Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide ...and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC.
Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided
= .0048 for PFS and .0128 for OS.
Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio HR, 0.75; 95% CI, 0.61 to 0.91;
= .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98;
= .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%.
Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.
Pembrolizumab monotherapy is standard first-line therapy for metastatic non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable ...driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population.
In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing
or
aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival.
Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37;
= .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30;
= .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo.
Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable
or
aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.
We report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC.
Chemotherapy-naive patients ...with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS).
The intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio HR = 0.60, 95% confidence interval CI: 0.49–0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64–1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71–1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively.
IMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified.
Summary Background Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that ...binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. Methods VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m2 intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0–1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov , number NCT00519285 Findings Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29–41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3–24·1) in the aflibercept group and 21·2 months (19·6–23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82–1·08; p=0·38). We recorded a higher incidence of grade 3–4 gastrointestinal disorders (182 30% vs 48 8·0%), haemorrhagic events (32 5·2% vs ten 1·7%), hypertension (81 13% vs 20 3·3%), fatigue (97 16% vs 46 7·7%), infections (123 20% vs 60 10%) and treatment-related fatal adverse events (21 3·4% vs nine 1·5%) in the aflibercept group than in the placebo group. Interpretation Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate-resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo. Docetaxel plus prednisone remains the standard treatment for such men who need first-line chemotherapy. Funding Sanofi and Regeneron Pharmaceuticals Inc.
Introduction
Stage III non‐small‐cell lung cancer (NSCLC) management is challenging given the heterogeneous nature of the disease. The LATAM subset of the real‐world, global KINDLE study reported the ...treatment patterns and clinical outcomes for LATAM from the pre‐immuno‐oncology era.
Methods
The study was conducted in seven countries (Argentina, Chile, Colombia, Dominican Republic, Mexico, Peru and Uruguay) in stage III NSCLC (American Joint Committee on Cancer, 7th edition) diagnosed between January 2013 and December 2017. Retrospective data from patients' medical records (index date to the end of follow‐up) were collected. Summary statistics, Kaplan–Meier survival estimates and a two‐sided 95% confidence interval (CI) were provided. Cox proportional hazard model was used for univariate and multi‐variate analyses.
Results
A total of 231 patients was enrolled, the median age was 65.0 years (range 21.0–89.0), 60.6% were males, 76.6% had smoking history, 64.0% had adenocarcinoma and 28.7% underwent curative resection. Multiple treatment regimens (>25) were used; chemotherapy alone was the most common (24.8%). The overall median progression‐free survival (mPFS) and median overall survival (mOS) were 14.8 months (95% CI, 12.1–18.6) and 48.6 months (95% CI, 34.7 to not calculable). Significantly better mPFS and mOS were observed for stage IIIA with curative surgery and resectable tumours and stage IIIB with an Eastern Cooperative Oncology Group score of 0/1, female gender, resectable tumours, adenocarcinoma and curative surgery (p < 0.05).
Conclusion
Results show diversity in treatment practices and the corresponding clinical outcomes in stage III NSCLC. There is a need to streamline treatment selection and sequencing to decrease relapse rates after initial therapy.
Frequent Treatment Modalities for Stage III NSCLC ‐ Initial Therapy. The frequency of the various initial treatment modalities used, are shown by stage (IIIA vs IIIB) and overall. cCRT, concurrent chemoradiotherapy; NSCLC, non‐small‑cell lung cancer; sCRT, sequential chemoradiotherapy. Note: The cut‑off used for selection of treatment modalities is 5% in either of the groups.
In the phase 3 KEYNOTE-604 study (NCT03066778), pembrolizumab plus etoposide and platinum chemotherapy (EP) significantly improved progression-free survival versus placebo plus EP in previously ...untreated extensive-stage SCLC (ES-SCLC). We present health-related quality of life (HRQoL) results from KEYNOTE-604.
Patients with stage IV SCLC were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles plus four cycles of EP. Secondary end points included mean change from baseline to week 18 in the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire—Core 30 (QLQ-C30) global health status/quality of life (GHS/QoL) scale and time to deterioration in the composite outcome of cough, chest pain, or dyspnea from QLQ-C30 and QLQ—Lung Cancer Module 13. Two-sided, nominal p values are reported.
