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Monalizumab and Durvalumab in patients with recurrent / metastatic microsatellite-stable: dose escalation and expansion trial


Updated preliminary clinical data from an ongoing phase I dose escalation and expansion study evaluating the safety and efficacy of the combination of Monalizumab, a first-in-class monoclonal antibody targeting NK and T cell checkpoint receptor NKG2A, with Durvalumab in patients with recurrent / metastatic microsatellite-stable colorectal cancer ( MSS-CRC ).

The combination of Monalizumab and Durvalumab has shown encouraging anti-tumor activity in this difficult-to-treat patient subset.
AstraZeneca / MedImmune have expanded the study with additional patient cohorts to explore the novel combination of Monalizumab and Durvalumab on top of current standard of care therapies in patients with less heavily pretreated disease.

Updated preliminary clinical data on the expansion cohort of microsatellite-stable colorectal cancer patients ( MSS-CRC ) presented at ASCO are based on the cut-off date of April 23, 2018.
Forty patients were evaluable for safety and 39, for efficacy.
Thirty five ( 88% ) patients had 2 or more prior lines of therapy for recurrent / metastatic disease.
Efficacy data have shown an overall response rate ( ORR ) of 8%, with confirmed partial response in 3 patients ( 8% ) and stable disease ( SD ) in 11 patients ( 28% ), including 3 SD patients with tumor reduction who continued therapy for more than 200 days.
The median duration of response was 16.1 weeks at the cut-off date.
Data have demonstrated a disease control rate ( DCR ) of 31% at 16 weeks.

The safety profile of the Monalizumab and Durvalumab combination was consistent with the monotherapy profiles of each agent.
In the MSS-CRC expansion cohort, the most common treatment-related adverse effects included arthralgia ( 7.5% ), increased AST ( 7.5% ), hypothyroidism ( 7.5% ), pruritus ( 7.5% ), and rash ( 7.5% ).
Grade 3/4 adverse reactions that occurred in three patients were limited to sepsis ( n=1, grade 4 ) and increased lipase ( n=1, grade 3 ), that both could be resolved, and increased AST ( n=1, grade 3 ).

Monalizumab is a first-in-class antibody targeting NKG2A receptors expressed on tumor infiltrating cytotoxic NK and CD8 T lymphocytes.
NKG2A is an inhibitory checkpoint receptor binding HLA-E. By expressing HLA-E, cancer cells can protect themselves from killing by NKG2A+ immune cells.
HLA-E is frequently up-regulated on cancer cells of many solid tumors and hematological malignancies.
Hence, Monalizumab may re-establish a broad anti-tumor response mediated by NK and T cells. Monalizumab may also enhance the cytotoxic potential of other therapeutic antibodies.

Durvalumab, a human monoclonal antibody directed against PD-L1, blocks PD-L1 interaction with PD-1 and CD80 on T cells, countering the tumor's immune-evading tactics and inducing an immune response.

Colorectal cancer is the 3rd most commonly diagnosed cancer, with 1.65 million new cases and 835,000 deaths per year worldwide ( WHO, GLOBOCAN database, 2015 ).
21% of colorectal cancer cases are metastatic at diagnosis, but given that some patients who are diagnosed with local disease at some point progress, the total number of patients with metastatic disease may account for roughly 50% of all colorectal cancer patients.
Despite advances in chemotherapy regimens in combination with biologics in the treatment of colorectal cancer, a significant number of patients progress within 6 months after receiving either first or second-line chemotherapy with or without biological agents such as Bevacizumab ( Avastin ) and Cetuximab ( Erbitux ).
Furthermore, among patients who are beyond second line treatment, efficacy data are even worse with low response rates and short progression free survival and overall survival rates.
Response rates reported for TAS102 ( Lonsurf ) and Regorafenib ( Stivarga ), two approved agents for patients with heavily pretreated colorectal cancer, were 1.6 and 1%, respectively. In the TAS102 pivotal trial, median overall survival was 7.1 months ( vs 5.3 months for the placebo group ); in the Regorafenib pivotal trial, median overall survival was 6.4 months (vs 5.0 months for the placebo group).
Initial studies with anti-PD-1 or anti-PD-L1 single-agent therapy have yielded limited to no activity in unselected patients with refractory MSS-CRC.
Collectively, these data indicate that patients with colorectal cancer after two lines of chemotherapy with or without biological agents constitute a group with a high unmet medical need. ( Xagena )

Source: American Society of Clinical Oncology ( ASCO ) Annual Meeting, 2018

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