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In patients with lung cancer, neoadjuvant treatment with nivolumab and chemotherapy resulted in a significantly higher percentage of patients with a pathological complete response than chemotherapy alone.

Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.

In a randomized trial involving patients with previously untreated advanced non–small-cell lung cancer, pembrolizumab was associated with a higher response rate, longer progression-free and overall survival, and fewer adverse events than was platinum-based chemotherapy. Approximately 23 to 28% of patients with advanced non–small-cell lung cancer (NSCLC) have a high level of programmed death ligand 1 (PD-L1) expression, which is defined as membranous PD-L1 expression on at least 50% of tumor cells, regardless of the staining intensity (i.e., a PD-L1 tumor proportion score of 50% or greater). 1 , 2 Data from the phase 1 KEYNOTE-001 and phase 3 KEYNOTE-010 studies indicated that patients with advanced NSCLC and a PD-L1 tumor proportion score of 50% or greater were more likely than those with lower tumor proportion scores to have a response to pembrolizumab, a highly selective, humanized . . .

Anti-angiogenic therapy combined with chemotherapy could improve the outcomes of patients with platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and oral etoposide, considering the potential advantage of home administration without hospital admission, in patients with platinum-resistant or platinum-refractory ovarian cancer. In this phase 2, single-arm, prospective study, we recruited patients aged 18–70 years with platinum-resistant or platinum-refractory ovarian cancer at the Sun Yat-sen University Cancer Center (China). The treatment consisted of apatinib at an initial dose of 500 mg once daily on a continuous basis, and oral etoposide at a dose of 50 mg once daily on days 1–14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1. We used Simon's two-stage design, and analysed efficacy in the intention-to-treat and per-protocol populations. Safety analyses included enrolled patients who had received at least one dose of study medication, but excluded those without any safety data. This study is registered with ClinicalTrials.gov, number NCT02867956. Between Aug 10, 2016, and Nov 9, 2017, we screened 38 and enrolled 35 patients. At the data cutoff date (Dec 31, 2017), 20 (57%) patients had discontinued the study, and 15 (43%) patients remained on treatment. Objective responses were achieved in 19 (54%; 95% CI 36·6–71·2) of 35 patients in the intention-to-treat population and in 19 (61%; 42·2–78·2) of 31 patients in the per-protocol population. The most common grade 3 or 4 adverse events were neutropenia (17 [50%]), fatigue (11 [32%]), anaemia (ten [29%]), and mucositis (eight [24%]). Serious adverse events were reported in two patients who were admitted to hospital (one patient had anaemia and anorexia; the other patient had increased ascites due to disease progression). No treatment-related deaths were recorded. The combination of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory ovarian cancer, and further study in phase 3 trials is warranted. None.

In a trial of adjuvant treatment for patients with resected ALK -positive non–small-cell lung cancer, disease-free survival at 2 years was 93.6% with the ALK inhibitor alectinib and 63.7% with standard chemotherapy.

Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer. JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints. Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6–21·9) for the combination group, 17·4 months (15·2–21·3) for the PLD group, and 18·2 months (15·8–21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3–5·1) in the combination group, 3·5 months (2·1–4·0) in the PLD group, and 1·9 months (1·8–1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59–1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32–2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7–18·7) in the combination group, 13·1 months (11·8–15·5) in the PLD group, and 11·8 months (8·9–14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74–1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95–1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction). Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer. Pfizer and Merck KGaA, Darmstadt, Germany.

Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1–5) plus either oral sorafenib 400 mg or placebo twice daily on days 6–15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01047891. Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43–0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8–7·6) with sorafenib versus 4·4 months (3·7–5·0) with placebo. The most common grade 3–4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]). Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies. Bayer, Amgen, and GlaxoSmithKline.

Monofunctional platinum(II) complexes of general formula cis -[Pt(NH ₃) ₂(N -heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N -heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N -heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis -[Pt(NH ₃) ₂(phenanthridine)Cl]NO ₃, which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5′-deoxyguanosine monophosphate than to N -acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links.

In a randomized trial involving 542 patients with relapsed urothelial cancer, treatment with pembrolizumab resulted in overall survival of more than 10 months, as compared with 7 months with chemotherapy. Urothelial cancer is highly lethal in the metastatic state. 1 Platinum-based combination chemotherapy remains the standard first-line treatment for metastatic disease. Carboplatin-based combinations are associated with a median overall survival of 9 months, 2 and cisplatin-based combinations with a median overall survival of 12 to 15 months. 3 However, after platinum-based chemotherapy, there is no internationally accepted standard of care. Single-agent paclitaxel and docetaxel are commonly used worldwide, 4 , 5 and in Europe, vinflunine has been approved on the basis of an overall survival advantage of 2 months over best supportive care. 6 , 7 Because the median overall survival with second-line therapy is only 6 . . .