4263 - M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-_, in patients (pts) with advanced SCCHN: results from a phase 1 cohort

Background

The TGF-β pathway promotes tumor immunosuppression, and its inhibition may enhance the antitumor activity of PD-(L)1 mAbs. M7824 is an innovative first-in-class bifunctional fusion protein composed of an anti–PD-L1 mAb fused with the extracellular domain of TGF-βRII (a TGF-β “trap”). We report results in pts with Stage III/IV ≥2L SCCHN not amenable to local therapy with curative intent that progressed/recurred <6 months since last platinum dose.

Methods

In the phase 1 trial NCT02517398, pts with SCCHN received M7824 1200 mg q2w until confirmed PD, unacceptable toxicity, or trial withdrawal; continuation of M7824 beyond PD was permitted if AEs were manageable, PS maintained and no new treatment indicated. Biomarkers include tumor cell PD-L1 level (antibody clone 73-10) and HPV status (by RNAseq). The primary endpoint is BOR per RECIST; secondary endpoints include safety/tolerability.

Results

As of 12 March 2018, 32 pts (75% had ≥2 prior lines of therapy) received M7824 for a median duration of 12.1 (range, 2–74) weeks. 5 pts had a confirmed PR by investigator read (RECIST v1.1 ORR 15.6%). 2 additional pts developed delayed PRs after initial increase in index lesions per RECIST (total ORR 21.9%). 6 pts had SD (total DCR 40.6%). 4/5 pts with PR (DOR 4.1–12.5+ months) and both pts with PD→PR remain on treatment. The ORR (including pts with PD→PR) in HPV+ was 50% (4/8; HPV- ORR 13.6% [3/22]). PD-L1 expression was not predictive for ORR (20% [5/25 pts)] in PD-L1≥1%; 33% [2/6] in PD-L1<1%). 12-month OS rate was 51.2%. 10 pts (31.3%) had grade 3 TRAEs (increased liver enzymes [3 pts], hyperglycemia, maculopapular rash [2 pts each], anemia, hyperthyroidism, diabetic ketoacidosis + hypothyroidism, keratoacanthoma + folliculitis, skin SCC [1 pt each]); there were no grade 4 TRAEs and no treatment-related discontinuations or deaths.

Conclusions

M7824 showed promising early clinical activity and a manageable safety profile in pts with refractory/metastatic ≥ 2L SCCHN. A total ORR of 21.9% was observed (including 2 pts with initial tumor growth), with a possible trend toward higher activity in HPV + (ORR 50%) and evidence of clinical activity irrespective of PD-L1 status.

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 funded by Merck KGaA, Darmstadt, Germany.

Disclosure

N. Isambert: Travel, accommodations, expenses: Roche, MedImmune, AstraZeneca, Novartis, Celgene, Pharmara. E. McClay: Honoraria: Genentech, Bristol-Myers Squibb; Speakers bureau: Genentech, Bristol-Myers Squibb, Merck. C. Borel: Honoraria: Merck, Bristol-Myers Squibb, AstraZeneca, Amgen; Consultancy: Bristol-Myers Squibb, AstraZeneca; Travel, accommodations, expenses: Merck. L. Ojalvo: Employment: EMD Serono. C. Helwig: Employment: Merck KGaA; Equity ownership: Merck KGaA. P.A. Rolfe: Employment: EMD Serono. All other authors have declared no conflicts of interest.