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Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors

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Summary

Purpose We investigated the combination of the MEK inhibitor, cobimetinib, and the pan-PI3K inhibitor, pictilisib, in an open-label, phase Ib study. Experimental Design Patients with advanced solid tumors were enrolled in 3 dose escalation schedules: (1) both agents once-daily for 21-days-on 7-days-off (“21/7”); (2) intermittent cobimetinib and 21/7 pictilisib (“intermittent”); or (3) both agents once-daily for 7-days-on 7-days-off (“7/7”). Starting doses for the 21/7, intermittent, and 7/7 schedules were 20/80, 100/130, and 40/130 mg of cobimetinib/pictilisib, respectively. Nine indication-specific expansion cohorts interrogated the recommended phase II dose and schedule. Results Of 178 enrollees (dose escalation: n = 98), 177 patients were dosed. The maximum tolerated doses for cobimetinib/pictilisib (mg) were 40/100, 125/180, and not reached, for the 21/7, intermittent, and 7/7 schedules, respectively. Six dose-limiting toxicities included grade 3 (G3) elevated lipase, G4 elevated creatine phosphokinase, and G3 events including fatigue concurrent with a serious adverse event (SAE) of diarrhea, decreased appetite, and SAEs of hypersensitivity and dehydration. Common drug-related adverse events included nausea, fatigue, vomiting, decreased appetite, dysgeusia, rash, and stomatitis. Pharmacokinetic parameters of the drugs used in combination were unaltered compared to monotherapy exposures. Confirmed partial responses were observed in patients with BRAF-mutant melanoma (n = 1) and KRAS-mutant endometrioid adenocarcinoma (n = 1). Eighteen patients remained on study ≥6 months. Biomarker data established successful blockade of MAP kinase (MAPK) and PI3K pathways. The metabolic response rate documented by FDG-PET was similar to that observed with cobimetinib monotherapy. Conclusions Cobimetinib and pictilisib combination therapy in patients with solid tumors had limited tolerability and efficacy.

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Acknowledgements

The authors thank the patients and their families. All authors participated in manuscript writing and approved the final version of the manuscript. Editing and writing assistance was provided by A. Daisy Goodrich (Genentech, Inc.) and funded by Genentech, Inc.

Funding

The work was supported by Genentech, Inc., South San Francisco, CA, USA.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, Mayer 446, 450 Brookline Avenue, Boston, MA, 02215, USA

    Geoffrey I. Shapiro & James M. Cleary

  2. Yale Cancer Center, New Haven, CT, USA

    Patricia LoRusso

  3. Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Eunice Kwak

  4. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Susan Pandya

  5. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Charles M. Rudin

  6. Stephenson Cancer Center University of Oklahoma, Oklahoma City, OK, USA

    Carla Kurkjian

  7. Wayne State University, Detroit, MI, USA

    Mary Jo Pilat

  8. Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA

    Suzanne Jones & Johanna Bendell

  9. Genentech, Inc., South San Francisco, CA, USA

    Alex de Crespigny, Jill Fredrickson, Luna Musib, Yibing Yan, Matthew Wongchenko, Hsin-Ju Hsieh, Mary R. Gates & Iris T. Chan

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Correspondence to Geoffrey I. Shapiro.

