Tarun Puri

Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations

PURPOSEnTo determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations.nnnPATIENTS AND METHODSnChemotherapy-naïve for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2:1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m(2) on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-free-survival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65).nnnRESULTSnPFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P = .014; two-sided P = .029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+G, but toxicities were manageable.nnnCONCLUSIONnP+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation-positive patients new treatment options and improved clinical outcomes compared with the current standard of care.

First-Line Pemetrexed plus Cisplatin followed by Gefitinib Maintenance Therapy versus Gefitinib Monotherapy in East Asian Never-Smoker Patients with Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer: Final Overall Survival Results from a Randomized Phase 3 Study.

Introduction: The primary analysis of this open‐label, randomized, multicenter phase 3 study revealed no significant difference in progression‐free survival between pemetrexed plus cisplatin followed by maintenance gefitinib (PC/G) and gefitinib monotherapy (G) in patients with advanced nonsquamous non–small cell lung cancer (NSCLC) and unknown epidermal growth factor receptor gene (EGFR) mutation status; however, the hazard ratio favored PC/G. This report describes the final overall survival (OS) results. Methods: Chemonaive, East Asian light ex‐smokers/never‐smokers with advanced nonsquamous NSCLC and unknown EGFR mutation status were randomized (1:1) to PC/G (n = 118) or G (n = 118). EGFR mutation status was retrospectively determined for 76 patients, 52 (68.4%) of whom had EGFR‐mutated tumors (exon 19 deletions in 26 and L858R point mutation in 24). OS was analyzed by the Kaplan‐Meier method. The study was registered at ClinicalTrials.gov (NCT01017874). Results: Median OS was similar in the PC/G (26.9 months) and G (27.9 months) groups (hazard ratio = 0.94, 95% confidence interval: 0.68–1.31, p = 0.717). Median OS was longer with PC/G than with G in patients with EGFR wild‐type tumors (28.4 versus 8.9 months) and longer with G than with PC/G in patients with EGFR‐mutated tumors (45.7 versus 32.4 months), especially those with exon 19 deletions. Second‐line postdiscontinuation therapy was common and included chemotherapy (PC/G, 41 of 118 [34.7%]; G, 73 of 118 [61.9%]) and rechallenge with an EGFR tyrosine kinase inhibitor (PC/G, 27 of 118 [22.9%]; G, 9 of 118 [7.6%]). Conclusions: The progression‐free survival and OS results from this study further demonstrate the importance of determining EGFR mutation status to select the most appropriate first‐line treatment for patients with advanced NSCLC.

East Asian subgroup analysis of a randomized, double-blind, phase 3 study of docetaxel and ramucirumab versus docetaxel and placebo in the treatment of stage IV non-small cell lung cancer following disease progression after one prior platinum-based therapy (REVEL)

Purpose REVEL demonstrated improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) with docetaxel+ramucirumab versus docetaxel+placebo in 1,253 intent-to-treat (ITT) stage IV non-small cell lung cancer patients with disease progression following platinum-based chemotherapy. Results from the East Asian subgroup analysis are reported. Materials and Methods Subgroup analyses were performed in the East Asian ITT population (n=89). Kaplan-Meier analysis and Cox proportional hazards regression were performed for OS and PFS, and the Cochran-Mantel-Haenszel test was performed for response rate. Results In docetaxel+ramucirumab (n=43) versus docetaxel+placebo (n=46), median OS was 15.44 months versus 10.17 months (hazard ratio [HR], 0.762; 95% confidence interval [CI], 0.444 to 1.307), median PFS was 4.88 months versus 2.79 months (HR, 0.658; 95% CI, 0.408 to 1.060), and ORR was 25.6% (95% CI, 13.5 to 41.2) versus 8.7% (95% CI, 2.4 to 20.8). Due to increased incidence of neutropenia and febrile neutropenia in East Asian patients, starting dose of docetaxel was reduced for newly enrolled East Asian patients (75 to 60 mg/m2, n=24). In docetaxel+ramucirumab versus docetaxel+placebo, incidence of neutropenia was 84.4% versus 72.7% (75 mg/m2) and 54.5% versus 38.5% (60 mg/m2). Incidence of febrile neutropenia was 43.8% versus 12.1% (75 mg/m2) and 0% versus 7.7% (60 mg/m2). Conclusion Results of this subgroup analysis showed a trend favoring ramucirumab+docetaxel for median OS, PFS, and improved ORR in East Asian patients, consistent with ITT population results. Reduction of starting dose of docetaxel in East Asian patients was associated with improved safety.

