Elizabeth Plimack, MD
Although the advent of checkpoint blockade immunotherapies has inspired more excitement among oncologists than any other recent anticancer therapeutic development,1,2 researchers and clinicians alike are wrestling with an array of questions concerning how best to translate this new modality into practice.
Despite the promising developments in this arena, many patients with cancer respond inadequately to immune checkpoint monotherapy, and others develop serious (grade 3-4) toxicities that require treatment cessation.3 Understanding the evidence and questions concerning dosing, treatment schedules, efficacy, and safety of immune checkpoint inhibitors as monotherapy and in combination regimens is essential to optimize their use in clinical practice.
Monoclonal antibodies that inhibit the CTLA-4 and PD-1/PD-L1 pathways significantly extend survival compared with conventional treatment in patients with targetable malignancies. The list of immune-responsive cancers now spans melanoma, non–small cell lung cancer (NSCLC), urothelial bladder cancer, head and neck squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, Hodgkin lymphoma, Merkel cell carcinoma, renal cell carcinoma (RCC), and tumors with high mutational loads in patients with germline mutations involving DNA mismatch repair, particularly colorectal cancer (CRC).3
As of December 5, the FDA had approved 6 checkpoint inhibitors to treat 1 or more of these malignancies: ipilimumab (Yervoy), a CTLA-4 inhibitor; nivolumab (Opdivo) and pembrolizumab (Keytruda), both PD-1 inhibitors; and atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), all PD-L1 inhibitors.
Although these agents broadly share similar adverse event (AE) profiles, each has a unique dosing recommendation and schedule (Table4-10) Several experts discussed relevant questions concerning the administration of these agents in interviews with OncologyLive®.
Table. FDA Recommendations for Checkpoint Immunotherapies4-10
Historically, most monoclonal antibodies were dosed according to body weight because body size was thought to affect pharmacokinetics (PKs).11 Early studies of pembrolizumab used the same approach, but as more PK data became available, researchers revisited the need for weight-based dosing. Pembrolizumab, nivolumab, and atezolizumab are now approved at fixed doses for treating several tumor types.
Evidence supports fixed checkpoint inhibitor dosing. In one recent study, researchers combined PK data on pembrolizumab with response data for patients with advanced melanoma or NSCLC.11 Comparing individual areas under the exposure curve with exposure ranges from pembrolizumab doses in early trials, 2 mg/kg every 3 weeks (Q3W) and 10 mg/kg Q3W or every 2 weeks (Q2W) showed that a 200-mg fixed dose pharmacokinetically resembled weight-based dosing among patients with CRC, head and neck cancer, NSCLC, and urothelial cancer. Although patients weighing more than 90 kg had the lowest PK exposure, they still fell well within the range associated with near-maximum efficacy in prior studies.11
Such findings make sense, according to Elizabeth Plimack, MD, MS, chief of genitourinary medical oncology and director of genitourinary clinical research at Fox Chase Cancer Center in Philadelphia. For inhibitors of the PD-1 pathway, “there’s no dose–response relationship,” she said. “We’re using much higher doses than are needed to saturate the receptors. An immune checkpoint inhibitor is training the immune system. The immune system has memory, and so we see that the durability of the antitumor effect continues after we stop treatment.”
Multiple studies’ findings have shown that dosing PD-1 agents above 1 mg/kg does not boost efficacy.12 In one systematic review and meta-analysis of data on patients with advanced melanoma or RCC, nivolumab doses of 2 or 10 mg/kg yielded similar objective response rates (ORRs) but significantly better progression-free survival (PFS) and overall survival (OS) than 0.3 mg/kg.13 Nivolumab is approved at 3 mg/kg or 240 mg, depending on the indication.7
Patients who received pembrolizumab had similar outcomes at either 2 or 10 mg/kg.13 “[Past] a certain dose [of either agent], no further improvement was observed in patient outcomes,” the reviewers concluded. “Therefore, effective and minimum doses need to be determined so that patients can achieve maximum therapeutic benefit with minimum adverse effects.”13