Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901

BackgroundThe role of maintenance therapy for malignant pleural mesothelioma (MPM) is unknown. We performed a randomized phase II trial to determine if continuation of pemetrexed after first-line pemetrexed and platinum would improve progression-free survival (PFS).Patients and MethodsEligible patients with unresectable MPM, without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression, stratified by number of cycles (< 6 or 6), cis- or carboplatin containing regimen, and histology. Study size was calculated based on the assumption that observation would produce a median PFS of 3 months and pemetrexed would yield median PFS of 6 months.ResultsA total of 72 patients were registered from December 2010 to June 2016. The study closed early after 53 patients were randomized; 49 eligible (22 on the observation arm and 27 on the pemetrexed arm) were included in the analysis. The median PFS was 3 months (95% confidence interval [CI], 2.6-11.9 months) on observation and 3.4 months (95% CI, 2.8-9.8 months) on pemetrexed (hazard ratio [HR], 0.99; 95% CI, 0.51-1.90; P = .9733). The median overall survival (OS) was 11.8 months (95% CI, 9.3-28.7 months) for observation, and 16.3 months (95% CI, 10.5-26.0 months) for pemetrexed (HR, 0.86; 95% CI, 0.44-1.71; P = .6737). Grade 3 or 4 toxicities on the pemetrexed arm included anemia (8%), lymphopenia (8%), neutropenia (4%), and fatigue (4%). A higher baseline level of soluble mesothelin-related peptide was associated with worse PFS (HR, 1.86; 95% CI, 1.00-3.46; P = .049).ConclusionMaintenance pemetrexed following initial pemetrexed and platinum chemotherapy does not improve PFS in patients with MPM.     

PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non–small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors

BackgroundRapid disease progression of patients with advanced epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer (NSCLC) has been recently associated with tumor heterogeneity, which may be mirrored by coexisting concomitant alterations. The aim of this analysis was to investigate the correlation between loss of function of PTEN and the efficacy of tyrosine kinase inhibitors in this population.Materials and MethodsArchival tumor blocks from patients with EGFR-mutant NSCLC who were administered upfront tyrosine kinase inhibitors were retrospectively collected. The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry, and it was correlated with overall response rate, overall survival (OS), and progression-free survival (PFS).ResultsFifty-one patients were included. In multivariate analysis, PTEN loss (hazard ratio [HR], 3.46; 95% confidence interval [CI], 1.56-7.66; P = .002), IGFR overexpression (HR, 2.22; 95% CI, 1.03-4.77; P = .04), liver metastases (HR, 3.55; 95% CI, 1.46-8.65; P = .005), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 1 (HR, 2.57; 95% CI, 1.04-6.34; P = .04) were significantly associated with shorter PFS. Patients with PTEN loss had a median PFS of 6 months (2-year PFS, 11.6%), whereas patients without PTEN loss had a median PFS of 18 months (2-year PFS, 43.6%) (log-rank P < .005). In the multivariate analysis, PTEN loss (HR, 5.92; 95% CI, 2.37-14.81; P < .005), liver metastases (HR, 2.63; 95% CI, 1.06-6.51; P = .037), and ECOG PS ≥ 1 (HR, 2.80; 95% CI, 1.15-6.81; P = .024) were significantly associated with shorter OS. Patients with PTEN loss had a median OS of 6 months (2-year OS, 12.2%), whereas in patients without PTEN loss, OS was not reached (2-year OS, 63.9%) (log-rank P < .0005).ConclusionsA low-cost and reproducible immunohistochemistry assay for PTEN loss analysis represents a potential tool for identifying tumor heterogeneity in patients with advanced EGFR-mutant NSCLC.     

