TY - JOUR
T1 - Phase I basket study of taselisib, an isoform-selective PI3K inhibitor, in patients with PIK3CA-mutant cancers
AU - Jhaveri, Komal
AU - Chang, Matthew T.
AU - Juric, Dejan
AU - Saura, Cristina
AU - Gambardella, Valentina
AU - Melnyk, Anton
AU - Patel, Manish R.
AU - Ribrag, Vincent
AU - Ma, Cynthia X.
AU - Aljumaily, Raid
AU - Bedard, Philippe L.
AU - Sachdev, Jasgit C.
AU - Dunn, Lara
AU - Won, Helen
AU - Bond, John
AU - Jones, Surai
AU - Savage, Heidi M.
AU - Scaltriti, Maurizio
AU - Wilson, Timothy R.
AU - Wei, Michael C.
AU - Hyman, David M.
N1 - Funding Information:
Inc.), Alison Cardenas (Genentech, Inc.), and Paul Ku (Genentech, Inc.) for their contributions. All authors received medical writing support for this manuscript from F. Hoffmann-La Roche Ltd. Support for third-party writing assistance was furnished by Islay Steele, PhD, and Stephen Salem, BSc, of Health Interactions. This study was funded by F. Hoffmann-La Roche Ltd and Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748). Additional support was received from the NIH (P30 CA008748), Cycle for Survival, and the Noona’s Garden Foundation.
Funding Information:
K. Jhaveri reports personal fees from Novartis, Pfizer, Genentech, AstraZeneca, Taiho Oncology, Seattle Genetics, Jounce Therapeutics, BMS, AbbVie, ADC Therapeutics, and Spectrum Pharmaceuticals, and other from Novartis, Genentech, Pfizer, Lilly Pharmaceuticals, AstraZeneca, Zymeworks, Puma Biotechnology, Clovis Oncology, Debio Pharmaceuticals, and Immunomedics outside the submitted work. M.T. Chang reports other from Genentech during the conduct of the study. D. Juric reports grants from Genentech during the conduct of the study; grants from Takeda, Amgen, Celgene, Placon Therapeutics, InventisBio, and Infinity Pharmaceuticals; grants and personal fees from Novartis, Eisai, EMD Serono, Syros, and Petra Pharma; and personal fees from Ipsen, Relay Therapeutics, MapKure, and Vibliome outside the submitted work. C. Saura reports personal fees from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann - La Roche Ltd, Genomic Health, Merck, Sharp and Dohme España S.A, Novartis, Odonate Therapeutics, Pfizer, Philips HealthWorks, Pierre Fabre, prIME Oncology, Puma, Synthon, and Sanofi Aventis outside the submitted work. V. Gambardella reports research funding from Bayer, Boehringer, and Roche, and institutional funding from Genentech, Merck Serono, Roche, BeiGene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, FibroGen, Amcure, Natera, Sierra Oncology, AstraZeneca, Medimmune, BMS, and MSD. M.R. Patel reports other from Genentech during the conduct of the study, and other from Genentech, Pfizer, EMD Serono, Pharmacyclics, Janssen, and Bayer outside the submitted work. C.X. Ma reports other from Washington University in St. Louis during the conduct of the study; personal fees from Eisai, Athenex, AstraZeneca, Seattle Genetics, Novartis, and Eli Lilly; and grants and personal fees from Puma and Pfizer outside the submitted work. R. Aljumaily reports other from Roche during the conduct of the study, and grants from Alliance Foundation Trials, LLC, Boston Biomedical, Inc, Syneos Health, Array BioPharma, Bristol-Myers Squibb, Huntsman Cancer Institute, Merck Co., AstraZeneca, AbbVie Inc., Regeneron, G1 Therapeutics, Inc., F. Hoffman-LA Roche AG, Genentech, Inc., MedImmune, LLC, GlaxoSmithKline, Novartis, Peloton Therapeutics, Inc, Baxalta, Eli Lilly and Company, EMD Serono Inc., Boehringer Ingelheim, TERSARO, Inc., Pfizer Inc., Checkpoint Therapeutics, Inc., and Eli Lily outside the submitted work. P.L. Bedard reports grants from Roche/Genentech during the conduct of the study, and grants from Roche/Genentech, BMS, AstraZeneca, Lilly, Seagen, Merck, Pfizer, Zymeworks, Servier, Mersana, Novartis, PTC Therapeutics, Amgen, and Sanofi outside the submitted work, and reports advisory board membership (uncompensated) with Roche/Genentech, Merck, Seagen, Lilly, Amgen, Sanofi, and Pfizer. J.C. Sachdev reports other from Genentech during the conduct of the study, and personal fees from Pfizer, Novartis, Ipsen, and Tempus outside the submitted work. L. Dunn reports personal fees from Merck, CUE-Biopharma, Pfizer, Regeneron, and Eisai outside the submitted work. J. Bond reports personal fees and nonfinancial support from Genentech during the conduct of the study and personal fees and nonfinancial support from Genentech outside the submitted work. H.M. Savage reports other from Roche/Genentech outside the submitted work. M. Scaltriti reports grants from AstraZeneca during the conduct of the study; grants from Menarini Ricerche, Immunomedics, TargImmune, and Puma Biotechnologies; and grants and personal fees from Daiichi Sankyo outside the submitted work. T.R. Wilson reports other from Genentech, Inc and Roche during the conduct of the study, as well as a patent for methods of treating with taselisib pending. M.C. Wei reports other from Genentech and F. Hoffman La-Roche Ltd during the conduct of the study. D.M. Hyman reports other from Loxo Oncology/Lilly during the conduct of the study. No disclosures were reported by the other authors.
Publisher Copyright:
2020 American Association for Cancer Research.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - Purpose: Somatic mutations in phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110a catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib. Patients and Methods: Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed. Results: A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. Conclusions: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.
AB - Purpose: Somatic mutations in phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110a catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib. Patients and Methods: Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed. Results: A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. Conclusions: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.
UR - http://www.scopus.com/inward/record.url?scp=85100180801&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-2657
DO - 10.1158/1078-0432.CCR-20-2657
M3 - Article
C2 - 33148674
AN - SCOPUS:85100180801
SN - 1078-0432
VL - 27
SP - 447
EP - 459
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -