mutation Is Targetable by EGFR Kinase Inhibitors. [2022]

7. Spain pubmed.ncbi.nlm.nih.gov

Mobocertinib in non-small cell lung cancer. [2022]

8. England 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. [2022]