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Clinical Trial
. 2023 Jun 2;28(6):553-e472.
doi: 10.1093/oncolo/oyad022.

Atezolizumab Plus PEGPH20 Versus Chemotherapy in Advanced Pancreatic Ductal Adenocarcinoma and Gastric Cancer: MORPHEUS Phase Ib/II Umbrella Randomized Study Platform

Andrew H Ko  1 , Kyu-Pyo Kim  2 , Jens T Siveke  3 , Charles D Lopez  4 , Jill Lacy  5 , Eileen M O'Reilly  6 , Teresa Macarulla  7 , Gulam A Manji  8 , Jeeyun Lee  9 , Jaffer Ajani  10 , Maria Alsina Maqueda  7 , Sun-Young Rha  11 , Janet Lau  12 , Nedal Al-Sakaff  13 , Simon Allen  12 , Danny Lu  14 , Colby S Shemesh  12 , Xinxin Gan  15 , Edward Cha  12 , Do-Youn Oh  16   17   18
Affiliations
Clinical Trial

Atezolizumab Plus PEGPH20 Versus Chemotherapy in Advanced Pancreatic Ductal Adenocarcinoma and Gastric Cancer: MORPHEUS Phase Ib/II Umbrella Randomized Study Platform

Andrew H Ko et al. Oncologist. .

Abstract

Background: The MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 [PD-L1]) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20).

Methods: In 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel [MORPHEUS-PDAC]; ramucirumab plus paclitaxel [MORPHEUS-GC]). Primary endpoints were objective response rates (ORR) per RECIST 1.1 and safety.

Results: In MORPHEUS-PDAC, ORRs with atezolizumab plus PEGPH20 (n = 66) were 6.1% (95% CI, 1.68%-14.80%) vs. 2.4% (95% CI, 0.06%-12.57%) with chemotherapy (n = 42). In the respective arms, 65.2% and 61.9% had grade 3/4 adverse events (AEs); 4.5% and 2.4% had grade 5 AEs. In MORPHEUS-GC, confirmed ORRs with atezolizumab plus PEGPH20 (n = 13) were 0% (95% CI, 0%-24.7%) vs. 16.7% (95% CI, 2.1%-48.4%) with control (n = 12). Grade 3/4 AEs occurred in 30.8% and 75.0% of patients, respectively; no grade 5 AEs occurred.

Conclusion: Atezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent's known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369).

Keywords: PD-L1; basket study; combination therapy; gastric cancer; hyaluronan; immunotherapy; pancreatic cancer; proof of concept.

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Conflict of interest statement