A total of 439 patients completed more than or equal to one QLQ-C30 and QLQ—Lung Cancer Module 13 assessments (pembrolizumab + EP, n = 221; placebo + EP, n = 218). GHS/QoL scores improved from baseline to week 18: least squares mean (95% confidence interval CI) changes were 8.7 (5.3–12.1) for pembrolizumab plus EP and 4.2 (0.9–7.5) for placebo plus EP. Between-group differences in least squares means scores were improved for pembrolizumab plus EP (4.4 95% CI: 0.2–8.7, p = 0.040). Median time to deterioration for the composite end point was not reached and 8.7 (95% CI: 5.9–not reached) months, respectively (hazard ratio = 0.80 0.56–1.14, p = 0.208).
First-line pembrolizumab plus EP therapy maintained HRQoL in patients with ES-SCLC and may be associated with greater improvement than placebo plus EP. Together with the efficacy and safety findings in KEYNOTE-604, HRQoL data support the benefit of pembrolizumab in ES-SCLC.
Lung cancer is a leading cause of cancer-related deaths in Latin America, with non-small cell lung cancer (NSCLC) being the most prevalent. The current study aimed to report real-world data on ...epidermal growth factor receptor (EGFR) mutational testing and treatment regimens at diagnosis and progression in patients with metastatic NSCLC across four Latin American countries (Argentina, Chile, Colombia and Uruguay). A retrospective, multicenter, observational study was conducted in patients with NSCLC using medical records from participating countries. The study population was categorized into two cohorts: Cohort 1 comprised of newly diagnosed, treatment-naive patients with stage IV NSCLC; and cohort 2 comprised of stage IV NSCLC EGFR mutation (EGFRm)-positive patients who had progressed after first- or second-generation EGFR-tyrosine kinase inhibitor (TKI) treatment. Measures included demographic variables, health characteristics, treatment regimen, molecular testing rate and turnaround time at diagnosis and at progression for cohorts 1 and 2, respectively. Descriptive statistics were used to summarize all study measures. Of the 462 patients enrolled, 431 were newly diagnosed or treatment naive with metastatic NSCLC. In cohort 1, the majority of patients with private health insurance (57.31%) underwent molecular diagnosis while only 41.3% of patients within the public sector had access to testing. The average molecular testing rate in cohort 1 varied across countries, with Argentina having the highest testing rate (79%) and Uruguay the lowest (27.63%). EGFRm was observed in 22% of patients. Cohort 2 comprised 31 patients who had progressed after first- or second-generation EGFR-TKI treatment and of these, only 22 (70.97%) underwent testing after progression. Access to molecular testing is still a challenge impacting the choice of first-line treatment in Latin American patients with NSCLC. These findings underline the unmet needs of ensuring early diagnosis, molecular profiling and use of correct treatment to alleviate NSCLC burden in the region. Key words: lung cancer, epidermal growth factor receptor, non-small cell lung cancer, Latin America, tyrosine kinase inhibitor
To present a summary of the treatment and follow-up recommendations for the biochemical recurrence in castration-sensitive prostate cancer (PCa) acquired through a questionnaire administered to 99 ...PCa experts from developing countries during the Prostate Cancer Consensus Conference for Developing Countries.
A total of 27 questions were identified as related to this topic from more than 300 questions. The clinician's responses were tallied and presented in a percentage format. Topics included the use of imaging for staging biochemical recurrence, treatment recommendations for three different clinical scenarios, the field of radiation recommended, and follow-up. Each question had 5-7 relevant response options, including "abstain" and/or "unqualified to answer," and investigated not only recommendations but also if a limitation in resources would change the recommendation.
For most questions, a clear majority (> 50%) of clinicians agreed on a recommended treatment for imaging, treatment scenarios, and follow-up, although only a few topics reached a consensus > 75%. Limited resources did affect several areas of treatment, although in many cases, they reinforced more stringent criteria for treatment such as prostate-specific antigen values > 0.2 ng/mL and STAMPEDE inclusion criteria as a basis for recommending treatment.
A majority of clinicians working in developing countries with limited resources use similar cutoff points and selection criteria to manage patients treated for biochemically recurrent castration-sensitive PCa.
IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 PD-L1) to carboplatin ...plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden bTMB) are reported.
Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously IV, day 1) plus ET (100 mg/m
IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted.
Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive
= .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status.
Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.
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