3681 - Durvalumab + monalizumab, mFOLFOX6, and bevacizumab in patients (pts) with metastatic microsatellite-stable colorectal cancer (MSS-CRC)

Background

Immune checkpoint inhibitors have shown limited clinical benefits in MSS-CRC; dual targeting of non-redundant pathways may enhance antitumor immune response. In a phase I/II, multicenter, open-label study, the anti-PD-L1 antibody durvalumab (D) was combined with monalizumab (M), an IgG4 mAb that blocks NKG2A binding to HLA-E to reduce inhibition of NK and CD8+ T cells. The combination (D+M) was well tolerated and showed encouraging activity in heavily pretreated pts with advanced MSS-CRC. In a dose-exploration cohort, D+M was assessed in combination with standard of care (SOC) chemotherapy and bevacizumab, an anti-VEGF agent, as first-line therapy for advanced/metastatic MSS-CRC.

Methods

Eligible pts had histologically defined MSS-CRC, regardless of RAS/RAF mutational status, ECOG 0–1 and no prior systemic therapy. They received durvalumab 1500 mg Q4W, monalizumab 750 mg Q2W, modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) Q2W and bevacizumab 5 mg/kg Q2W until end of treatment; dose modifications were allowed according to SOC practice except during the DLT evaluation period. The primary endpoint was safety and tolerability of D+M with FOLFOX6 and bevacizumab; secondary endpoints included antitumor activity.

Results

As of Mar 25, 2019, 18 pts were enrolled with median follow-up of 6.2 months. Monalizumab-related adverse events (AEs) occurred in 13 (72%), serious in 1 (6%; embolism). Durvalumab-related AEs occurred in 14 (78%; none serious). All pts had chemotherapy-related AEs, serious in 1 (6%; febrile neutropenia) and 10 (56%) had bevacizumab-related AEs, serious in 2 (11%; embolism and febrile neutropenia). There were no grade 5 or dose-limiting toxicities. At 16 weeks, 17 pts were evaluable for response; 9 (53%) had partial responses (7 confirmed, 2 unconfirmed), 6 (35%) had stable disease and 2 (12%) had progressive disease; there were no complete responses. Median time to response for the 7 confirmed responders was 15.4 weeks; median duration of response was not yet reached.

Conclusions

First-line D+M combined with SOC showed manageable safety and preliminary activity in pts with advanced/metastatic MSS-CRC. Accrual is complete.

Clinical trial identification

NCT02671435.

Editorial acknowledgement

Medical writing support was provided by Hashem Dbouk, PhD, of Cirrus Communications (Lyndhurst, NJ), an Ashfield company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

J.C. Bendell: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Gilead; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution): Five Prime; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Taiho; Advisory / Consultancy, Research grant / Funding (institution): MacroGenics; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: OncoMed; Advisory / Consultancy, Research grant / Funding (institution): LEAP; Advisory / Consultancy, Research grant / Funding (institution): TG Therapeutics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BI; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy, Research grant / Funding (institution): Apexigen; Research grant / Funding (institution): Koltan; Research grant / Funding (institution): SynDevRex; Research grant / Funding (institution): Forty Seven; Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Array; Research grant / Funding (institution): Onyx; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Celldex; Advisory / Consultancy, Research grant / Funding (institution): Agios; Research grant / Funding (institution): Cytomx; Research grant / Funding (institution): Nektar; Research grant / Funding (institution), Travel / Accommodation / Expenses: ARMO; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Tyrogenex; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Oncogenex; Research grant / Funding (institution): Marshall Edwards; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Evelo; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Forma; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Jacobio; Research grant / Funding (institution): Effector; Research grant / Funding (institution): Novocare; Research grant / Funding (institution): Arrys; Research grant / Funding (institution): Tracon; Research grant / Funding (institution): Sierra; Advisory / Consultancy, Research grant / Funding (institution): Innate; Advisory / Consultancy, Research grant / Funding (institution): Arch Oncology; Advisory / Consultancy, Research grant / Funding (institution): Prelude Oncology; Research grant / Funding (institution): Unum Therapeutics; Research grant / Funding (institution): Vyriad; Research grant / Funding (institution): Harpoon; Research grant / Funding (institution): ADC; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Imclone; Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (institution): Rgenix; Research grant / Funding (institution): Bellicum; Advisory / Consultancy: Phoenix Bio; Advisory / Consultancy: Cyteir; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: Innate; Advisory / Consultancy: Torque; Advisory / Consultancy: Tizona; Advisory / Consultancy: Janssen; Advisory / Consultancy: Tolero; Advisory / Consultancy: TD2 (Translational Drug Development); Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Moderna Therapeutics; Advisory / Consultancy: Tanabe Research Laboratories; Advisory / Consultancy: Beigene; Advisory / Consultancy: Continuum Clinical; Advisory / Consultancy: Kyn. J. Naidoo: Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: BMS. X. Li: Full / Part-time employment: AstraZeneca. P. Kourtesis: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S.E. Abdullah: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S. Patel: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Illumina; Advisory / Consultancy: Nektar; Advisory / Consultancy: Tempus; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Fate; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Fate Therapeutics; Research grant / Funding (institution): Genocea; Research grant / Funding (institution): Iovance. All other authors have declared no conflicts of interest.