Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy. In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS). Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%–49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18–37) and median overall survival was 22.1 months (95% CI 17.1–27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%–71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%–36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths. Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%. KEYNOTE-001 (ClinicalTrials.gov, NCT01295827).

Background: In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab plus chemotherapy and then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522. Methods: Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel plus carboplatin and then 4 cycles of doxorubicin (or epirubicin) plus cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23) were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1 of cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with at least 60% completion and at least 80% compliance were assessed using a longitudinal model (no alpha error assigned). Results: Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab plus chemotherapy [n = 762] vs placebo plus chemotherapy [n = 383]) in LS mean change from baseline to week 21 in QLQ-C30 global health status/quality of life (GHS/QoL), emotional functioning, and physical functioning were −1.04 (95% confidence interval = −3.46 to 1.38), −0.69 (95% CI = −3.13 to 1.75), and −2.85 (95% CI = −5.11 to −0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [n = 539] vs placebo [n = 308]) in LS mean change from baseline to week 24 were −0.41 (95% CI = −2.60 to 1.77), −0.60 (95% CI = −2.99 to 1.79), and −1.57 (95% CI = −3.36 to 0.21). Conclusions: No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo plus chemotherapy in early-stage TNBC. Trial registration: ClinicalTrials.gov, NCT03036488.

Purpose:FGFR1 gene is amplified in 14% of HR⁺/ HER2^- breast cancer patients. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3 and PDGFRα/β, were assessed. Experimental Design: HR⁺/ HER2^- MBC patients received oral lucitanib in 3 centrally confirmed cohorts: 1) FGFR1 amplified, 2) FGFR1 non-amplified, 11q13 amplified, 3) FGFR1 and 11q13 non-amplified. Key inclusion criteria included ECOG PS <2, >1 line of anti-cancer therapy, but <2 lines of chemotherapy. Primary endpoint was ORR by RECIST1.1. Simon's 2-stage design was used: if >2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. FGFR1 copy number variation (CNV) were determined by FISH and ddPCR, while FGFR1 expression by IHC. Results: 76 patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The pre-specified primary endpoint was met in cohort 1 with ORR of 19% (95%CI:9-35%), but not in cohorts 2 and 3 with ORR of 0% (0-18%) and 15% (6-34%) respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%) and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high FGFR1 amplification (>4 CNV) than those without high amplification (22% versus 9%). ORR in patients with FGFR1-high tumors (IHC, H-score >50) was 25% versus 8% in FGFR1-low cancers. Conclusions:Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR⁺/ HER2^- MBC. Although based on small sample sizes, exploratory biomarker analyses suggested patients with high FGFR1 amplification or expression might derive greater benefit.

Background: Expression of programmed cell death ligand 1 (PD-L1) on tumor cells with or without immune cells is widely reported in clinical trials of programmed cell death receptor 1 (PD-1) blockade in metastatic non-small cell lung cancer. Various cutpoints have been studied. Methods: We performed a systematic search of MEDLINE, EMBASE, and conference proceedings up to December 2019 for randomized and nonrandomized clinical trials of anti-PD-1 or anti-PD-L1 monotherapy in metastatic non-small cell lung cancer. We retrieved data on objective response rate (ORR), 1-year and 2-year progression-free survival (PFS), and 2-year and 3-year overall survival (OS) in various PD-L1 subgroups. Results were pooled and analyzed based on different cutpoints, with nonrandomized comparisons made with pooled chemotherapy outcomes. Results: A total of 9810 patients in 27 studies were included. In treatment-naïve patients, benefits with PD-1 blockade over chemotherapy were seen in ORR in patients having PD-L1 50% or greater, in 2-year OS for PD-L1 1% or greater, and in 1-year PFS, 2-year PFS, and 3-year OS for unselected patients. First-line PD-1 blockade compared with chemotherapy demonstrated higher ORR, 2-year PFS, and 3-year OS if PD-L1 was 50% or greater; lower ORR, higher 2-year PFS, and similar 3-year OS if PD-L1 was 1%-49%; and lower ORR, similar 1-year PFS, and lower 2-year OS if PD-L1 was less than 1%. In previously treated patients, PD-1 blockade demonstrated similar or superior outcomes to chemotherapy in all PD-L1 subgroups. Conclusions: PD-L1 should guide the choice of PD-1 blockade vs chemotherapy in treatment-naïve patients. In previously treated patients, PD-1 blockade provides a favorable outcome profile to chemotherapy in all PD-L1 subgroups.

Immune-mediated adverse events (imAEs), including all-cause immune-mediated pneumonitis, were reported in approximately 25% of patients in the placebo-controlled, phase III PACIFIC trial of durvalumab monotherapy (for up to 12 months) in patients with unresectable, stage III NSCLC and no disease progression after concurrent chemoradiotherapy; only 3.4% of patients experienced grade 3/4 imAEs. With broad application of the PACIFIC regimen (consolidation durvalumab after chemoradiotherapy), now standard-of-care in this setting, there is a need to better characterize the occurrence of imAEs with this regimen. We performed descriptive, post-hoc, exploratory analyses to characterize the occurrence of imAEs (pneumonitis and non-pneumonitis) in PACIFIC in terms of: incidence, severity, and timing; clinical management and outcomes; and associations between the occurrence of imAEs and (1) all-cause AEs and (2) baseline patient, disease, and treatment characteristics. Any-grade immune-mediated pneumonitis (9.4%) and non-pneumonitis imAEs (10.7%) occurred infrequently and were more common with durvalumab versus placebo. Grade 3/4 immune-mediated pneumonitis (1.9%) and non-pneumonitis imAEs (1.7%) were uncommon with durvalumab, as were fatal imAEs (0.8%; all pneumonitis). The most common non-pneumonitis imAEs with durvalumab were thyroid disorders, dermatitis/rash, and diarrhea/colitis. Dermatitis/rash had the shortest time to onset (from durvalumab initiation), followed by pneumonitis; dermatitis/rash had the longest time to resolution, followed by thyroid disorders. Most patients with immune-mediated pneumonitis (78.4%) and non-pneumonitis imAEs (56.3%) had these events occur ≤ 3 months after initiating durvalumab. ImAEs were well managed with administration of systemic corticosteroids, administration of endocrine replacement therapy, and interruption/discontinuation of durvalumab. Time elapsed from completion of prior radiotherapy to trial randomization (<14 vs. ≥ 14 days) did not impact either incidence or severity of imAEs. Durvalumab had a manageable safety profile broadly irrespective of whether patients experienced imAEs. The risk of imAEs should not deter use of the PACIFIC regimen in eligible patients, as these events are generally well managed through appropriate clinical intervention.