A Randomized,Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407

IntroductionIn the randomized KEYNOTE-407 study (ClinicalTrials.gov, NCT02775435), pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC. We report updated efficacy outcomes from the protocol-specified final analysis and, for the first time, progression on next line of treatment.MethodsEligible patients were randomized to chemotherapy plus either pembrolizumab (n = 278) or placebo (n = 281). After positive results from the second interim analysis, patients still receiving placebo could cross over to pembrolizumab monotherapy at the time of confirmed progressive disease. The primary end points were OS and PFS. PFS-2 (time from randomization to progression on next-line treatment/death, whichever occurred first) was an exploratory end point.ResultsAfter median (range) follow-up of 14.3 (0.1–31.3) months, pembrolizumab plus chemotherapy continued to exhibit a clinically meaningful improvement over placebo plus chemotherapy in OS (median, 17.1 mo [95% confidence interval (CI): 14.4‒19.9] versus 11.6 mo [95% CI: 10.1‒13.7]; hazard ratio [HR], 0.71 [95% CI: 0.58‒0.88]) and PFS (median, 8.0 mo [95% CI: 6.3‒8.4] versus 5.1 mo [95% CI: 4.3‒6.0]; HR, 0.57 [95% CI: 0.47‒0.69]). PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy (HR, 0.59 [95% CI: 0.49‒0.72]). Grade 3 to 5 adverse events occurred in 74.1% and 69.6% of patients receiving pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively.ConclusionsPembrolizumab plus chemotherapy continued to exhibit substantially improved OS and PFS in patients with metastatic squamous NSCLC. The PFS-2 outcomes support pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.     

On-target Toxicities Predictive of Survival in Metastatic Renal Cell Carcinoma (mRCC) Treated With Sunitinib: A Multicenter Retrospective Study

BackgroundPreliminary studies suggested that selected drug-related toxicities of sunitinib may correlate with a better prognosis.Patients and MethodsFrom January 2006 through December 2015, we retrospectively analyzed data of 145 patients with metastatic renal cell carcinoma treated with sunitinib as a first-line therapy in 7 different Italian oncology departments. Hypertension, hypothyroidism, thrombocytopenia, neutropenia, and anemia were evaluated. Overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were compared in patients who developed and who did not develop a drug-related toxicity. A multivariate analysis using the Cox regression model was performed.ResultsWe evaluated 145 patients (92 males; median age, 70 years); 105 (62.4%) patients experienced at least 1 toxicity: 66 (45.5%) patients developed hypothyroidism, 41 (28.3%) thrombocytopenia, 39 (26.9%) hypertension that required medical therapy, 22 (15.2%) anemia, and 11 (7.6%) neutropenia. The median PFS of patients who developed hypertension was 12 months (95% confidence interval [CI], 9-21 months) versus 9 months (95% CI, 7-12 months) in patients who did not develop toxicity; the median OS was 36 months (95% CI, 22 months to not reached) versus 26 months (95% CI, 18-34 months). For neutropenia, the median PFS was 17.5 months (95% CI, 9-65 months) versus 10 months (95% CI, 8-12 months); the median OS was 23 months (95% CI, 13 months to not reached) versus 28 months (95% CI, 22-35 months). At univariate and multivariate analysis, we observed a protective effect of hypertension and neutropenia on tumor progression (hazard ratio, 0.47; 95% CI, 0.28-0.78 and hazard ratio, 0.26; 95% CI, 0.09-0.76, respectively).ConclusionsMany patients developed toxicities during treatment with sunitinib; hypertension and neutropenia were related to longer PFS in our cohort.     

Neoadjuvant chemotherapy followed by interval debulking surgery for advanced epithelial ovarian cancer: GOTIC-019 study

Introduction

Three randomized controlled trials have resulted in extremely extensive application of the strategy of using neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) for patients with advanced epithelial ovarian cancer in Japan. This study aimed to evaluate the status and effectiveness of treatment strategies using NAC followed by IDS in Japanese clinical practice.

Patients and methods

We conducted a multi-institutional observational study of 940 women with Federation of Gynecology and Obstetrics (FIGO) stages III–IV epithelial ovarian cancer treated at one of nine centers between 2010 and 2015. Progression-free survival (PFS) and overall survival (OS) were compared between 486 propensity-score matched participants who underwent NAC followed by IDS and primary debulking surgery (PDS) followed by adjuvant chemotherapy.