A phase 2 study of sequential neoadjuvant chemotherapy with gemcitabine and doxorubicin followed by gemcitabine and cisplatin in patients with large or locally advanced operable breast cancer: results from long-term follow-up

BackgroundNeoadjuvant chemotherapy (NACT) is being increasingly used for patients with large-size operable breast cancer. This phase 2 study of sequential NACT with gemcitabine and doxorubicin (Gemxa0+xa0Dox) followed by gemcitabine and cisplatin (Gemxa0+xa0Cis) was conducted in women with large or locally advanced breast cancer. The objectives were to evaluate the pathological complete response (pCR) rate, toxicity, pathological and genetic markers predicting response, the proportion of patients undergoing breast conservation surgery, progression-free survival (PFS) and overall survival (OS) after 5xa0years, and time to treatment failure (TtTF). In this manuscript, we report the long-term OS, PFS, and TtTF results.MethodsFemale patients aged at least 18xa0years with large T2 (at least 3xa0cm) or locally advanced (T3, T4, or N2) breast carcinoma were included. Treatment consisted of 4 cycles of Gemxa0+xa0Dox (gemcitabine 1,200xa0mg/m2 on days 1 and 8 plus doxorubicin 60xa0mg/m2 on day 1 of each 21-day cycle), followed by 4 cycles of Gemxa0+xa0Cis (gemcitabine 1,000xa0mg/m2 on days 1 and 8 plus cisplatin 70xa0mg/m2 on day 1 of each 21-day cycle), and then surgery.ResultsSixty-five patients were enrolled. The pCR rate was 20%. The 5-year OS probability was 71% (95% CI 56–82%), and the 4-year PFS and TtTF probabilities were 63% (95% CI 48–74%) and 45% (95% CI 32–57%), respectively.ConclusionsNACT with Gemxa0+xa0Dox followed by Gemxa0+xa0Cis was efficacious in patients with operable breast cancer.

First-Line Pemetrexed Plus Cisplatin Followed by Gefitinib Maintenance Therapy Versus Gefitinib Monotherapy in East Asian Never-Smoker Patients With Locally Advanced or Metastatic Nonsquamous Non–Small-cell Lung Cancer: Quality of Life Results From a Randomized Phase III Trial

BACKGROUNDnThe efficacy results from an open-label, randomized, multicenter study found no significant difference in progression-free survival between pemetrexed plus cisplatin followed by maintenance gefitinib (PC/G) and gefitinib monotherapy (G) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) and unknown epidermal growth factor receptor (EGFR) mutation status (hazard ratio favored PC/G). The present report describes the quality of life (QoL) results from that trial.nnnPATIENTS AND METHODSnChemotherapy-naive, East Asian, light ex-smokers or never-smokers with advanced nonsquamous NSCLC and unknown EGFR mutation status (n = 236) were randomly assigned (1:1) to PC/G or G. EGFR mutation status was subsequently determined for 74 patients. The symptoms and QoL were assessed using the Lung Cancer Symptom Scale (LCSS). The time to worsening of symptoms (TWS) was analyzed using the Kaplan-Meier method.nnnRESULTSnIn the overall population, the TWS was generally longer in the G group (n = 109) than in the PC/G group (n = 109) for the LCSS symptoms classified as treatment-related (loss of appetite, fatigue) and tumor-related (cough, dyspnea, hemoptysis, pain). In the subgroup of patients with wild-type EGFR, the TWS was generally longer in the PC/G group (n = 13) than in the G group (n = 8) for the tumor-related LCSS symptoms.nnnCONCLUSIONnIn this study population clinically selected to respond to gefitinib, the LCSS scores were more favorable in the G group than in the PC/G group. Patients with wild-type EGFR tended to show greater improvement in tumor-related LCSS symptoms with chemotherapy than with gefitinib alone. These LCSS outcomes provide further evidence that patients with wild-type EGFR might not benefit from first-line treatment of advanced NSCLC with gefitinib.

