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ATIM-16. PHASE 1 STUDY RESULTS OF M7824 (MSB0011359C), A BIFUNCTIONAL FUSION PROTEIN TARGETING TGF- AND PD-L1, AMONG PATIENTS WITH RECURRENT GLIOBLASTOMA (rGBM)

ABSTRACT: Abstract BACKGROUND TGF- signaling promotes tumor immunosuppression; TGF- inhibition in the tumor microenvironment may enhance the response to antiPD-L1 treatment. M7824 is an innovative, first-in-class, bifunctional fusion protein composed of a human antiPD-L1 IgG1 monoclonal antibody fused with two extracellular domains of TGF RII to function as a TGF- trap. We report safety and efficacy of M7824 in patients with rGBM. METHODS In this efficacy expansion cohort of the ongoing, phase 1 trial NCT02517398, patients with rGBM who progressed after chemoradiation received M7824 1200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal. The primary objective was disease control rate (DCR) per RANO; secondary objectives included safety/tolerability. RESULTS Among 35 patients, median age was 57 years, 68.6% were male, and 91.4% were at first recurrence. At 15 months minimum follow-up, median treatment duration was 8.1 (range, 2.0–72.1) weeks; four patients remained on treatment at >1 year, and one additional patient decided to stop treatment per protocol at 12 months. Two patients had a partial response, and nine had stable disease (DCR, 31.4% [95% CI, 16.9–49.3]), of which two exhibited early progressive disease and subsequent durable stable disease ongoing for >12 months per investigators assessment. The most common treatment-related adverse events (TRAEs) were gingival bleeding (17.1%), asthenia (14.3%), pruritus, and rash (each 11.4%). Grade 3 TRAEs (6 patients, 17.1%) included diarrhea, eczema, increased liver/pancreatic enzymes, papular rash, papules, one grade 4 asymptomatic increased lipase, and one grade 5 intratumoral hemorrhage (investigator-assessed) coterminous with disease progression. CONCLUSIONS M7824 demonstrated a manageable safety profile and encouraging efficacy in rGBM, including two durable partial responses and a DCR of 31.4%. Further investigation of M7824 in GBM is warranted; future development aims to define molecular characteristics of responders.

SUBMITTER: Khasraw M

PROVIDER: S-EPMC6216129 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Project description:Purpose: To find out the patients who are most sensitive and effective to the anti-PD-L1 and TGF-β bifunctional fusion protein in the treatment of recurrent cervical cancer. Patients and methods: We report two cases of recurrent cervical cancer treated with the anti-PD-L1 and TGF-β bifunctional fusion protein. We described the clinical course, clinical characteristics, and genetic characteristics of the two patients, and analyzed the changes of gene expression in the two patients after treatment. Results: Although PD-L1 expression and HPV status were same in the two patients, the treatment effect of two patients with recurrent cervical cancer was different, according to the evaluation of enhanced computed tomography (CT), one was partial response (PR) and the other was progressive disease (PD), which may indicate that PD-L1 expression and HPV status of patients is not enough to predict the effectiveness of the anti-PD-L1 and TGF-β bifunctional fusion protein treatments. Then, we demonstrated that the changes of peripheral blood lymphocytes of two patients during the treatment had different trends. Moreover, number of alterable genes in PR patient is much greater than that in PD patient, indicating PR patient may be more sensible to the anti-PD-L1 and TGF-β bifunctional fusion protein treatments. Total 4844 genes changing-fate gene set selected which is believed conducting anti-cancer function during the anti-PD-L1 and TGF-β bifunctional fusion protein treatments. Furthermore, we identified that changing-fate genes were correlated with female reproductive organ cancer, infectious disease, inflammatory disease, immune system, indicating these genes may conducting anti-cancer, anti-inflammation and immune function. Conclusion: Anti-PD-L1 and TGF-β bifunctional fusion protein is feasible for the treatment of recurrent cervical cancer. Multi-center, large-sample prospective clinical studies are still needed to further explore the efficacy of anti-PD-L1 and TGF-β bifunctional fusion protein in recurrent cervical cancer and screen appropriate patients, so as to achieve the maximum survival benefit of patients.

