Novel Agent Stimulates T-Cell Activity in Tumor Microenvironment

Publication
Article
Oncology Live®Vol. 19/No. 18
Volume 19
Issue 18

Investigators are hopeful that M7824, a bifunctional fusion protein that inhibits the PD-L1 and TGF-β pathways, will improve immune system responses across tumor types.

Julius Strauss, MD

Julius Strauss, MD

Julius Strauss, MD

Investigators are hopeful that M7824 (MSB0011359C), a bifunctional fusion protein that inhibits the PD-L1 and TGF-β pathways, will improve immune system responses across tumor types. M7824 is composed of an anti-PD-L1 antibody fused to the extracellular domain of TGF-β receptor II, which serves as a “trap” for TGF-β linked to carcinogenesis. Early trial results have been encouraging.

“[M7824] is a drug that is targeting 2 independent aspects of the immune system,” said Julius Strauss, MD, codirector and assistant research physician of the clinical trials group for the Laboratory of Tumor Immunology and Biology at the Center for Cancer Research at the National Cancer Institute. “It’s building off the notable clinical efficacy and responses observed with anti—PD-1 and anti–PD-L1 monoclonal antibodies against a wide array of solid tumors, where patients have had durable objective responses.”

A phase I dose escalation and expansion study of M7824 (NCT02517398) allowed enrollment of patients with metastatic or locally advanced solid tumors, without stratification, and supported selection of a 1200 mg dose administered intravenously every 2 weeks for future clinical studies. The same study has moved into the expansion phase and investigators seek to enroll 587 patients, also with metastatic or locally advanced solid tumors (TABLE).1

M7824 MECHANISM OF ACTION10

CAF indicates cancer-associated fibroblast; EMT, epithelial-mesenchymal transition; NK, natural killer; TAM, tumor-associated macrophage.

PHASE I TRIAL OF M7824 IN PATIENTS WITH SOLID TUMORS10

ECOG indicates Eastern Cooperative Oncology Group.

Patients will be grouped based on their tumor type, with approximately 30 patients in each cohort. Tumor types include non—small cell lung cancer (NSCLC), colorectal cancer (CRC), and gastric cancer, among others. Patients must have an ECOG performance status of 0 or 1, adequate organ function, and no active central nervous system metastases. The primary endpoints vary depending on the cohort. M7824 is composed of a fully human anti–PD-L1 lgG1 monoclonal antibody linked to the 2 extracellular domains of TGF-β receptor II molecules. The TGF-β receptor II portion serves as a trap for all 3 TGF-β isoforms, and by targeting the tumor with the anti-PD-L1 portion, M7824 may reduce the amount of TGF-β within the tumor micro- environment (FIGURE).2-4

“TGF-β is also an immunosuppressive cytokine which [regulates] the T cells in the tumor microenvironment, and blocking it or sequestering it allows for the effector T cells to be reactivated,” Strauss said. The expression of TGF-β receptor on CD8-positive T cells maintains a stimulation threshold that restricts T-cell activation. This threshold is lowered by the suppression of TGF-β signaling, which allows for activation of CD8-positive T-cells against lower-affinity antigens. It is believed that the sequestration of TGF-β isoforms by M7824 thereby increases the diversity of responding CD8-positive T cell clones during the antitumor response.4

“TGF-β also has many other roles in helping tumor growth that can be treated by blocking it and has an important role in epithelial to mesenchymal transition or mesenchymalization of tumor cells, which is a process that makes tumor cells much more resistant to cytotoxic therapies as well as immunotherapies,” Strauss added. Strauss also explained that TGF-β, as part of the mesenchymalization process, can induce metastasis, and when cancer cells are confined to the epithelial phenotype, they are more likely to respond to cytotoxins and immunotherapy and less likely to metastasize. Studies have found that M7824, by targeting TGF-β, has the ability to control mesenchymalization.5 M7824 can also enhance the efficacy of immunotherapy, because it counteracts the TGF-β-mediated differentiation of regulatory T cells and immune tolerance.6 Studies have also shown that M7824 has the ability to mediate antibody-dependent cellular cytotoxicity of tumor cells, although in some cases to a lesser extent than anti—PD-L1.7

In preclinical studies, M7824 was found to extend survival and encourage long-term protective immunity, relative to monotherapies, in murine models. It was also found to enhance CD8-positive T cell and natural killer cell activity.3, 4

Preliminary results of the phase I trial demonstrated that among 32 heavily pretreated patients with recurrent or refractory (R/R) unresectable advanced colorectal cancer, 1 patient had a confirmed partial response (PR), which was ongoing at 8.3 months.8 Further encouraging results came from a second cohort of 31 heavily pretreated Asian patients with R/R unresectable advanced gastric and gastroesophageal adenocarcinoma who were unselected for PD-L1 status. Preliminary data showed a confirmed overall response rate (ORR) of 19.4%, with 1 confirmed complete response (ongoing at more than 5.4 months and 5 confirmed PRs (4 still ongoing at more than 1.5, 3.6, 5.4, and 6.9 months), along with 6 patients with stable disease.