Results

Patients with FIGO stage IIIC receiving NAC had a shorter OS (median OS: 48.1 vs. 68.2 months, hazard ratio [HR]: 1.34; 95% confidence interval [CI] 0.99–1.82, p = 0.06) but not PFS (median PFS: 19.7 vs. 19.4 months, HR: 1.02; 95% CI: 0.80–1.31, p = 0.88). However, patients with FIGO stage IV receiving NAC and PDS had comparable PFS (median PFS: 16.6 vs. 14.7 months, HR: 1.07 95% CI: 0.74–1.53, p = 0.73) and OS (median PFS: 45.2 vs. 35.7 months, HR: 0.98; 95% CI: 0.65–1.47, p = 0.93).

Conclusions

NAC followed by IDS did not improve survival. In patients with FIGO stage IIIC, NAC may be associated with a shorter OS.

     

Impact of primary metastatic bone disease in germ cell tumors: results of an International Global Germ Cell Tumor Collaborative Group G3 Registry Study

BackgroundBone metastases (BM) are rare in germ cell tumor (GCT) patients. Systematic data on risk factors, treatment and outcome are largely lacking.Patients and methodsA database created by an international consortium including 123 GCT patients with BM at primary diagnosis was retrospectively analysed. Survival estimates were calculated by the method of Kaplan–Meier and compared by log-rank testing. Cox regression analysis was applied for risk factor analyses.ResultsIn our cohort of patients, BM at primary diagnosis more often affected multiple sites (61%) and BM as the only metastatic site were scarce (9%). Histology was non-seminoma in 77% and seminoma in 23% of patients. After a median follow-up of 18 months (range, 0–228), estimated median PFS and OS were 21 (range, 0–225) and 98 months (^95%CI, 36–160), respective 2-year PFS and OS rates were 34% and 45%. Negative prognosticators in univariate analysis were a mediastinal primary (PFS; HR 1.92;^95%CI, 1.05–3.50; OS; HR 2.16;^95%CI, 1.14–4.09) and the presence of liver and/or brain metastases (PFS; HR 1.89;^95%CI, 1.13–3.17; OS; HR 1.91;^95%CI, 0.024) Seminomatous histology was the strongest predictor for favorable PFS (multivariate Cox regression; HR, 0.32;P=0.011) with respective 2-year PFS and OS rates of 68% and 75% compared with 24% and 36% for non-seminoma patients.ConclusionsOutcome of GCT patients with primary metastatic bone disease is particularly poor in non-seminoma patients, even worse than the expected outcomes of the general IGCCCG ‘poor prognosis’ group. This series does not indicate that mutlimodal treatment improves the prognosis over stage-adapted chemotherapy alone, however, the statistical power of these results is limited due to low patient numbers in each specific subgroup.     

A Randomized Phase II Study of Perioperative Chemotherapy Plus Bevacizumab Versus Postoperative Chemotherapy Plus Bevacizumab in Patients With Upfront Resectable Hepatic Colorectal Metastases

IntroductionWhether patients with resectable colorectal liver metastases (CRLM) gain a survival benefit from perioperative chemotherapy remains controversial. The benefit of including bevacizumab in chemotherapy also remains unclear.Material and MethodsSeventy-six patients with CRLM were randomly assigned to either 6 cycles of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin)/FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) with bevacizumab before and after surgery or 12 cycles after surgery. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and compared by the log-rank test.ResultsThe median PFS of all patients was 37.4 months at 5.4 years follow-up, and the median overall survival (OS) was not reached. The PFS between the perioperative group and the postoperative group did not reveal a statistical difference (P = .280). The OS was significantly better in the perioperative group (hazard ratio [HR], 0.60; 95% confidence interval [CI],) 0.35-1.02; P = .049). In subgroup patients with carcinoembryonic antigens (CEA) ≥ 5 ng/mL or those with over 2 liver metastases, perioperative group had longer OS than postoperative group (CEA: HR, 0.49; 95% CI, 0.25-0.93; P = .030; number of liver metastases: HR, 0.55; 95% CI, 0.30-0.99; P = .049). The largest liver metastases size, disease-free interval, and sidedness did not affect PFS or OS. There was no difference between the 2 groups in postoperative complications with bevacizumab or adverse events during chemotherapy.ConclusionsIn patients with resectable CRLMs, perioperative chemotherapy had no effect on PFS, but improved OS. Patients with high CEA levels or over 2 liver metastases may benefit from perioperative chemotherapy.     

