US FDA Continues Shift From Companion To Complementary PD-L1 Diagnostics With AstraZeneca Imfinzi Approval

AstraZeneca's Imfinzi (durvalumab) is the third PD-1/L1 inhibitor approved for second-line bladder cancer with labeling that describes better response rates in patients with higher PD-L1 expression, but without a requirement for diagnostic testing.

FDA's approval of AstraZeneca PLC's Imfinzi (durvalumab) is the latest example of the agency's growing preference for complementary diagnostics over the companion diagnostic paradigm that dominated the early days of targeted therapy and immunotherapy for cancer.

While the indications for many targeted therapies and early immunotherapy approvals specified use of a companion diagnostic test, FDA has been moving toward a less prescriptive approach that describes clinical data organized by biomarker expression on a diagnostic test, but leaves use of the test to the physician's discretion – a complementary diagnostic.

Imfinzi is the third PD-1/L1 inhibitor approved by FDA for second-line bladder cancer use, and the third to keep PD-1/L1 expression data in labeling but out of the indication.

FDA cleared Imfinzi on May 1 for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant platinum therapy. (Also see "AstraZeneca's Imfinzi Debuts In Bladder Cancer With Combo Coming Soon" - Scrip, 1 May, 2017.)

PD-L1 status is not mentioned in the indication statement, although labeling describes clinical findings of higher response rates in patients with higher PD-L1 expression.

The complementary diagnostic approach has become a regular, if not an exclusive, feature of FDA's handling of biomarker-guided drug development. The first PD-1 inhibitors to reach the market, Bristol-Myers Squibb Co.'s Opdivo (nivolumab) and Merck & Co. Inc.'s Keytruda (pembrolizumab), illustrate the agency's flexibility: Keytruda's non-small cell lung cancer indication came with a required companion diagnostic from Dako AS, while Opdivo was approved with a complementary diagnostic, also from Dako.

Divergent approaches can also be seen with other personalized medicines. Just days before the Imfinzi approval, FDA approved Novartis AG's Rydapt (midostaurin), a targeted kinase inhibitor with a conventional companion diagnostic claim in the indication, which reads "newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test." (Also see "Rydapt And Alunbrig Approvals Headline Good Week For Targeted Oncologics At US FDA" - Pink Sheet, 29 Apr, 2017.)

In March, the agency approved a PARP inhibitor, Tesaro Inc.'s Zejula (niraparib) for breast cancer with a complementary approach to BRCA diagnostics, describing the data for patients with and without BRCA mutations but not including the diagnostic in the indication. (Also see "US FDA Shows Relaxed Approach On Personalized Medicine In Zejula Approval" - Pink Sheet, 30 Mar, 2017.)

Consistently Better Response With Higher PD-L1 Expression

PD-1/L1 inhibitors are rapidly advancing in bladder cancer. Roche's Tecentriq (atezolizumab) and Opdivo are also approved for similar indications in platinum-experienced mUC, and Tecentriq added a first-line claim in April. (Also see "Keeping Track: US FDA Expands Indications For Roche Tecentriq, Lucentis, Approves Second Infliximab Biosimilar" - Pink Sheet, 23 Apr, 2017.) Keytruda is under review for first-line and second-line indications, with June 14 user fee goals. Merck KGAA and Pfizer Inc.'s Bavencio (avelumab) has an Aug. 27 for a second-line mUC indication. (Keep track of FDA's action goals for pending applications with the Pink Sheet FDA Performance Tracker's User Fee Goal Dates chart.)

Keytruda's second-line indication could be the first full approval for a PD-1/L1 inhibitor in mUC. All the other approvals and Bavencio use the accelerated approval pathway.

Response rate data for the three immunotherapies approved in the post-platinum chemotherapy mUC setting is consistent in showing a greater benefit in patients with higher levels of PD-L1 expression (see chart below).

The definition of high and low PD-L1 expression, however, is not consistent across the three development programs. Tecentriq used a threshold of PD-L1-stained tumor-infiltrating immune cells covering 5% of the tumor sample, using Roche subsidiary Ventana Medical Systems Inc.'s Ventana PD-L1 (SP142) Assay; the low PD-L1 cohort had less than 5%. For Opdivo, the standard was 1% or more to be in the high expression group, using Dako's PD-L1 IHC 28-8 pharmDx assay.

The Infinzi trials used another Ventana test, the Ventana PD-L1 (SP263) Assay, and a more complicated PD-L1 cutoff using a 1% threshold.

Objective Response Rates For PD-L1 Inhibitors In Second-Line Urothelial Carcinoma
	All Patients	Low PD-L1 Expression	High PD-L1 Expression
Infinzi	17% for 182 patients	4.1% for 73 patients	26.3% for 95 patients
Tecentriq	14.8% for 310 patients	9.5% for 210 patients	26% for 100 patients
Opdivo	19% for 270 patients	15.1% for 146 patients	25% for 124 patients
Source: FDA-approved labeling for treatment of metastatic urothelial carcinoma patients who progressed during or after platinum chemotherapy