In a subset analysis of patients treated within the dose-escalation cohort with human papillomavirus (HPV)-associated disease (n = 17), including patients with anal, cervical, and squamous cell carcinoma of the head and neck, there was an ORR of 35.3%, and an ORR of 41.7% in patients with known HPV-positive disease (n = 12). Antitumor activity was seen in all 3 tumor types, and the responses were durable and ongoing as of the data cutoff date.9

Another cohort of patients with advanced NSCLC in second-line treatment without prior immunotherapy showed clinical activity for M7824 regardless of PD-L1 expression levels. The confirmed ORR was 40.7% in patients treated at the recommended phase II dose (1200 mg every 2 weeks) with PD— L1–positive tumors (n = 27). In patients with high-PD-L1 expressing tumors, the ORR was 71.4% (n = 7).10 The safety profile of the drug is similar to those seen with other PD-1 and PD-L1 inhibitors, according to Strauss. In the NSCLC second-line cohort, the most common treatment-related adverse events (TRAEs) were pruritus (20.0%), maculopapular rash (18.8%), and decreased appetite (12.5%). Grade 3 TRAEs were experienced by 21 patients (26.3%); grade 4 TRAEs occurred in 2 patients (2.5%). The most common events were skin and subcutaneous tissue disorders. Eight patients (10%) discontinued treatment due to TRAEs.10

Strauss noted that a small proportion of patients treated with M7824 may develop kera- toacanthomas or early, low-grade squamous cell carcinomas of the skin. In the second-line NSCLC cohort, 8.8% (n = 7) of patients developed these potentially TGF-β-mediated skin lesions. Drug discontinuation is not required and these lesions can be locally treated or resected if necessary. “A unique feature of the squamous cell carcinomas that develop in these patients is that they may regress and self-resolve within a few weeks of [patients] either taking a break or completing treatment. They often don’t require local therapy except in select cases and are not life-threatening,” Strauss said.

Because the safety profile is similar to PD-1/ PD-L1 inhibitors and the drug has positive anti- tumor activity, it could represent a treatment option for patients who have tumors with a typically low response rate to PD-1 and PD-L1 inhibitors, Strauss said. Additionally, M7824 is being assessed in a phase II trial in patients with HPV-associated cancers (NCT03427411).

References

  1. Vugmeyster Y, Wilkins J, Harrison-Moench E, Geng W, Koenig A, Cao L. Selection of the recommended phase 2 dose (RP2D) for M7824 (MSB0011359C), a bifunctional fusion protein targeting TGFβ and PD-L1. Abstract presented at: 2018 ASCO Annual Meeting; June 1-5, 2018: Chicago, IL. meetinglibrary.asco.org/record/158584/abstract.
  2. Jochems C, Tritsch SR, Pellom ST, et al. Analyses of functions of an anti-PD-L1/TGFβR2 bispecific fusion protein (M7824). Oncotarget. 2017;8(43):75217-75231. doi: 10.18632/oncotarget.20680.
  3. Lan Y, Zhang D, Xu C, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med. 2018;10(424). pii: eaan5488. doi: 10.1126/ scitranslmed.aan5488.
  4. Knudson KM, Hicks KC, Luo X, Chen JQ, Schlom J, Gameiro SR. M7824, a novel bifunctional anti-PD-L1/TGFβ trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. Oncoimmunology. 2018;7(5):e1426519. doi: 10.1080/2162402X.2018.1426519.
  5. David JM, Dominguez C, McCampbell KK, et al. A novel bifunctional anti-PD-L1/TGF-β trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. OncoImmunology. 2017;6(10):e1349589. doi: 10.1080/2162402X.2017.1349589.
  6. Ravi R, Noonan KA, Pham V, et al. Bifunctional immune checkpoint- targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun. 2018;9(1):741. doi: 10.1038/s41467-017-02696-6.
  7. Grenga I, Donahue RN, Gargulak ML, et al. Anti-PD-L1/TGFβR2 (M7824) fusion protein induces immunogenic modulation of human urothelial car- cinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis. Urol Oncol. 2018;36(3):93.e1-93.e11. doi: 10.1016/j.urolonc.2017.09.027.
  8. Merck KGaA, Darmstadt, Germany presents data on bifunctional immunothera- py M7824 at ASCO 2018 Gastrointestinal Cancers Symposium [press release]. Darmstadt, Germany: Merck KGaA; January 16, 2018. emdgroup.com/en/ news/asco-gi-curtain-raiser-16-01-2018.html. Accessed August 20, 2018.
  9. Strauss J, Gatti-Mays ME, Redman J, et al. Safety and activity of M7824, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with HPV associated cancers. Presented at: 2018 ASCO Annual Meeting June 1-5, 2018: Chicago, IL. meetinglibrary.asco.org/record/159142/abstract.
  10. Merck KGaA, Darmstadt, Germany presented updated clinical results for bifunctional immunotherapy at ASCO 2018 [press release]. Darmstadt, Germany: Merck KGaA; June 4, 2018. prnewswire.com/news-releases/ merck-kgaa-darmstadt-germany-presents-updated-clinical-results-for-bi- functional-immunotherapy-m7824-at-asco-2018-684461311.html. Accessed August 20, 2018.
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