In November 2018, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin (BV) for the treatment of adult patients with previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP). Approval was based on ECHELON-2, a randomized, double-blind, actively controlled trial that compared BV+CHP with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in 452 patients with newly diagnosed, CD30-expressing PTCL. Efficacy was based on independent review facility-assessed progression-free survival (PFS). The median PFS was 48.2 months with BV+CHP versus 20.8 months with CHOP, resulting in a hazard ratio (HR) of 0.71 (95% confidence interval [CI]: 0.54–0.93). The trial also demonstrated improvement in overall survival (HR 0.66; 95% CI: 0.46–0.95), complete response rate (68% vs. 56%), and overall response rate (83% vs. 72%) with BV+CHP. The most common adverse reactions (incidence ≥20%) observed ≥2% more with BV+CHP were nausea, diarrhea, fatigue or asthenia, mucositis, pyrexia, vomiting, and anemia. Peripheral neuropathy rates were similar (52% with BV+CHP, 55% with CHOP). Through the Real-Time Oncology Review pilot program, which allows FDA early access to key data, FDA granted this approval less than 2 weeks after official submission of the application. Implications for Practice This is the first U.S. Food and Drug Administration approval for treatment of patients with newly diagnosed peripheral T-cell lymphomas (PTCL). Improvement in progression-free and overall survival over cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, which has been the standard of care for decades, is unprecedented. The new regimen represents a major advance for the frontline treatment of patients with CD30-expressing PTCL.

Background Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval. Materials and Methods This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease ( n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded. Results Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4–9.0 months). Estimated median OS was 4.7 months (3.4–6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7–10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS. Conclusion This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies. Implications for Practice This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.

The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). The primary endpoint, confirmed objective response rate, was 23.5% (95% confidence interval [CI]: 16.2%–32.2%) in patients receiving atezolizumab and 28.6% (95% CI: 24.1%–33.5%) in patients receiving pembrolizumab. The median duration of response was not reached in either study and responses were seen regardless of PD-L1 status. The safety profiles of both drugs were generally consistent with approved agents targeting PD-1/PD-L1. Two ongoing trials (IMvigor130 and KEYNOTE-361) are verifying benefit of these drugs. Based on concerning preliminary reports from these trials, FDA revised the indications for both agents in cisplatin-ineligible patients. Both drugs are now indicated for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors/infiltrating immune cells express a high level of PD-L1. The indications for atezolizumab and pembrolizumab in patients who have received prior platinum-based therapy have not been changed. This article summarizes the FDA thought process and data supporting the accelerated approval of both agents and the subsequent revision of the indications. Implications for Practice The accelerated approvals of atezolizumab and pembrolizumab for cisplatin-ineligible patients with advanced urothelial carcinoma represent the first approved therapies for this patient population. These approvals were based on single-arm trials demonstrating reasonable objective response rates and favorable durations of response with an acceptable toxicity profile compared with available non-cisplatin-containing chemotherapy regimens. However, based on concerning preliminary reports from two ongoing phase III trials, the FDA revised the indication for both agents in cisplatin-ineligible patients. Both are now indicated either for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors have high expression of PD-L1.

On September 22, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab (Keytruda, Merck & Co., Inc., Whitehouse Station, NJ) for the treatment of patients with recurrent, locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after two or more systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test. Approval was based on demonstration of durable overall response rate (ORR) in a multicenter, open-label, multicohort trial (KEYNOTE-059/Cohort 1) that enrolled 259 patients with locally advanced or metastatic gastric or GEJ adenocarcinoma. Among the 55% ( n = 143) of patients whose tumors expressed PD-L1 based on a combined positive score ≥1 and either were microsatellite stable or had undetermined microsatellite instability or mismatch repair status, the confirmed ORR as determined by blinded independent central review was 13.3% (95% CI, 8.2–20.0); 1.4% had complete responses. Response durations ranged from 2.8+ to 19.4+ months; 11 patients (58%) had response durations of 6 months or longer, and 5 patients (26%) had response durations of 12 months or longer. The most common (≥20%) adverse reactions of pembrolizumab observed in KEYNOTE-059/Cohort 1 were fatigue, decreased appetite, nausea, and constipation. The most frequent (≥2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Pembrolizumab was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx test (Dako, Agilent, Santa Clara, CA) for selection of patients with gastric cancer for treatment with pembrolizumab based on PD-L1 tumor expression. Implications for Practice This report presents key information on the basis for Food and Drug Administration approval of pembrolizumab for the treatment of patients with locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1. The report discusses the basis for limiting the indication to patients with PD-L1-expressing tumors and the basis for recommending that PD-L1 status be assessed using a fresh tumor specimen if PD-L1 expression is not detected in an archival gastric or GEJ cancer specimen.

On December 22, 2017, the U.S. Food and Drug Administration (FDA) updated the product label for nilotinib to include information for providers on how to discontinue this drug in certain patients. With the updated dosing recommendations, select patients with chronic phase myeloid leukemia (CML) taking nilotinib for 3 years or more and whose leukemia has responded with sustained molecular remission (MR4.5, BCR-ABL transcripts of ≤0.0032%) as determined by a FDA-approved test may be eligible to discontinue nilotinib. The updated dosing regimen was based on the efficacy results from two trials that measured how long patients could stop taking nilotinib without the leukemia returning (treatment-free remission). Trial results demonstrated that, among selected patients who received nilotinib as first-line therapy or after transition from imatinib, approximately 50% continued to be in remission at 96 weeks after stopping therapy. Relapses continued to occur throughout the study, indicating that long-term monitoring is needed for safety and disease monitoring. Discontinuation of treatment was associated with an increased risk of low grade musculoskeletal adverse events, some of which were prolonged. Overall, the results support the approval of updates to the dosing recommendations with regard to treatment discontinuation in selected patients who have received nilotinib for at least 3 years, are in a sustained molecular remission, and who can undergo appropriate monitoring. Implications for Practice The updated dosing information provides eligibility criteria for treatment discontinuation, strict monitoring criteria after nilotinib discontinuation, and guidance for treatment reinitiation in eligible patients with chronic phase myeloid leukemia. About half of appropriately selected patients remained in remission 96 weeks after treatment discontinuation. Patients may experience musculoskeletal pain on withdrawal of treatment, incidence of which appears to decrease over time; however, some patients may have long lasting events. The decision to withdraw or continue treatment with nilotinib should be based on clinical condition and patient preferences.