Project description:Background Biliary tract cancers (BTCs) are a group of cancers with poor prognosis and few treatment options. For 2L chemotherapy, no standard-of-care therapy exists, and overall response rates ORRs) are <10%. M7824 is an innovative first-in-class bifunctional fusion protein composed of 2 extracellular domains of transforming growth factor (TGF)-βRII (a TGF-β “trap”) fused to a human IgG1 mAb against PD-L1. We report the safety and efficacy of M7824 in Asian patients with pretreated BTC. Methods Patients with BTC [including intrahepatic (IHCC) and extrahepatic (EHCC) cholangiocarcinomas, gallbladder carcinoma (GC), and ampullary carcinoma (AC)] who progressed after ≥1 line of chemotherapy received M7824 1,200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal in this expansion cohort of the ongoing phase 1, open-label trial NCT02699515. The primary objective is safety/tolerability; secondary objectives include best overall response per RECIST v1.1. Results At 39 weeks median follow-up, 30 patients received M7824 for a median of 8.9 (range, 2.0–57.6) weeks; 5 patients were on active treatment. Treatment-related adverse events (TRAEs) occurred in 60% of patients; most common were maculopapular rash and pyrexia (13.3% each), as well as lipase increase and rash (10.0% each). Ten patients (33.3%) experienced grade ≥3 TRAEs, including 3 of grade 5 [1 septic shock (bacteremia, unknown etiology; 249 and 14 days after first and last dose, respectively), 2 interstitial lung disease (ILD) AEs (1 on treatment post 3 doses, 1 occurring 6 months after initial ILD diagnosis and last dose)]. Objective responses were observed in 7 patients (ORR, 23.3%; IHCC, 4/10 patients; EHCC, 1/7 patients; GC, 2/12 patients; AC, 0/1 patients), with 1 durable CR (5.6+ months) and 4/6 PRs ongoing at data cutoff (0.7+, 2.8, 3.9+, 5.5+, 5.6, 6.9+ months). One additional patient with GC had an ongoing PR for 7.6+ months after initial pseudoprogression. Conclusions M7824 monotherapy has an acceptable safety profile and promising efficacy in Asian patients with pretreated BTC, with durable responses in 8/30 patients (27%; includes 1 patient with pseudoprogression) across BTC subtypes, including responses in patients with IHCC, EHCC, and GC (ORRs, 40%, 14%, and 17%, respectively). Previously presented at ESMO Asia 2018, FPN 153O, Yoo et al. Reused with permission.

Project description:Abstract Ad-RTS-hIL-12 (Ad) is a gene therapy candidate for intratumoral (IT) delivery that conditionally expresses IL-12 (IL-12) under the transcriptional control of orally administered veledimex (V) acting via the RheoSwitch Therapeutic Systemâ gene switch. Increased PD-1 expression in samples of rGBM following Ad+V (ASCO 2020) supports combination immunotherapy with a PD-1 inhibitor. Phase 1 trials in rGBM of Ad+V as monotherapy and in combination with PD-1 inhibitor revealed encouraging safety and survival data. This phase 2 trial (NCT04006119) in adults with rGBM is evaluating safety and efficacy (overall survival) of Ad + V with pre/post-operative cemiplimab-rwlc (cemi) 350 mg IV, Days -7, 15, then Q3W; Ad single IT injection (2 x 1011 viral particles, day of resection (Day 0) /craniotomy); and V (20 mg PO, Days 0–14). Longitudinal sampling of serum assessed IL-12 and endogenous cytokines production. Anti-tumor effects were described upon preliminary review. Serial MRI evaluated tumor response. Follow-up described overall survival. Initial safety data (51 unique adverse reactions in 28 subjects) appeared similar to Ad+V and the cemi label, respectively, being manageable without synergistic toxicities and generally reversible. Of 35 SAEs reported in 18 subjects, 10 SAEs in 7 subjects were related to Ad+V. IL-12 and IFN-g levels increased after Ad+V administration peaking on Day 3 at 34 ± 11 pg/mL and 13 ± 5 pg/mL (mean ± SEM), respectively. Immune-mediated anti-tumor effects were noted, including a post-treatment biopsy to rule out progression which demonstrated an immune infiltrate consistent with pseudoprogression and loss of tumor cell heterogeneity suggesting immunoediting. Enrollment is anticipated to be completed in 2Q2020 with follow-up ongoing and initial survival data will be presented. V crossed the blood-brain barrier to produce functional IL-12. Controlled IL-12 therapy and cemi is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile.

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ATIM-16. PHASE 1 STUDY RESULTS OF M7824 (MSB0011359C), A BIFUNCTIONAL FUSION PROTEIN TARGETING TGF- AND PD-L1, AMONG PATIENTS WITH RECURRENT GLIOBLASTOMA (rGBM)

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