4622 - M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-_, in patients with post-platinum esophageal adenocarcinoma (EAC): preliminary results from a phase 1 cohort

Background

TGF-β and PD-(L)1 are 2 mechanisms of immune suppression in the tumor microenvironment; blocking both may enhance antitumor activity. M7824 is an innovative first-in-class bifunctional fusion protein composed of an anti–PD-L1 mAb fused with 2 extracellular domains of TGF-βRII (a TGF-β “trap”). Advanced EAC is treated per gastric cancer guidelines, with ORRs ≤14% with 2L SoC taxane monotherapy. We report results in patients (pts) with EAC that progressed on ≥ 1 platinum-based therapy. Emerging data with immunotherapies show clinical activity in advanced EAC, though none are currently approved in these pts.

Methods

In the ongoing trial NCT02517398, pts with advanced, post-platinum EAC received M7824 1200 mg q2w until confirmed PD per RECIST v1.1, unacceptable toxicity or trial withdrawal. The primary endpoint is BOR per RECIST; secondary endpoints include safety/tolerability. Biomarker analysis included tumor cell PD-L1 expression (antibody clone 73-10).

Results

As of August 23, 2017 (median follow-up, 14.4 [range, 1.3–43.3] weeks), 30 pts with advanced EAC (80% had ≥2 prior lines of therapy) received M7824. The median therapy duration was 6.1 (range, 2.0–40.0) weeks; treatment was ongoing in 4 pts (13.3%). 19 pts (63.3%) had TRAEs; 7 pts (23.3%) experienced grade 3 TRAEs (anemia [2 pts], Bowen’s disease, cancer pain, generalized rash, hemorrhagic gastritis, hypophysitis, hypopituitarism, and skin SCC [1 pt each]). No grade 4 TRAEs, study discontinuations, or deaths due to a TRAE were observed. 6 pts (confirmed ORR 20.0%) had a PR with 3 responses ongoing per RECIST (DOR, 1.4+, 2.0, 2.8, 2.9+, 3.6, 6.5+ months), and 4 pts (13.3%) had SD per RECIST by independent committee read. 9 pts (31.0% of 29 evaluable) had PD-L1 + (≥1%) tumors. ORR was 22.2% in pts with PD-L1+ and 20.0% in pts with PD-L1– tumors.

Conclusions

These preliminary data show that M7824 resulted in a manageable safety profile in pts with advanced EAC. Early signs of clinical efficacy in this heavily pretreated population are encouraging, with an ORR of 20%, irrespective of PD-L1 expression. Updated efficacy data and biomarker analysis will be presented.

Clinical trial identification

NCT02517398.

Legal entity responsible for the study

Merck KGaA, Darmstadt, Germany.

Funding

Merck KGaA, Darmstadt, Germany.

Editorial Acknowledgement

Medical writing support was provided by ClinicalThinking, and was funded by Merck KGaA, Darmstadt, Germany.

Disclosure

A. Khattak: Employee: Fiona Stanley Hospital; Consultancy: Merck, Bristol-Myers Squibb; Research funding: MSD, Cancer Council WA; Honoraria: MSD, Merck, Bristol-Myers Squibb, Novartis; Speakers bureau: MSD, Merck, Bristol-Myers Squibb, Novartis. E. Felip: Consultancy: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, MSD, Novartis, Pfizer, Roche, Takeda, Abbvie, Merck; Speakers bureau: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, MSD, Novartis, Pfizer, Roche, Takeda, Abbvie, Merck. C. Helwig: Employee, Equity ownership: Merck KGaA, Germany. I. Dussault: Employee: EMD Serono Consultancy (Includes expert testimony). L. Ojalvo: Employee: EMD Serono. N. Isambert: Travel, accommodations, expenses: Roche, MedImmune, AstraZeneca, Novartis, Celgene, Pharmara. All other authors have declared no conflicts of interest.