The treatment of lung cancer took a dramatic step forward late last year when pembrolizumab (Keytruda) was approved as first-line therapy for lung cancer. Previously, pembrolizumab and the two other FDA-approved immune checkpoint inhibitors, nivolumab (Opdivo) and atezolizumab (Tecentriq), had indications only as second-line therapies.
But there’s an important proviso to pembrolizumab’s promotion to first-line status: It’s only for a select group of metastatic non–small-cell lung cancer (NSCLC) patients who have a tumor progression score of 50% or more for the PD-L1 biomarker and whose tumor cells do not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations. The tumor progression score is the proportion of tumor cells exhibiting the PD-L1 protein.
In the KEYNOTE-024 clinical trial that was the basis of the FDA approval, the median progression-free survival was 10.3 months in the pembrolizumab group compared with six months in the group that received conventional chemotherapy. The objective response rate was 45% in the pembrolizumab group and 28% in the chemotherapy group, and overall survival was significantly longer for pembrolizumab patients.
Cancer treatment decisions are increasingly geared to changes at the molecular level, says Benjamin Levy, MD, a lung cancer specialist.
About 222,500 Americans will be diagnosed with lung cancer this year. But the obvious question is how many people with advanced NSCLC will meet the required PD-L1 threshold and qualify for treatment with pembrolizumab. Patient screening for the drug’s clinical trials have shown that between 24.9% and 30.2% of patients have tumors with PD-L1 expression on ≥50% of tumor cells.
The tumor progression score of ≥50% for pembrolizumab was established in the early phase 1 trials and lower levels were not extensively tested in phase 3 trials. Merck’s phase 3 trial of pembrolizumab, KEYNOTE-042, is comparing the checkpoint inhibitor with chemotherapy in a broader group of advanced NSCLC patients with tumor progression scores of 1% or greater, meaning just 1% or greater of their tumor cells express PD-L1. Investigators may report the results early in 2018.
Pembrolizumab’s approval as a first-line drug means new responsibilities for clinicians, notes Benjamin Levy, MD, a lung cancer specialist at Johns Hopkins. Now oncologists will have to test for PD-L1, in addition to EGFR and ALK aberrations, and the National Comprehensive Cancer Network has added routine PD-L1 testing to its guidelines. But testing for PD-L1 is more complicated than just adding another test to a panel. The immunohistochemistry (IHC) test for PD-L1 requires its own tumor sample separate from the one sent for molecular profiling of EGFR and ALK mutations. There can be real challenges in obtaining enough biopsy tissue and in coordinating the sample sent for each test, Levy explains.
There are also some questions about the validity of IHC testing. There are four commercially available tests with different platforms that may produce different results, says Alex Spira, MD, of Virginia Cancer Specialists, which is part of the US Oncology Network. The FDA’s approval of pembrolizumab specified one type of test, but oncologists may use other vendors. The problem stems partly from the inherent limitations of IHC testing, and the fact that the IHC tests for PD-L1 are largely unregulated, lab-developed tests that can vary from vendor to vendor. Moreover, variations in the concentration of PD-L1 cells in different regions of the sample can produce different test results.
Spira says these limitations argue for some flexibility in payers’ application of the ≥50% tumor progression score, but he says payers appear to be sticking with the FDA-specified threshold. Pembrolizumab and the other checkpoint drugs are priced well above $100,000 a year.
To Merck’s delight, pembrolizumab has sped past Bristol-Myers Squibb’s Opdivo and Genentech’s Tecentriq in getting a first-line indication for lung cancer. But Levy says the bigger story is that cancer treatment decisions are increasingly dependent on that PD-L1 and other molecular-level differences in tumor cells. A different era of cancer treatment may soon be upon us, if it isn’t already.