Progression-Free Survival Remains Poor Over Sequential Lines of Systemic Therapy in Patients With BRAF-Mutated Colorectal Cancer

BackgroundBRAF mutations occur in 5% to 10% of metastatic colorectal cancers and are biomarkers associated with a poor prognosis. However, the outcomes with standard chemotherapy over sequential lines of therapy in a large cohort of patients with BRAF-mutant tumors have not been described.Patients and MethodsWe searched the M.D. Anderson Cancer Center databases for patients with colorectal cancer and identified BRAF mutations between December 2003 and May 2012. Patients were analyzed for clinical characteristics, PFS, overall survival, and chemotherapeutic agents used. Survival was estimated according to the Kaplan–Meier method.ResultsAmong the 1567 patients tested for BRAF mutations at our institution, 127 (8.1%) had tumors with BRAF mutations. The 71 patients who presented with metastatic disease received a median of 2 lines of chemotherapy. For the first 3 lines of chemotherapy, median PFS was 6.3 months (n = 69 patients; 95% confidence interval [CI], 4.9-7.7 months), 2.5 months (n = 58 patients; 95% CI, 1.8-3.0 months), and 2.6 months (n = 31 patients; 95% CI, 1.0-4.2 months), respectively. Median PFS was not affected by the backbone chemotherapeutic agent in the first-line setting, whether oxaliplatin-based or irinotecan-based (6.4 months vs. 5.4 months, respectively; P = .99).ConclusionPFS is expectedly poor for patients with BRAF-mutated metastatic colorectal cancer. Despite the ascertainment bias present (with testing preferentially performed in patients suitable for clinical trials in refractory disease), these data provide historic controls suitable for future study design and support the idea that novel therapeutic options are essential in this population.     

First-line anthracycline-based chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: Pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials

BackgroundAngiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicin is the standard first-line chemotherapy for advanced STS. It is not known whether angiosarcoma response to anthracycline-based chemotherapy is different to other STS subtypes.MethodsPooled data were analysed from 11 prospective randomised and non-randomised European Organisation for Research and Treatment of Cancer (EORTC) clinical trials of first-line anthracycline-based chemotherapy for advanced STS. Baseline patient characteristics, chemotherapy response, progression free survival (PFS) and overall survival (OS) of angiosarcoma patients were compared with other STS patients. Analysis was performed to identify factors prognostic for angiosarcoma response to chemotherapy, PFS and OS.ResultsWith a median follow-up of 4.2 years, data from 108 locally advanced and metastatic angiosarcoma patients and 2557 patients with other STS histologies were analysed. 25% of angiosarcoma patients had a complete or partial response to chemotherapy compared to 21% for other STS histotypes. The median PFS was 4.9 months and OS 9.9 months, which were not significantly different from other STS histotypes. In univariate analysis, bone metastases were an adverse prognostic factor for OS (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.03–2.67; p = 0.036). Tumour grade was as an adverse prognostic factor for PFS (HR 1.72, 95% CI 1.01–2.92; p = 0.044) and OS (HR 2.03; 95% CI 1.16–3.56; p = 0.011). Compared to single agent anthracyclines, doxorubicin + ifosfamide was associated with improved PFS (HR 0.53, 95% CI 0.33–0.86; p = 0.010) and OS (HR 0.53, 95% CI 0.32–0.90; p = 0.018).ConclusionsAngiosarcoma response and survival following first-line anthracycline-based chemotherapy was similar to other STS histotypes. Our analysis provides a useful measure of angiosarcoma response to chemotherapy for comparison with future clinical trials.     