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Conflict of interest

Geoffrey I. Shapiro declares that he was on the advisory board at Almac, Angiex, Astex, Bayer, Bicycle Therapeutics, Cybrexa Therapeutics, Daiichi Sankyo, Fusion Pharmaceuticals, G1 Therapeutics, Ipsen, Lilly, Merck/EMD Serono, Pfizer, Roche, and Sierra Oncology; funding for an investigator-initiated clinical trial from Array and Pfizer; sponsored research agreements from Lilly, EMD Serono, Merck, and Sierra Oncology; support to the Dana-Farber Cancer Institute for this study from Genentech; travel from Bayer, Bicycle Therapeutics, G1 Therapeutics, Lilly, Pfizer, and Sierra Oncology; patent 9,872,874 issued for “Dosage regimen for sapacitabine and seliciclib” and provisional patent application 62/538,319 for “Compositions and methods for predicting response and resistance to CDK4/6 inhibition.” Patricia LoRusso declares that she was on the advisory board at Alexion, Ariad, GenMab, Glenmark, Menarini, Novartis, Genentech, CytomX, Omniox, Ignyta, and Takeda; data safety monitoring board at Agios, Halozyme, and FivePrime; imCORE alliance at Roche/Genentech; and consultant at SOTIO. Eunice Kwak declares that she is an employee of Novartis and former employee of Massachusetts General Hospital Cancer Center where this study was conducted. Susan Pandya declares that she is an employee of Agios and former employee of Beth Israel Deaconess Medical Center where this study was conducted. Charles M. Rudin declares that he was a consultant for AbbVie, Amgen, Ascentage, Astra Zeneca, Bicycle, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, Pharmamar, and scientific advisory board at Elucida and Harpoon. Carla Kurkjian declares that she has no conflict of interest. James M. Cleary declares research funding from Merck and Tesaro; consulting at Bristol Myers Squib; and travel funding from Bristol Myers Squib, Agios, and Roche. Mary Jo Pilat declares that she has no conflict of interest. Suzanne Jones declares that her institution received payment for services related to clinical trial from AbbVie, Acerta Pharma, Agios, Amgen, ARMO Biosciences, Array Biopharma, AstraZeneca, Blueprint Medicine, Boston Biomedical, Bristol Myers Squibb, CALGB, Celgene, Daiichi Sankyo, Eisai, EMD Serono, Genentech, Gilead Sciences, Imclone, Incyte, Ipsen Biopharma, Leap Therapeutics, Lilly, Macrogenics, MedImmune, Merck, Merrimack, Merus NV, Millennium, Novartis, Novocure, OncoMed Pharmaceuticals, Pfizer, Rgenix, Roche, Taiho Oncology, and Takeda Pharmaceuticals; and institution received payment for consulting services performed by Dr. Jones from Vertex, Novartis, Teva, Onyx, Clovis, and Janssen. Alex de Crespigny, Jill Fredrickson, Luna Musib, Yibing Yan, and Matthew Wongchenko declare that they are employees of Genentech, Inc., and are stockholders of Roche. Hsin-Ju Hsieh declares that she is an employee at MedImmune; former employment at Genentech, Inc., and stockholder of Roche. Mary R. Gates and Iris T. Chan declare that they are employees of Genentech, Inc. and are stockholders of Roche. Johanna Bendell declares that her institution received payment for services related to clinical trial from AbbVie, Acerta Pharma, Agios, Amgen, ARMO Biosciences, Array Biopharma, AstraZeneca, Blueprint Medicine, Boston Biomedical, Bristol Myers Squibb, CALGB, Celgene, Daiichi Sankyo, Eisai, EMD Serono, Genentech, Gilead Sciences, Imclone, Incyte, Ipsen Biopharma, Leap Therapeutics, Lilly, Macrogenics, MedImmune, Merck, Merrimack, Merus NV, Millennium, Novartis, Novocure, OncoMed Pharmaceuticals, Pfizer, Rgenix, Roche, Taiho Oncology, and Takeda Pharmaceuticals; institution received payment for consulting services performed by Dr. Bendell from Amgen, Arrys Therapeutics, BeiGene, Bristol Myers Squibb, Celgene, Cerulean, Continuum Clinical, Daiichi Sankyo, Evelo Biosciences, Five Prime Therapeutics, Forma Therapeutics, Genentech, Janssen, MedImmune, Merck, Merrimack, Moderna Therapeutics, Roche, Seattle Genetics, Taiho Oncology, Tanabe Research Laboratories, Tolero, and Translational Drug Development; Dr. Bendell received non-financial support including travel reimbursement and medical editing support from Genentech; and Dr. Bendell also received in-kind support for food and beverage from Genentech.

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Shapiro, G.I., LoRusso, P., Kwak, E. et al. Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors. Invest New Drugs 38, 419–432 (2020). https://doi.org/10.1007/s10637-019-00776-6

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