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259 Phase Ib/II open-label, randomized evaluation of atezolizumab (atezo) + selicrelumab (seli) + gemcitabine+nab-paclitaxel (gem+nabP) or bevacizumab (bev) vs control in MORPHEUS-PDAC, -TNBC and -CRC
  1. Gulam Manji1,
  2. Nathan Bahary2,
  3. Vincent Chung3,
  4. Florence Dalenc4,
  5. Michel Ducreux5,
  6. Carlos Gomez-Roca4,
  7. Seock-Ah Im6,
  8. Jeremy Kortmansky7,
  9. Jill Lacy7,
  10. Neil Segal8,
  11. Olivier Tredan9,
  12. Olivera Cirovic10,
  13. Kelly DuPree11,
  14. Christelle Lenain12,
  15. Danny Lu13,
  16. Lidia Robert11,
  17. Jeffrey Xu14,
  18. Xiaosong Zhang11 and
  19. Sung-Bae Kim15
  1. 1Columbia University Medical Center, New York, NY, USA
  2. 2University of Pittsburgh Medical Center, Pittsburgh, PA, USA
  3. 3City of Hope National Medical Center, Duarte, CA, USA
  4. 4Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France
  5. 5Institut Gustave Roussy, Villejuif, France
  6. 6Seoul National University Hospital, Seoul, Korea, Republic of
  7. 7Yale University School of Medicine, New Haven, CT, USA
  8. 8Memorial Sloan Kettering Cancer Center, New York, NY, USA
  9. 9Centre Léon Bérard, Lyon, France
  10. 10Roche Innovation Center Basel, Basel, Switzerland
  11. 11Genentech, Inc., South San Francisco, CA, USA
  12. 12F. Hoffmann-La Roche AG, Basel, Switzerland
  13. 13Hoffmann-La Roche Limited, Mississauga, Canada
  14. 14Roche (China) Holding Ltd, Shanghai, China
  15. 15Asan Medical Center, Seoul, Korea, Republic of


Background The MORPHEUS platform comprises multiple randomized Phase Ib/II trials to identify early safety and efficacy signals for treatment combinations across cancers. Seli interacts with CD40 on antigen presenting cells, resulting in activation and priming of CD8 T-cells. Atezo (anti-PD-L1)+seli (CD40 agonist) was evaluated with gem+nabP for pancreatic ductal adenocarcinoma (PDAC), or with bev for triple-negative breast cancer (TNBC) and colorectal cancer (CRC).

Methods MORPHEUS-PDAC, MORPHEUS-TNBC and MORPHEUS-CRC enrolled 1L metastatic (m) PDAC, 2L locally advanced or mTNBC or 3L mCRC patients, respectively. Experimental arm patients received atezo (840 mg IV q2w) and seli (16 mg SC on D1 every 28-day cycle for C1-4 and every third cycle thereafter). Patients also received gem (1000 mg/m2) and nabP (1000 mg/m2, 125 mg/m2 respectively, IV on D1, 8, 15 every 28-day cycle) in PDAC or bev (10 mg/kg IV q2w) in TNBC and CRC. Control treatments were gem+nabP in PDAC, capecitabine in TNBC, and regorafenib in CRC. Primary endpoints were safety and objective response rate (ORR; investigator-assessed RECIST 1.1). PD-L1 and CD8/panCK IHC were tested in all biopsies.

Results All treated patients were safety evaluable. MORPHEUS-PDAC (20-week interim analysis): 9 patients received atezo+seli+gem+nabP and 4 received control. Treatment-related adverse events (TRAEs) were seen in all. Treatment-related serious AEs (SAEs) occurred in 6 patients (67%) receiving atezo+seli+gem+nabP and 1 (25%) receiving control. Confirmed ORRs: 44% (95%CI:14–79) and 25% (95%CI:6–81), respectively. MORPHEUS-TNBC (27-week interim analysis): 6 patients received atezo+seli+bev and 24 received control. TRAEs were seen in 5 patients (83%) receiving atezo+seli+bev and 18 (75%) receiving control. Treatment-related SAEs occurred in 1 patient in each arm (17% and 4%, respectively). Confirmed ORRs: 17% (95%CI:0.4–64) and 21% (95%CI:7–42), respectively. All 6 patients receiving atezo+seli+bev were PD-L1 negative (SP142 IHC assay) at baseline; the only patient with partial response (PR) showed upregulation of PD-L1 expression at week 3. MORPHEUS-CRC (18-week interim analysis): 6 patients received atezo+seli+bev and 13 received control. TRAEs were seen in all patients receiving atezo+seli+bev and 12 (92%) receiving control. Treatment-related SAEs occurred in 3 patients (50%) receiving atezo+seli+bev and 1 (8%) receiving control. No responses occurred in either study arm. Paired biopsies for 3 patients (60%) receiving atezo+seli+bev suggest on-treatment increases in CD8 T-cell infiltration into tumors.

Conclusions Toxicities related to the atezo+seli combinations were consistent with individual study treatments. Preliminary efficacy was observed for atezo+seli+gem+nabP in PDAC. Together with preliminary evidence of on-treatment pharmacodynamic effects in CRC and TNBC tumor samples, CD40 agonist strategies warrant further investigation.

Trial Registration MORPHEUS-PDAC: NCT03193190; MORPHEUS-TNBC: NCT03424005; MORPHEUS-CRC: NCT03555149.

Ethics Approval The trial was conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent. Protocol approval was obtained from independent review boards or ethics committees at each site.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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