Systemic Therapy in Patients With Metastatic Xp11.2 Translocation Renal Cell Carcinoma

BackgroundXp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a unique subtype with poor prognosis, its response to systemic therapy is not fully understood, we evaluated the benefit of systemic therapy in these patients.Patients and MethodsBetween May 2006 and December 2019, patients diagnosed with Xp11.2 tRCC from Peking university cancer hospital were collected. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions.ResultsMetastatic Xp11.2 tRCC was found in 45 patients. The median PFS and median OS was 7.4 months (4.5-8.8) and 17.9 months (12.4-24.4), respectively. First-line treatment mainly included sunitinib (n = 14), sorafenib (n = 15), axitinib (n = 6), and pazopanib (n = 5), and the median PFS of these regimens were 7.4 months, 5.4 months, 9.4 months, 8.9 months, respectively. Two patients who received Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) plus immune checkpoint inhibitor (ICI) as first line therapy had a PFS of more than 16.6 months and more than 25.6 months, respectively. Twenty-four patients received subsequent therapies, which included VEGFR-TKI/ICI, VEGFR-TKI and mTOR inhibitor. The ORR and median PFS was 33% and 7.1 months, 7.7% and 4.3 months, 0% and 2.1 months for these treatments, respectively. The estimated median OS was 17.3 months (95% CI, 11.2 to not reached) in patients with TKI/ICI treatment and 11.0 months (95% CI, 6.1 to not reached) without TKI/ICI treatment in subsequent therapies (P = .04). Patients with serous cavity effusion or IMDC poor risk groups had significantly shorter median PFS and median OS.ConclusionMetastatic Xp11.2 tRCC is an aggressive disease. VEGFR-TKI agents appeared to demonstrate some efficacy, VEGFR-TKI /ICI combination might be a useful tool for the treatment of metastatic Xp11.2 tRCC.     

Treatment of Metastatic Urothelial Carcinoma After Previous Cisplatin-based Chemotherapy for Localized Disease: A Retrospective Comparison of Different Chemotherapy Regimens

BackgroundOptimal chemotherapy for patients who received cisplatin for localized urothelial carcinoma (UC) and develop metastatic disease is unclear. We compared the efficacy of platinum-based (PBC) versus non–platinum-based (NPBC) first-line chemotherapy for metastasis.Patients and MethodsData were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3024 patients from 28 international academic centers from 2005 to 2012. Patient inclusion criteria included: (1) predominant UC; (2) any primary tumor site; (3) cT2-4, cN0-N2, cM0; (4) prior receipt of perioperative/radiation cisplatin-containing chemotherapy; and (5) receipt of cytotoxic chemotherapy in the first-line metastatic setting. Multivariate Cox proportional hazards models were used to show progression-free survival (PFS) and overall survival (OS) from the first day of chemotherapy for metastatic disease to date of censor.ResultsEligibility criteria was met by 132 patients (n = 74 PBC; n = 58 NPBC). The median OS was 8.13 months (interquartile range, 4.87-16.64 months) and 8.77 months (interquartile range, 4.01-13.49 months) for PBC and NPBC, respectively. Neither OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.64-1.69; P = .87) nor PFS (HR, 0.86; 95% CI, 0.56-1.31; P = .48) differed for PBC versus NPBC. However, for patients who received chemotherapy more than a year after perioperative/radiation chemotherapy, OS was superior for PBC over NPBC (HR, 0.31; 95% CI, 0.10-0.92; P = .03).ConclusionsThere is no significant outcome difference between PBC and NPBC in patients with metastatic UC who previously received cisplatin-based chemotherapy for localized disease. However, if over a year has elapsed, return to PBC is associated with superior OS.     

