The Immune checkpoint inhibitors drug class has raised the bar for cancer treatment across multiple tumor types including NSCLC, malignant melanoma, bladder cancer, and Hodgkin’s lymphoma, and the list is rapidly expanding.

 

Since Yervoy’s initial approval in malignant melanoma in 2011, three PD-1/PD-L1 pathway inhibitors have launched on the oncology market: BMS’s Opdivo (2014), Merck & Co.’s Keytruda (2014), and Roche/Genentech’s Tecentriq (2016). These three agents have then gained successive approvals across six oncology indications, namely malignant melanoma, NSCLC, renal cell carcinoma, Hodgkin’s lymphoma, SCCHN, and bladder cancer.

Extensive and ambitious clinical development programs for these approved agents are likely to lead to label expansions – which will boost the agents’ already significant commercial success even more. Indeed, the main barrier to the growth of immune checkpoint inhibitors sales is competition within the class itself. Opdivo and Keytruda are already competing with each other in malignant melanoma, NSCLC, SCCHN, and Hodgkin’s lymphoma, while Opdivo and Tecentriq are competing with each other in NSCLC and bladder cancer. In addition, even more agents of this drug class are set to enter these same indications in the coming years.

One indication, which has yet to see the entrance of an immune checkpoint inhibitor is prostate cancer. In January 2017 however, Roche initiated the only Phase III trial of an immune checkpoint inhibitor in prostate cancer—Tecentriq in combination with Xtandi (enzalutamide), in patients with metastatic castrate-resistant prostate cancer (mCRPC). Supporting the Tecentriq/Xtandi combination is a solid scientific rationale; androgen ablation has been shown to mediate anti-tumor immune responses. In addition, via a mechanism of non-androgen receptor resistance, Xtandi-resistant tumors could potentially suppress the immune response through intrinsic PD-L1 expression – as well as through the induction of PD-L1 expression on circulating dendritic cells1,2,3. Indeed, the trial is recruiting patients previously treated with an androgen synthesis inhibitor.

There are no clinical data available to date demonstrating Tecentriq’s activity in mCRPC, but the combination with Xtandi could potentially hold promise. Many experts however, are reserved in their opinion of the potential of immune checkpoint inhibitors in prostate cancer following a number of high profile failures. Yervoy failed in two pivotal Phase III trials in mCRPC, one in docetaxel-pretreated patients, and the other in chemotherapy-naive, asymptomatic or minimally symptomatic patients. In addition, Opdivo monotherapy did not lead to any clinical responses in seventeen patients with mCRPC. If Tecentriq proves to be successful in its Phase III trial, it could signal the entry of an immune checkpoint inhibitor in a new oncology indication that has a significant unmet need. Drug developers, however, will need to work hard to change physician perception of this drug class in prostate cancer.

 

  1. Graff J, et al.  Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. 2016;7(33):52810-52817.
  2. Gannon PO, et al. Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients. J Immunol Methods. 2009 Aug 31;348(1-2):9-17
  3. Bishop J, et al. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. 2014;6:234-242

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