Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer.

Oncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial. Adult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108 plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring. Thirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+ T cells on treatment. PexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers. NCT03206073.

Monge C ，Xie C ，Myojin Y ，Coffman K ，Hrones DM ，Wang S ，Hernandez JM ，Wood BJ ，Levy EB ，Juburi I ，Hewitt SM ，Kleiner DE ，Steinberg SM ，Figg WD ，Redd B ，Homan P ，Cam M ，Ruf B ，Duffy AG ，Greten TF ... -  《Journal for ImmunoTherapy of Cancer》

Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study.

Chen EX ，Jonker DJ ，Loree JM ，Kennecke HF ，Berry SR ，Couture F ，Ahmad CE ，Goffin JR ，Kavan P ，Harb M ，Colwell B ，Samimi S ，Samson B ，Abbas T ，Aucoin N ，Aubin F ，Koski SL ，Wei AC ，Magoski NM ，Tu D ，O'Callaghan CJ ... -  《-》

Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair-proficient Metastatic Colorectal Cancer.

Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models. In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles. We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9-26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0-27.0]. The median progression-free survival was 1.8 (95% CI, 1.7-1.9) months, median overall survival was 11.4 (95% CI, 10.1-17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3-4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response. This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.

Segal NH ，Cercek A ，Ku G ，Wu AJ ，Rimner A ，Khalil DN ，Reidy-Lagunes D ，Cuaron J ，Yang TJ ，Weiser MR ，Romesser PB ，Stadler ZK ，Varghese AM ，Ganesh K ，Yaeger R ，Connell LC ，Faleck D ，Abou-Alfa GK ，Mcauliffe KC ，Vaiskauskas P ，Solter ML ，Ogle M ，Adamow MJ ，Holland A ，Vedantam P ，Wong P ，Merghoub T ，Vakiani E ，Hollmann TJ ，Juluru K ，Chou JF ，Capanu M ，Erinjeri J ，Solomon S ，Yamada Y ，Kemeny N ，Crane CH ，Saltz LB ... -  《-》

Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial.

Rizvi NA ，Cho BC ，Reinmuth N ，Lee KH ，Luft A ，Ahn MJ ，van den Heuvel MM ，Cobo M ，Vicente D ，Smolin A ，Moiseyenko V ，Antonia SJ ，Le Moulec S ，Robinet G ，Natale R ，Schneider J ，Shepherd FA ，Geater SL ，Garon EB ，Kim ES ，Goldberg SB ，Nakagawa K ，Raja R ，Higgs BW ，Boothman AM ，Zhao L ，Scheuring U ，Stockman PK ，Chand VK ，Peters S ，MYSTIC Investigators ... -  《-》

Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study.

Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority of whom progressed on prior checkpoint inhibitors. In this open-label, multicenter, phase 1b, dose-escalation trial, HLA-A*02:01-positive patients with mCM received weekly intravenous tebentafusp with increasing monthly doses of durvalumab and/or tremelimumab starting day 15 of each cycle. The primary objective was to identify the maximum tolerated dose (MTD) or recommended phase 2 dose for each combination. Efficacy analyses were performed in all tebentafusp with durvalumab±tremelimumab treated patients with a sensitivity analysis in those who progressed on prior anti-PD(L)1 therapy. 85 patients were assigned to receive tebentafusp in combination with durvalumab (n=43), tremelimumab (n=13), or durvalumab and tremelimumab (n=29). Patients were heavily pretreated with a median of 3 prior lines of therapy, including 76 (89%) who received prior anti-PD(L)1. Maximum target doses of tebentafusp (68 mcg) alone or in combination with durvalumab (20 mg/kg) and tremelimumab (1 mg/kg) were tolerated; MTD was not formally identified for any arm. Adverse event profile was consistent with each individual therapy and there were no new safety signals nor treatment-related deaths. In the efficacy subset (n=72), the response rate was 14%, tumor shrinkage rate was 41% and 1-year OS rate was 76% (95% CI: 70% to 81%). The 1-year OS for triplet combination (79%; 95% CI: 71% to 86%) was similar to tebentafusp plus durvalumab (74%; 95% CI: 67% to 80%). At maximum target doses, the safety of tebentafusp with checkpoint inhibitors was consistent with safety of each individual therapy. Tebentafusp with durvalumab demonstrated promising efficacy in heavily pretreated patients with mCM, including those who progressed on prior anti-PD(L)1. NCT02535078.

Hamid O ，Hassel JC ，Shoushtari AN ，Meier F ，Bauer TM ，Salama AKS ，Kirkwood JM ，Ascierto PA ，Lorigan PC ，Mauch C ，Orloff M ，Evans TRJ ，Holland C ，Edukulla R ，Abedin SE ，Middleton MR ... -  《-》