Role of Bone Metastases in Patients Receiving Immunotherapy for Pre-Treated Urothelial Carcinoma: The Multicentre,Retrospective Meet-URO-1 Bone Study

BackgroundConsiderable numbers of patients with metastatic urothelial carcinoma (mUC) develop bone metastases (BoM). Their impact on the efficacy of immune-checkpoint inhibitors (ICIs) is not yet investigated.MethodsBetween July 2014 and August 2020 data on pts treated with single-agent ICIs after failure of at least 1 previous line of chemotherapy for advanced disease, were retrospectively collected across 14 Italian centers. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Cox regression analysis was performed evaluating potential prognostic factors for OS and PFS. Each factor was evaluated in univariable (UVA) and multivariable analysis (MVA).ResultsA total of 208 evaluable patients treated with ICIs were identified, including 122 (59%) without BoM (BoM-) and 86 (41%) with bone metastases (BoM+). After a median follow-up of 22.3 months, BoM+ patients showed shorter OS (median 3.9 vs 7.8 months, HR 1.59 [95%CI, 1.15-2.20], P = .005) and shorter PFS (median 2.0 vs 2.6 months, HR 1.76 [95%CI, 1.31-2.37], P < .001). Probability of being alive was 62% vs 40% after 6 months, 38% vs 23% after 1 year and 24% vs 13% after 2 years, in BoM- and BoM+ respectively. Within each Bellmunt score, OS and PFS of BoM+ patients were shorter. Both presence of BoM and higher Bellmunt risk score were significantly associated with shorter OS and PFS in UVA and MVA.ConclusionPatients treated with single-agent ICIs for BoM+ mUC have a dismal prognosis compared to BoM-. Further research is needed to understand the mechanism behind these outcomes.     

Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort

BackgroundAnticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456).Patients and MethodsTumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables.ResultsPD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1–expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1–stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1–positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047).ConclusionAlthough high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.     

Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC—an Update From the PACIFIC Trial

IntroductionIn the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53–0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42–65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized.MethodsPatients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan–Meier method.ResultsOverall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2–64.9), updated OS (HR = 0.71; 95% CI: 0.57–0.88) and PFS (HR = 0.55; 95% CI: 0.44–0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively.ConclusionThese updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%).     

EZH2 Overexpression in Multiple Myeloma: Prognostic Value,Correlation With Clinical Characteristics,and Possible Mechanisms

BackgroundEZH2 is a histone methyltransferase that suppresses genes involved in cell cycle control. Overexpression of EZH2 has been associated with a poor prognosis in various malignancies. Pawlyn et al recently reported poor outcomes in patients with multiple myeloma and overexpression of EZH2. In order to validate these findings, we analyzed EZH2 expression and outcomes among patients from the CoMMpass study.Patients and MethodsWe extracted clinical, expression, and genomic data from Interim Analysis 13 of the MMRF CoMMpass study, which harbors data from over 1000 patients with multiple myeloma. Correlations were drawn between EZH2 expression and common genetic mutations. We analyzed the association of EZH2 overexpression with progression-free (PFS) and overall survival (OS).ResultsThe estimated median PFS for patients with EZH2 overexpression was 20.2 months (95% confidence interval [CI], 16.3-25.5 months) compared with 37.2 months (95% CI, 31.5-40.7 months) for patients without (P < .001). The estimated median OS for patients with EZH2 overexpression was 52.3 months (95% CI, 38.5 months to unable to quantitate), whereas the median OS had not been reached for those without (P < .001). EZH2 overexpression was more common in those with 17p and 1q deletions, TP53 missense mutations, and certain KRAS mutations. Coinciding BRAF and EZH2 amplification occurred frequently.ConclusionEZH2 overexpression is associated with worse outcomes among patients with multiple myeloma from the CoMMpass study. Its known association with p53 and other drivers of malignancy support further lab-based and clinical study in multiple myeloma.     

Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial

IntroductionEMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, investigated cemiplimab (antiprogrammed cell death protein 1) plus chemotherapy versus placebo plus chemotherapy in patients with advanced NSCLC without EGFR, ALK, or ROS1 aberrations, with either squamous or nonsquamous histology, irrespective of programmed death-ligand 1 levels. At primary analysis, after 16.4 months of follow-up, cemiplimab plus chemotherapy improved median overall survival (OS) versus chemotherapy alone (21.9 versus 13.0 mo, hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.53–0.93, p = 0.014). Here, we report protocol-specified final OS and 2-year follow-up results.MethodsPatients (N = 466) were randomized 2:1 to receive histology-specific platinum-doublet chemotherapy, with 350 mg cemiplimab (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks. Primary end point was OS; secondary end points included progression-free survival and objective response rates.ResultsAfter 28.4 months of median follow-up, median OS was 21.1 months (95% CI: 15.9–23.5) for cemiplimab plus chemotherapy versus 12.9 months (95% CI: 10.6–15.7) for chemotherapy alone (HR = 0.65, 95% CI: 0.51–0.82, p = 0.0003); median progression-free survival was 8.2 months (95% CI: 6.4–9.0) versus 5.5 months (95% CI: 4.3–6.2) (HR = 0.55, 95% CI: 0.44–0.68, p < 0.0001), and objective response rates were 43.6% versus 22.1%, respectively. Safety was generally consistent with previously reported data. Incidence of treatment-emergent adverse events of grade 3 or higher was 48.7% with cemiplimab plus chemotherapy and 32.7% with chemotherapy alone.ConclusionsAt protocol-specified final OS analysis with 28.4 months of follow-up, the EMPOWER-Lung 3 study continued to reveal benefit of cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced squamous or nonsquamous NSCLC, across programmed death-ligand 1 levels.     

First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients

BackgroundBevacizumab has consistently demonstrated improved progression-free survival (PFS) and response rate when combined with first-line chemotherapy for HER2-negative metastatic breast cancer (mBC). However, the lack of a significant overall survival (OS) difference continues to attract debate, and identification of patients deriving greatest benefit from bevacizumab remains elusive.Patients and methodsIndividual patient data from three randomised phase III trials in the first-line HER2-negative mBC setting were analysed, focusing specifically on efficacy in poor-prognosis patients.ResultsThe meta-analysis (n = 2447) demonstrated a PFS hazard ratio (HR) of 0.64 (95% confidence interval [CI] 0.57–0.71; median 9.2 months with bevacizumab versus 6.7 months with non-bevacizumab therapy) and response rate of 49% versus 32%, respectively. The OS HR was 0.97 (95% CI 0.86–1.08); median 26.7 versus 26.4 months, respectively. In patients with triple-negative mBC, the HRs for PFS and OS were 0.63 (95% CI 0.52–0.76) and 0.96 (95% CI 0.79–1.16), respectively. Median PFS was 8.1 months with bevacizumab versus 5.4 months with chemotherapy alone, median OS was 18.9 versus 17.5 months, respectively, and 1-year OS rates were 71% versus 65%.ConclusionsBevacizumab improves efficacy, including 1-year OS rates, both overall and in subgroups of poor-prognosis patients with limited treatment options.     

Angiogenic and Antiangiogenic VEGFA Splice Variants in Colorectal Cancer: Prospective Retrospective Cohort Study in Patients Treated With Irinotecan-Based Chemotherapy and Bevacizumab

