Monalizumab and MEDI5752 in Patients With MSI and/or dMMR Metastatic Cancer
Status:
Not yet recruiting
Trial end date:
2028-12-01
Target enrollment:
Participant gender:
Summary
MSI is a molecular indicator of defective DNA mismatch repair (dMMR). The MSI/dMMR status is
observed in all tumor types, representing notably 5% of metastatic colorectal cancers (mCRC),
25% of advanced endometrial cancer and 8% of metastatic gastric cancer.
MSI/dMMR cancers are highly immunogenic. MSI/dMMR tumors are characterized by a high tumor
mutational burden with highly immunogenic neoantigens. These tumors are associated with an
upregulation of immune checkpoints (PD1, PDL1, CTLA4, etc.) that protects MSI cancer cells
from their hostile immune micro-environment, characterized by a high infiltration of
activated cytotoxic T CD8+ and NK lymphocytes. Consequently, MSI/dMMR cancers are highly
sensitive to ICIs, whatever the tumor location. MSI/dMMR status is a predictive biomarker for
the efficacy of immunotherapy, regardless of the tumor type. Then, by several phase II and
III studies The efficacy of immunotherapy has been demonstrated as front-line treatment for
patients with chemotherapy-naive MSI/dMMR mCRC and gastric cancer. The phase III KEYNOTE-177
trial evaluating first-line treatment of pembrolizumab in patients with MSI/dMMR mCRC
demonstrated its superiority over first-line chemotherapy, with a significant improvement of
health-related quality of life. At final analysis, the median follow-up was 44.5 months.
Median PFS was 16.5 versus 8.2 months (HR = 0.59; 95%CI 0.45-0.79). The hazard ratio favored
pembrolizumab versus chemotherapy with a trend toward reduction in the risk of death (HR
0.74; 95% CI, 0.53-1.03; P=0.0359), despite a 60% effective crossover rate. Pembrolizumab has
been approved by the FDA and the EMA for patients with newly diagnosed MSI/dMMR mCRC and is
now the standard of care for this population. Also, the phase III CHECKMATE-649 trial reveal
that the Combination of immunotherapy and cytotoxic chemotherapy is the new standard of care
for patients with newly diagnosed metastatic oesogastric cancer. Importantly, results of the
CHECKMATE-649 are outstanding for the subgroup population of MSI/dMMR gastric cancer patients
(N = 44). Indeed, the unstratified hazard ratio for OS with nivolumab plus chemotherapy
versus chemotherapy alone was 0.33 (95% CI 0.12-0.87) for patients with MSI/dMMR tumors. All
in all, ICIs are the standard of care in first-line setting for patients with mCRC or
metastatic oesogastric cancer. Besides, several phase II studies suggest that ICI
combinations might overcome primary resistance to anti-PD1 monotherapy These data justify the
development of bispecific monoclonal antibodies targeting both PD1 and CTLA4 such as
MEDI5752. MEDI5752 has been developed based on the observation that there is a higher
expression of PD-1/CTLA-4 on tumor resident versus peripheral T cells. Preclinical data show
MEDI5752 fully suppresses PD-1 and preferentially inhibits CTLA-4 in the tumor versus the
periphery, which is meant to uncouple CTLA-4 dependant peripheral toxicity from antitumor
activity Natural killer cells are integral to the functioning of the innate immune system and
play an important role in innate antitumor immunity. There is a growing body of evidence for
targeting the NKG2A/HLA-E axis in combination with other ICIs to sensitize tumors to ICI
therapy. NKG2A recognizes the non-classical HLA class I molecule HLA-E. The NKG2A receptor is
found on peripheral NK cells and subsets of T cells in cancer patients. It is also present in
tumor-infiltrating NK and cytotoxic T cells. Importantly, NK cells and the NKG2A/HLA-E axis
play a crucial role in MSI/dMMR tumors. Therefore, a combined blockade of non-redundant
checkpoint pathways to unleash NK and T cells seems particularly promising for MSI/dMMR
neoplasms. Monalizumab specifically binds and blocks the inhibitory receptor NKG2A.
Monalizumab has been investigated in combination with ibrutinib (in chronic lymphoid
leukemia), cetuximab +/- durvalumab (in squamous cell carcinoma of the head and neck, and in
solid tumors), durvalumab +/- FOLFOX (in solid tumors). In the first-in-human dose escalation
of monalizumab plus durvalumab, a manageable toxicity profile was shown.
Taken together, these data provide a strong rational to combine an inhibitor of the
NKG2A/HLA-E axis with a bispecific monoclonal antibody targeting both PD1 and CTLA4 for
patients with metastatic MSI/dMMR cancers.