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Review
. 2023 Apr 18;7(1):37.
doi: 10.1038/s41698-023-00369-w.

Phase I study of sapanisertib with carboplatin and paclitaxel in mTOR pathway altered solid malignancies

Omar Alhalabi  1   2 , Roman Groisberg  3 , Ralph Zinner  4 , Andrew W Hahn  5 , Aung Naing  2 , Shizhen Zhang  2 , Apostolia M Tsimberidou  2 , Jordi Rodon  2 , Siqing Fu  2 , Timothy A Yap  2 , David S Hong  2 , Ming Sun  2 , Yunfang Jiang  2 , Shubham Pant  2 , Amishi Y Shah  1 , Amado Zurita  1 , Nizar M Tannir  1 , Raghunandan Vikram  6 , Jason Roszik  7   8 , Funda Meric-Bernstam  2 , Vivek Subbiah  9
Affiliations
Review

Phase I study of sapanisertib with carboplatin and paclitaxel in mTOR pathway altered solid malignancies

Omar Alhalabi et al. NPJ Precis Oncol. .

Abstract

Pre-clinically, the mTORC1/2 inhibitor sapanisertib restored sensitivity to platinums and enhanced paclitaxel-induced cancer cell killing. NCT03430882 enrolled patients with mTOR pathway aberrant tumors to receive sapanisertib, carboplatin and paclitaxel. Primary objective was safety and secondary objectives were clinical response and survival. One patient had a dose-limiting toxicity at dose level 4. There were no unanticipated toxicities. Grade 3-4 treatment-related adverse events included anemia (21%), neutropenia (21%), thrombocytopenia (10.5%), and transaminitis (5%). Of 17 patients evaluable for response, 2 and 11 patients achieved partial response and stable disease, respectively. Responders included a patient with unclassified renal cell carcinoma harboring EWSR1-POU5F1 fusion and a patient with castrate resistant prostate cancer harboring PTEN loss. Median progression free survival was 3.84 months. Sapanisertib in combination with carboplatin plus paclitaxel demonstrated a manageable safety profile, with preliminary antitumor activity observed in advanced malignancies harboring mTOR pathway alterations.

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Conflict of interest statement

V.S. reports research funding and grant support for clinical trials: Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Medimmune, Altum, Dragonfly therapeutics, Takeda and, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning point therapeutics, Boston Pharmaceuticals Travel: Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte, Consultancy/Advisory board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, Medimmune, Novartis. Other: Medscape. A.N. reports research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, Immune Deficiency Foundation (Spouse). Advisory board: CytomX Therapeutics, Novartis, Kymab, Genome. Travel and accommodation expenses: ARMO BioSciences. D.S.H. reports research funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, GSK, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics. Travel, Accommodations, Expenses: Bayer, LOXO, miRNA, Genmab, AACR, ASCO, SITC. Consulting or Advisory Role: Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD. Other ownership interests: Molecular Match (Advisor), OncoResponse (Founder), Presagia Inc (Advisor). S.P. reports research funds from Mirati Therapeutics, Inc., Eli Lilly, Red Hill Biopharma Ltd., Xencor, Five Prime Therapeutics, Novartis, Rgenix, Sanofi-Aventis, Arqule, Bristol-Myers Squibb, Onco Response, Sanofi US Services Inc., GlaxoSmith Kline. Financial Relationship/Speakers Bureau Consultant: Tyme, Inc., Zymeworks, Xencor and 4-D Pharma. F.M.B. reports consulting: Aduro BioTech Inc., DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks. Advisory Committee: Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals. Sponsored Research: Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co. Honoraria: Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey. T.Y. reports employment at University of Texas MD Anderson Cancer Center, where he is the Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios. He also reports grant/research support (to Institution): Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace and Zenith. He also reports consultancies from AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, Xinthera, Zai Labs and ZielBio. He also reports stocks in Seagen. The rest of the authors report no competing interests.

Figures

Fig. 1
Fig. 1. Oncoplot representing diagnosis, best response, dose level and targeted sequencing of DNA alterations and RNA fusion products in enrolled patients.
Highlighted in red are genes implicated in the mTOR pathway. Key: PR partial response, SD stable disease, PD progressive disease, HR hormone receptor, HER2 human epidermal growth factor receptor 2, CRPC castration resistant prostate cancer, NSCLC non-small cell lung cancer, RCC renal cell cancer, SCC squamous cell carcinoma.
Fig. 2
Fig. 2. Representative sections of computerized tomography in patient #22 with unclassified renal cell carcinoma harboring EWSR1-POU5F1 fusion t(6;22)(p21;q12).
Panels (a), (b), (c) show partial response per RECIST version 1.1 in mediastinal adenopathy (a), lung metastasis (b) and pelvic adenopathy (c) in Left and right panels reflect baseline and nadir after therapy, respectively.
Fig. 3
Fig. 3. Representative sections of computerized tomography and PSA trend in patient #17 with metastatic castrate resistant prostate cancer harboring PTEN deletion.
Panels (a), (b) show response in mediastinal (a) and retroperitoneal (b) nodal metastases. c XY plot of the PSA (ng/mL) levels (blue, left Y axis) and % change from baseline (RECIST v1.1) in relation to time. Plot was created using GraphPad Prism version 9.2.0 for Mac OS, GraphPad Software, San Diego, California, USA, www.graphpad.com.
Fig. 4
Fig. 4. Hypothesized interaction between genomic alteration and sapanisertib in the two responders.
a Schema highlighting the EWSR1-POU5F1 fusion t(6;22)(p21;q12) peptide. POU5F1 (OCT4) belongs to the homeobox gene superfamily and encodes a transcription factor that act as a master regulator of development. POU5F1 has preserved homaeodomains (HD) that bind DNA. The fusion peptide brings the HD of POU5F1 in proximity to N-terminal transcriptional activation domain (TAD) of EWSR1. This fusion peptide hypothetically leads to enrichment of EWSR1-related signaling pathways including the mTOR signaling pathway, p53 signaling pathway, and WNT signaling pathway. b Schema depicting the downstream signaling pathways following the activation of receptor tyrosine kinase including the RAF/MERK/ERK and the PI3K/AKT/mTOR pathways. Figure was created using biorender.com.
Fig. 5
Fig. 5. Trial schema (NCT03430882).
Patients were treated with as many as six, 21-day cycles of the combination regimen. The regimen is comprised of carboplatin AUC 5 intravenously every 3 weeks on Day 1 of each cycle plus sapanisertib (TAK-228 or MLN0128) daily on Day 2–4 of each week at 2 mg, 3 mg and 4 mg orally and paclitaxel 40 mg/m2, 60 mg/m2, 80 mg/m2 QW IV on Day 1, 8, and 15 of each cycle. Evaluation of the composite toxicity/efficacy endpoint was done at Day 21 of treatment. After the 6 cycles were completed, patients were treated to progression with sapanisertib 3 mg PO daily.
See this image and copyright information in PMC

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