BackgroundAlternative splicing of vascular endothelial growth factor A (VEGFA) results in VEGFAxxxb antiangiogenic isoforms that fail to activate angiogenesis. Bevacizumab, widely used in patients with metastatic colorectal cancer (CRC), binds both VEGFA and VEGFAxxxb isoforms.Patients and MethodsFormalin-fixed, paraffin-embedded primary tumors from metastatic CRC patients treated with first-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) + bevacizumab (n = 285) or FOLFIRI only (n = 75) were collected. The relative expression of VEGFA121a, 121b, 145a, 145b, 165a, and 165b was assessed with custom TaqMan-MGB assays and quantitative PCR.ResultsAt a median follow-up of 101.5 months, left-sided primary CRC was a favorable prognosticator (median survival, 29.2 vs. 18.2 months; P = .015). Positive high VEGFA145b was an unfavorable factor for progression-free survival (PFS; hazard ratio [HR] = 1.66; 95% confidence interval [CI], 1.13-2.44; P = .009) in patients who received FOLFIRI + bevacizumab, without prognostic significance in FOLFIRI-only patients (HR = 0.70; 95% CI, 0.34-1.44; P = .33). The adverse effect on PFS of 145b was more pronounced in patients with right-sided colon cancer (HR = 2.62; 95% CI, 1.35-5.12; P = .005), especially in those who received bevacizumab (HR = 2.85; 95% CI, 1.31-6.21; P = .008). In patients with right-sided colon primary tumors, isoform 121b correlated with inferior PFS (HR = 1.73; 95% CI, 0.94-3.18; P = .076) and overall survival (OS; HR = 2.0; 95% CI, 1.08-3.72; P = .028). In patients with left-sided primary tumors, positive high 165b correlated with superior PFS (HR = 0.76; 95% CI, 0.59-0.99; P = .044) and OS (HR = 0.68; 95% CI, 0.52-0.90; P = .006). At multivariate analysis, right-sided primary tumor was associated with inferior PFS (HR = 1.28; 95% CI, 1.00-1.64), while 145b consistently retained predictive significance for lack of benefit in PFS with bevacizumab (HR = 1.71; 95% CI, 1.16-2.53). Multivariate analysis for OS showed that VEGFA165b expression was favorable in patients with left-sided but unfavorable in patients with right-sided primary tumors (P_interaction < .001).ConclusionThe antiangiogenic isoform VEGFA145b messenger RNA may predict resistance to bevacizumab. Differences in biological relevance and prognostic significance of various VEGFA isoforms were found for right- versus left-sided primary tumors.     

Outcomes of long-term nivolumab and subsequent chemotherapy in Japanese patients with head and neck cancer: 2-year follow-up from a multicenter real-world study

Background

We have previously reported the effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) in real-world clinical practice in Japan. Here, we report long-term outcomes from this study in the overall population and subgroups stratified by subsequent chemotherapy.

Methods

In this multicenter, retrospective observational study, Japanese patients with recurrent or metastatic (R/M) HNC receiving nivolumab were followed up for 2 years. Effectiveness endpoints included overall survival (OS), OS rate, progression-free survival (PFS), and PFS rate. Safety endpoints included the incidence of immune-related adverse events (irAEs).

Results

Overall, 256 patients received a median of 6.0 doses (range: 1–52) of nivolumab over a median duration of 72.5 days (range: 1–736). Median OS was 9.5 months [95% confidence interval (CI) 8.2–12.0] and median PFS was 2.1 months (95% CI 1.8–2.7). A significant difference between 2-year survivors (n = 62) and non-2-year survivors was observed by median age (P = 0.0227) and ECOG PS (P = 0.0001). Of 95 patients who received subsequent chemotherapy, 54.7% received paclitaxel ± cetuximab. The median OS and PFS from the start of paclitaxel ± cetuximab were 6.9 months (95% CI 5.9–11.9) and 3.5 months (95% CI 2.3–5.5), respectively. IrAEs were reported in 17.2% of patients. Endocrine (7.0%) and lung (4.3%) disorders were the most common irAEs; kidney disorder (n = 1) was newly identified in this follow-up analysis.

Conclusions

Results demonstrated the long-term effectiveness of nivolumab and potential effectiveness of subsequent chemotherapy in patients with R/M HNC in the real-world setting. Safety was consistent with that over the 1-year follow-up.