Dataset Information

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review.

ABSTRACT:

Introduction

Cancer immunotherapy represents one of the most important innovations in modern medicine. Durvalumab is an anti-programmed cell death ligand 1 (PDL-1) agent which is currently under investigation in several studies in combination with the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) drug tremelimumab. The aim of this review was to systematically identify and revise the current scientific literature investigating the combination of these two drugs in solid tumors.

Methods

A digital search on the Medline (PubMed interface) and Scopus databases for articles published from inception to 26 February 2021 was performed. The terms used for the search were durvalumab AND tremelimumab. Trials reported in English involving adult patients with solid cancers treated with the combination durvalumab plus tremelimumab were retrieved; the references of the articles were cross-checked to identify missing papers.

Results

The electronic search produced 267 results; after exclusion of duplicates, irrelevant articles, reviews, and papers not in English or missing data, 19 articles were included for revision. The total number of patients treated with the combination of durvalumab and tremelimumab in the studies retrieved was 2052.

Conclusion

The combination of durvalumab plus tremelimumab showed some oncological advantages in comparison with traditional chemotherapies in some subsets of tumors, but generally has not shown consistent advantages in comparison with the employment of durvalumab monotherapy. A number of the studies examined had intrinsic methodological limitations; therefore, future well-designed studies involving larger cohorts are warranted.

SUBMITTER: Arru C

PROVIDER: S-EPMC8279985 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAnti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) agents have only moderate antitumor activity in some advanced solid tumors (AST), including breast cancer (BC), prostate cancer (PC), cervical cancer (CC), and head and neck cancer (HNC). Combining anti-PD-L1 with anti-cytotoxic T-lymphocyte-associated protein (CTLA) and chemotherapy may significantly improve efficacy.Patients and methodsMOVIE is a multicohort phase I/II study examining the combination of anti-PD-L1 durvalumab (Durv; 1500 mg IV Q4W) plus anti-CTLA tremelimumab (Trem; 75 mg IV Q4W) with metronomic vinorelbine (MVino; 20-40 mg orally daily) in various AST resistant to conventional therapies. The primary objective of the phase I part was to determine the maximum tolerated dose (MTD) and recommended dose for phase II (RP2D).ResultsAmong the 14 patients enrolled during phase I, including 13 women and 1 man, 9 had BC, 1 PC, 2 CC, and 2 miscellaneous cancers with high mutational loads. Median age was 53 years. A total of 12 patients were assessable for the dose-escalation part in which only one dose-limiting toxicity (DLT) was observed [one neutropenia without fever, grade (G) 4]. Two (14.3%), four (28.6%), and four (28.6%) patients had G ≥3 adverse events (AEs) related to MVino, Durv, and Trem, respectively. Treatment-related events included mostly clinical AEs with asthenia (eight G2; three G3), colitis (one G2, one G3), diarrhea (one G3), nausea (two G2), dry skin (two G2), maculopapular rash (one G3), and hyperthyroidism (three G2). No toxic death was reported. Preliminary data showed one patient (CC) who presented a complete response and four patients with stable disease (SD).ConclusionsMTD was not reached and dose level 2 (MVino 40 mg, Durv 1500 mg, Trem 75 mg) was selected as RP2D. The safety profile of the combination was manageable and consistent with previous reports of Trem + Durv or MVino. Phase II is currently ongoing in BC, PC, CC, HNC, and miscellaneous cohorts.

Project description:BackgroundThe combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors.Main bodyImmunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8+ T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8+ and granzyme B+ cells were observed.ConclusionsAlthough efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME.Trial registration numberNCT02671435.

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