All authors received support from F. Hoffmann-La Roche/Genentech during the conduct of this study. Andrew H. Ko: Roche/Genentech (consulting/advisory relationship and research funding). Jens T. Siveke: AstraZeneca, Bayer, Immunocore, Roche/Genentech, Servier (honoraria), Bristol Myers Squibb, Celgene, Roche/Genentech, Pharma15 (Board of Directors, consulting/advisory relationship), Bristol Myers Squibb, Celgene, Roche/Genentech (research funding), and Pharma15 (intellectual property rights/inventor/patent holder). Charles D. Lopez: Servier Pharmaceuticals, Taiho Pharmaceuticals, Genentech/Roche (research funding). Jill Lacy: Ipsen, Novartis, Deciphera, Merck, Equinox, Techspert, Guidepoint, KeyQuest, FirstWorld Group, Aptitude Health, Brass Tacks Health (consulting/advisory relationship). Eileen M. O’Reilly: CytomX Therapeutics and Rafael Therapeutics (DSMB), Seagen, Boehringer Ingelheim, BioNTech, Ipsen, Merck, IDEAYA, Silenseed, Novartis, AstraZeneca, Noxxon, BioSapien, Cend Therapeutics, Thetis, Autem, ZielBio, Tempus (consulting/advisory relationship), Agios, Genentech-Roche, Eisai, Zymeworks (spouse: consulting/advisory relationship), Genentech/Roche, Celgene/BMS, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute (research funding). Teresa Macarulla: Ability Pharmaceuticals SL, Amgen, Aptitude Health, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd., Celgene, Eisai, Ellipses, Genzyme, Hirslanden/GITZ, Imedex, Incyte, Ipsen Bioscience, Inc., Janssen, Lilly, Marketing Farmacéutico & Investigación Clínica, S.L., MDS, Medscape, Novocure, Paraxel, PPD Development, Polaris, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Scilink Comunicación Científica SC, Surface Oncology, Zymeworks (consulting/advisory relationship), Abbvie Farmaceútica, Ability Pharmaceuticals, Agios Pharmaceuticals, AMC Medical Research, Amgen, Armo Biosciences, Aslan Pharmaceuticals, AstraZeneca, Basilea Pharmaceutica International, Bayer, BeiGene, BioKeralty Research Institute, BioLineRx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, European Organisation for Research and Treatment of Cancer (EORTC), F. Hoffmann-La Roche, FibroGen, Halozyme, Incyte, Ipsen Bioscience, Ipsen Pharma, Lilly, Loxo Oncology, Medimmune, Merck Sharp & Dohme, Nelum, Novartis, Novocure, OncoMed Pharmaceuticals, QED Therapeutics, VCN Biosciences, Zymeworks (research funding), Servier, prIME, AstraZeneca, Sanofi, and Incyte (H). Gulam A. Manji: Roche/Genentech, CEND Pharmaceutical (consulting/advisory relationship), Roche/Genentech, Regeneron, BiolonRX, Merck (research funding), Amgen, Lilly, Roche (honoraria), CEND Pharmaceuticals (intellectual property rights/inventor/patent holder). Jeeyun Lee: OncXerna, Mirati, Guardant (consulting/advisory relationship), AstraZeneca, Merck MSD (research funding). Jaffer Ajani: BMS, Merck, Astellas, Amgen, Novartis, Zymeworks (honoraria), BMS, Roche, Merck, Prolinx, DF, Zymeworks, Astellas, Taiho, Leap, Gilead, LaNova (research funding). Maria Alsina Maqueda: Amgen, BMS, Lilly, MSD, Roche, Servier (honoraria), BMS, Lilly, MSD, Servier (consulting/advisory relationship). Sun-Young Rha: MSD, BMS/Ono, Daiichi Sankyo, Amgen, Indivumed, LG Biochemical (consulting/advisory relationship), Lilly, Merck, BMS, MSD (expert testimony), Amgen, BMS/Ono, Daiichi Sankyo, AstraZeneca, Roche, Merck, Lilly, MSD, BeiGene, Zymeworks (research funding). Janet Lau, Simon Allen, Danny Lu, Colby S. Shemesh, Xinxin Gan, Edward Cha, and Nedal Al-Sakaff: F. Hoffmann-La Roche Ltd./Genentech Inc. (employment and intellectual property rights/inventor/patent holder). Do-Youn Oh: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA (consulting/advisory relationship), AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok (research funding).

Figures

Figure 1.
Figure 1.
Study design of (A) MORPHEUS-PDAC and (B) MORPHEUS-GC. FU, fluorouracil; GC, gastric cancer; GEJ, gastroesophageal junction; mFOLFOX6, 5-fluorouracil, leucovorin, and oxaliplatin; PD, progressive disease; PDAC, pancreatic ductal adenocarcinoma; PEGPH20, PEGylated recombinant human hyaluronidase; R, randomization.
Figure 2.
Figure 2.
Waterfall plots of confirmed best overall response by treatment in (A) MORPHEUS-PDAC and (B) MORPHEUS-GC. mFOLFOX6, 5-fluorouracil, leucovorin, and oxaliplatin; PEGPH20, PEGylated recombinant human hyaluronidase.
Figure 3.
Figure 3.
Swimlane plots of confirmed best overall responses in (A) MORPHEUS-PDAC and (B) MORPHEUS-GC. Darker colored bars, treatment period; lighter colored bars, follow-up. mFOLFOX6, 5-fluorouracil, leucovorin, and oxaliplatin; NA, not assessed; NE, not evaluable, PD, progressive disease; PEGPH20, PEGylated recombinant human hyaluronidase; PR, partial response; SD, stable disease.
Figure 4.
Figure 4.
Kaplan-Meier plot of investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 in (A) MORPHEUS-PDAC and (B) MORPHEUS-GC. Atezo, atezolizumab; HR, hazard ratio; NE, not evaluable; PEGPH20, PEGylated recombinant human hyaluronidase.
Figure 5.
Figure 5.
Kaplan-Meier curve of overall survival in (A) MORPHEUS-PDAC and (B) MORPHEUS-GC. Atezo, atezolizumab; HR, hazard ratio; NE, not evaluable; PEGPH20, PEGylated recombinant human hyaluronidase.
Figure 6.
Figure 6.
Overall survival by biomarker status in MORPHEUS-PDAC. Atezo, atezolizumab; HA, hyaluronic acid; HR, hazard ratio; mFOLFOX6, 5-fluorouracil, leucovorin, and oxaliplatin; NA, not assessed; OS, overall survival; PD-L1, programmed cell death 1 ligand 1; PEGPH20, PEGylated recombinant human hyaluronidase.
See this image and copyright information in PMC

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