Phase Ib Dose-Finding Study of Varlitinib Combined with Weekly Paclitaxel With or Without Carboplatin ± Trastuzumab in Advanced Solid Tumors

Abstract

Background: Varlitinib is a highly potent, small-molecule, pan-HER inhibitor targeting HER1, HER2, and HER4. It has demonstrated activity in gastric, biliary tract, and breast cancers.

Objective: We conducted a phase Ib dose confirmation study to determine safety and early efficacy signals of varlitinib in combination with chemotherapy (paclitaxel ± carboplatin) ± subcutaneous trastuzumab.

Methods: Eligible patients had advanced or metastatic solid tumors. A 3+3 dose de-escalation study design was used and pharmacokinetic analyses of varlitinib and paclitaxel were performed.

Results: Thirty-seven patients were enrolled into eight cohorts with median 4 (0-14) prior lines of palliative systemic therapies. Carboplatin area under the curve 1.5 and paclitaxel 80 mg/m2 weekly with varlitinib 500 mg twice daily continuously was de-escalated over four dose levels to 300 mg twice daily intermittently (4 days on, 3 days off) due to dose-limiting toxicities, most commonly neutropenia, febrile neutropenia, and electrolyte disturbances, with the triplet combination deemed intolerable and unable to be developed further. Varlitinib was then combined with paclitaxel alone; the recommended phase II dose of varlitinib was 300 mg twice daily intermittently. The addition of subcutaneous trastuzumab 600 mg was safe with no dose-limiting toxicities. Thirty-one patients were evaluable for response: 35.5% partial response, 41.9% stable disease. Twenty patients had HER2+ metastatic breast cancer with a median of 4 (0-14) treatment lines, 8/20 continued on single-agent varlitinib after completing chemotherapy for a median of 5.1 (range 2.0-13.3) months. A pharmacokinetic analysis showed that plasma exposure of varlitinib was dose dependent. Varlitinib administration did not significantly affect the maximum concentration or area under the curve of paclitaxel.

Conclusions: The recommended phase II dose of varlitinib with paclitaxel is 300 mg twice daily intermittently dosed. This is active in HER2+ metastatic breast cancer. Subcutaneous trastuzumab can be added safely to varlitinib and paclitaxel. This combination is currently being evaluated as neoadjuvant therapy in HER2+ breast cancer (NCT02396108).

Clinical trial registration: NCT02396108, date of registration: 25 March, 2015.

Conflict of interest statement

Andrea Wong has received honoraria from Pfizer, Novartis, and Eisai; and has advisory activity with Otsuka. Samuel Ow has received honoraria from Pfizer, AstraZeneca, Eli Lilly, Novartis, and Roche. Raghav Sundar has received honoraria from Bristol-Myers Squibb, Lilly, Roche, Taiho, Astra Zeneca, DKSH, and MSD; has advisory activity with Bristol-Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, and AstraZeneca; received research funding from MSD and Paxman Coolers; and has received travel grants from AstraZeneca, Eisai, Roche, and Taiho Pharmaceutical. David Tan has received honoraria and travel support from AstraZeneca, Novartis, Roche, Merck Serono, MSD, Bayer, Genmab, Takeda, Eisai, and Clovis; has advisory activity with Astra Zeneca, MSD, Roche, Bayer, Genmab, Tessa Therapeutics, and Eisai; has received research funding from Astra Zeneca, Karyopharm Therapeutics, Bayer, Roche (Foundation Medicine), National Medical Research Council Singapore, Pangestu Family Foundation Gynaecological Cancer Research Fund, and Cancer Science Institute Singapore; and has stock ownership with Asian Microbiome Library (AMiLi). Ross Soo has advisory activity with Amgen, Astra-Zeneca, Bayer, BMS, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, and Yuhan; and has received research funding from AstraZeneca and Boehringer Ingelheim. Joline Lim has advisory activity with Pfizer and Novartis; has received research funding from Synthon; and has received conference support from Novartis, Pfizer, and AstraZeneca. Wei Peng Yong has advisory activity with Abbvie, Amgen, AstraZeneca, BMS, Ipsen, Novartis, and MSD; and has received support on the speaker bureaus for Bayer, Eisai, Lilly, Sanofi, and Taiho. Boon Cher Goh has received research funding from MSD, Adagene, Bayer Healthcare, and Alx Oncology; has advisory activity with Adagene, MSD, and Novartis; and has stock ownership with Merus Therapeutics and Gilead Sciences. Soo Chin Lee has advisory activity with Pfizer, Novartis, Astra Zeneca, ACT Genomics, Eli Lilly, MSD, and Roche; has received research funding from Pfizer, Eisai, Taiho, ACT Genomics, Bayer, and Karyopharm; and has received conference support from Amgen, Pfizer, and Roche. Matilda Lee, Siew Eng Lim, and Ling Zhi Wang declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

© 2022. The Author(s).

Figures

Fig. 1

Responses to treatment. Waterfall plot summarizes the best percentage change from the baseline sum of target lesions (Response Evaluation Criteria for Solid Tumors version 1.1) during treatment of the patients evaluable for radiologic response. 35.5% (11/31) achieved confirmed partial response (PR), 41.9% (13/31) had stable disease. The majority of patients with a PR had HER2+ metastatic breast cancer. Each bar is labeled with the dose cohort the patient was enrolled into. Responses to therapy were observed in patients across all cohorts of differing varlitinib doses. HER2+ MBC HER2+ metastatic breast cancer, PD progressive disease, * indicates PD with new lesions

Fig. 2

Swimmer’s plot represents the progression-free survival (PFS) of individual patients (median PFS 3.7 months, range 0.3–17.1 months) and the duration of treatment while on maintenance single-agent varlitinib (median duration 5.1 months, range 2.0–13.3 months). Patients with HER2+ metastatic breast cancer (*) [HER2+ MBC] tended to have longer PFS (median PFS 5.4 months, range 1.2–17.1 months). PD progressive disease, PR partial response, SD stable disease