KEYNOTE-045 is a randomized Phase II study where Keytruda monotherapy was compared to investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine) in patients with locally advanced/metastatic, unresectable bladder cancer that had recurred or progressed following platinum-based chemotherapy. In this study, the co-primary endpoints were OS and progression-free survival (PFS), and the secondary endpoints were overall response rate (ORR), duration of response (DOR), and safety. This study enrolled 542 patients, including PD-L1-positive and PD-L1-negative patients. In this particular trial, patients with tumors that were PD-L1+, defined as expression of 10% or more, made up 27% of the total study population.
In the OS analysis of the total population, a significant improvement in OS was seen in Keytruda-treated patients, who achieved a median OS of 10.3 months, compared with 7.4 months seen in the chemotherapy arm. However, in PD-L1+ patients, the median OS was 8.0 months, compared to 5.2 months in the chemotherapy arm. Unlike other cancers in which PD-L1-positivity has correlated with improved response to Keytruda, such as in non-small cell lung cancer (NSCLC), in the KEYNOTE-045 trial, PD-L1+ metastatic bladder cancer patients actually fared worse in terms of OS than PD-L1-low- and non-expressers.
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Analysis of the secondary endpoint, ORR, showed a statistically significant result in favor of Keytruda in the total patient population, at 21.1%, compared with 11.4% in the chemotherapy arm. Surprisingly, in PD-L1+ patients, the ORR was 21.6%, suggesting that as a group, they did not respond at a higher frequency than PD-L1-low- or non-expressing patients (defined as those whose tumors expressed <10% of PD-L1).
One explanation for why PD-L1+ patients did not see more benefit with Keytruda treatment may be found in the trial design of KEYNOTE-045. In this study, PD-L1 status was determined using archived biopsy tissue from primary resected tumors. It is possible that these primary tumors did not reflect the status of PD-L1 expression in patients at the time they received Keytruda, given these patients had received first-line chemotherapy following their primary tumor resection, which could have altered the PD-L1 expression levels on their tumors. Further, it is possible that patients above the tumor PD-L1 ≥50% cutoff, which has been previously used in trials for NSCLC, may have constituted a small percentage of the PD-L1+ patient group in KEYNOTE-045, and thus, any significant benefit they received from Keytruda treatment may have been diminished when they were grouped together with patients who had more than 10%, but less than 50% tumor PD-L1 expression.
These data continue to fuel the debate over the use of tumor PD-L1 as a biomarker. Data from preliminary analysis of BMS’ Opdivo’s Phase II trial in bladder cancer have also failed to show increased response rates in tumor PD-L1 expressers versus low- and non-expressers, echoing Merck & Co.’s results with Keytruda. Interestingly, Roche’s Tecentriq, the only currently approved PD-1 checkpoint modulator in bladder cancer, used PD-L1 expression on tumor-infiltrating immune cells, rather than tumor cells, to stratify patients in its pivotal IMvigor 210 trial. In this study, patients with immune cell-associated PD-L1 levels of IC2/3 (corresponding to ≥5% expression) had a significantly higher ORR of 28%, compared with IC0/1 patients (those with <5% tumor PD-L1 levels), who had a 10% ORR. In addition to increased response rates, the median OS in the IC2/3 group was also higher, at 11.9 months, compared with just 6.7 months in the IC0/1 group. Taken together, these data suggested increased efficacy of Tecentriq in patients with at least 5% PD-L1-positivity, with increased PD-L1 expression on tumor-infiltrating immune cells correlating to better responses to drug treatment.
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As of now, the debate over using tumor PD-L1 as a biomarker is somewhat academic, given Merck & Co. and BMS will be seeking approval for Keytruda and Opdivo, respectively, in all patients, regardless of PD-L1 status. However, as payers and government health agencies move to narrow the eligible patient population that can receive expensive PD-1 checkpoint modulator therapy, to control rising costs, the availability of a biomarker that is predictive of response to treatment will become increasingly important.
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