Ahmad Mokatrin

Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients

The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the ‘cancer immunity cycle’ by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1–PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.

Intratumoral characteristics of tumor and immune cells at baseline and on-treatment correlated with clinical responses to MPDL3280A, an engineered antibody against PD-L1

PD-L1, PD-L2 and other immune-related molecules regulate Th1 and Th2 immune responses. Tumor-expressed PD-L1, when bound to PD-1 or B7.1 on activated T cells, can mediate cancer immune evasion. While inhibiting PD-L1 receptor binding represents an attractive strategy to restore tumor-specific T-cell immunity, other immune-related factors and cell types within the tumor microenvironment affect anti-tumor T-cell responses. MPDL3280A, a human mAb containing an engineered Fc-domain designed to optimize efficacy and safety and to promote Th1-driven responses, is described here with PhI biomarker results. MPDL3280A was administered IV q3w in >300 pts with locally advanced or metastatic solid tumors. ORR was assessed by RECIST v1.1, including u/cCR and u/cPR. PD-L1 and CD8 were measured by IHC. The expression of ≈90 immune-related markers, including PD-L1 and PD-L2, were evaluated at baseline (BL) and on-treatment. BL tumor samples were available for 103 pts, and matched on-treatment samples were available for 26 pts. As of Feb 1, 2013, 140 pts enrolled prior to Aug 1, 2012 were evaluable for efficacy. Responses were observed in multiple tumor types including NSCLC (9/41), RCC (6/47), melanoma (11/38), CRC (1/4) and gastric cancer (1/1). An ORR of 21% (29/140) was observed in nonselected solid tumors with a duration of response of 1+ to 253+ days. Elevated pretreatment PD-L1 expression (IHC) was associated with response to MPDL3280A, and coordinated expression of PD-L1 and CD8+ T cells was seen. The ORR was 36% (13/36) for pts with PD-L1-pos tumors vs 13% (9/67) for pts with PD-L1-neg tumors. 81 pts had tumors evaluable for PD-L2. Median PD-L2 expression was ≈2x higher in PD-L1-pos tumors vs PD-L1-neg tumors. A T-cell gene signature (eg, CD8, EOMES, IFNγ, Granzyme A) was associated with treatment response. On treatment, responding tumors had increased PD-L1 expression and a Th1-dominant immune infiltrate, evidence of adaptive PD-L1 upregulation. Nonresponders showed minimal tumor CD8+ T-cell infiltration and an absence of T-cell activation. Additionally, elevated expression of immune suppressors, including FOXP3 and RORC, correlated with lack of response. Both the presence of Th1-related CD8 biology at BL and adaptive tumor PD-L1 enhancement with MPDL3280A treatment correlated with tumor response, as did PD-L1 status. Updated data will be presented.

Abstract LB-288: A phase I study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Programmed Death-Ligand 1 (PD-L1) is the predominant ligand that binds Programmed Death-1 (PD-1), an inhibitory receptor expressed on T cells following T-cell activation. PD-L1 is highly expressed in many human tumors and elevated expression is often associated with a worse prognosis. PD-L1 exerts an immune suppressive signal through binding to PD-1 and B7.1, and tumor expression of PD-L1 can mediate tumor immune evasion. Therefore, inhibition of PD-L1 binding represents an attractive strategy to reinvigorate tumor-specific T-cell immunity. MPDL3280A is a human monoclonal antibody engineered to optimize efficacy and safety through a modification in the Fc region of the antibody. MPDL3280A targets PD-L1, inhibiting interaction with its receptors that include PD-1 and B7.1. In preclinical models, inhibition of PD-L1 can lead to durable antitumor activity. Methods: A phase I, multicenter, open-label study was conducted to evaluate the safety, pharmacokinetics (PK), and antitumor activity of MPDL3280A administered intravenously every 3 weeks (q3w) in pts with locally advanced or metastatic solid tumors. The study includes 3+3 dose-escalation cohorts with a 21-day window to evaluate dose-limiting toxicity (DLT). Results: As of September 14, 2012, results from the dose escalation include 30 patients (pts) (median age 66 years, range 39-80 years), all PS 0-1, with a median of 2 (range 1-3) prior treatments, received a median of 5.5 doses (range 2-16) of MPDL3280A in 8 dose-escalation cohorts (0.01-20 mg/kg). No DLTs or [Grade (G) ≥4 adverse events (AEs) attributed to MPDL3280A] have been reported; related G3 AEs were limited to rash in 1 pt. Pneumonitis was not observed in any of the patients in the dose-escalation cohorts. MPDL3280A exposure increased with dose; furthermore, PK was linear at doses ≥1 mg/kg q3w and consistent with that expected for an IgG1 in humans. RECIST-based responses were observed in a variety of different tumor types with ongoing responses in all responding patients. Conclusions: MPDL3280A was well tolerated with an acceptable safety and efficacy profile in pts with a variety of advanced tumors. PK supports dosing intervals that include q2wk or q3wk administration. An expansion phase in numerous tumor types with biomarker assessments is ongoing. Citation Format: Michael S. Gordon, Omid Hamid, John Powderly, Maria Anderson, Gregg Fine, Ahmad Mokatrin, Marcin Kowanetz, Leabman Maya, Bryan A. Irving, Daniel S. Chen, F Stephen Hodi. A phase I study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-288. doi:10.1158/1538-7445.AM2013-LB-288