A Review of Regimens Combining Pemetrexed With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in the Treatment of Advanced Nonsquamous Non–Small-Cell Lung Cancer

Abstract Pemetrexed is a standard first‐line treatment for advanced nonsquamous non–small‐cell lung cancer (NSCLC), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard first‐line treatment for advanced nonsquamous NSCLC with activating EGFR mutations. Pemetrexed and EGFR TKIs have different mechanisms of action and minimally overlapping toxicity profiles; therefore, it is hypothesized that their combination might result in acceptable toxicity, provided that the synergistic antitumor activity observed in preclinical studies is achieved. This review summarizes clinical trials of pemetrexed in combination with an EGFR TKI for the treatment of advanced nonsquamous NSCLC in the first‐ and second‐line settings, using intercalated, sequential, and concurrent treatment strategies. As would be expected, such strategies were most efficacious in patients with the activating EGFR mutations associated with response to an EGFR TKI. In the studies that compared a pemetrexed‐EGFR TKI combination with pemetrexed alone or the EGFR TKI alone, the pemetrexed‐EGFR TKI combination was more efficacious than the single‐agent regimens. The pemetrexed‐EGFR TKI combinations were generally associated with a higher incidence of grade 3/4 treatment‐related adverse events than the single‐agent regimens; however, such toxicities were clinically manageable. Future studies of pemetrexed‐EGFR TKI combinations should focus on optimizing treatment strategies in patients with activating EGFR mutations.

Efficacy and Safety of First-Line Necitumumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin In East Asian Patients with Stage IV Squamous Non-Small Cell Lung Cancer: A Subgroup Analysis of the Phase 3, Open-Label, Randomized SQUIRE Study.

Purpose The phase 3 randomized SQUIRE study revealed significantly longer overall survival (OS) and progression-free survival (PFS) for necitumumab plus gemcitabine and cisplatin (neci+GC) than for gemcitabine and cisplatin alone (GC) in 1,093 patients with previously untreated advanced squamous non-small cell lung cancer (NSCLC). This post hoc subgroup analysis assessed the efficacy and safety of neci+GC among East Asian (EA) patients enrolled in the study. Materials and Methods All patients received up to six 3-week cycles of gemcitabine (days 1 and 8, 1,250 mg/m²) and cisplatin (day 1, 75 mg/m²). Patients in the neci+GC arm also received necitumumab (days 1 and 8, 800 mg) until disease progression or unacceptable toxicity. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from stratified Cox proportional hazards models. Results In EA patients, there were improvements for neci+GC (n=43) versus GC (n=41) in OS (HR, 0.805; 95% CI, 0.484 to 1.341) and PFS (HR, 0.720; 95% CI, 0.439 to 1.180), consistent with the results for non-EA patients observed in the present study. The overall safety data were consistent between EA and non-EA patients. A numerically higher proportion of patients experienced serious adverse events (AEs), grade ≥ 3 AEs, and AEs with an outcome of death for neci+GC versus GC in EA patients and EA patients versus non-EA patients for neci+GC. Conclusion Although limited by the small sample size and post hoc nature of the analysis, these findings are consistent with those of the overall study and suggest that neci+GC offers a survival advantage and favorable benefit/risk for EA patients with advanced squamous NSCLC.

An East Asian subgroup analysis of PROCLAIM, a phase III trial of pemetrexed and cisplatin or etoposide and cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small cell lung cancer.

PROCLAIM, a phase III trial of patients with nonsquamous non–small cell lung cancer comparing concurrent pemetrexed‐cisplatin and thoracic radiation therapy followed by consolidation pemetrexed, did not meet its primary endpoint of superior overall survival versus etoposide‐cisplatin and thoracic radiation therapy followed by a consolidation platinum doublet of choice. The results from an East Asian subgroup analysis are presented here.

Cost effectiveness of concurrent gemcitabine and cisplatin and radiation followed by adjuvant gemcitabine and cisplatin in stages IIB–IVA cervical cancer

To the Editor, n nWe read with interest the two articles published in Gynecologic Oncology on the cost-effectiveness of gemcitabine with cisplatin chemoradiation in locally advanced cervical cancer (LACC) (Phippen et al., 2012, Smith et al., 2013). These two articles are useful additions, from a health economics perspective, to the evidence for the appropriate care of patients with LACC. The two articles reported cost-effectiveness analyses based on data from the same large, randomized, multinational Phase III study reported by Duenas-Gonzalez et al. (Duenas-Gonzalez et al., 2011), but came to different conclusions, raising the question of which conclusion is more appropriate. Our concern is that these different conclusions may confuse readers regarding the health economics associated with the improved outcomes of this regimen for LACC. The clinical data from the study are compelling in terms of statistically significant improvements in progression-free survival (PFS) and overall survival (OS) with acceptable toxicity. We hope that clarifying some of the major differences in the approaches taken in these two cost-effectiveness analyses will help readers make the appropriate access recommendation for their situation or critically evaluate a local access decision. n nThe Duenas-Gonzalez study compared concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin (arm A; nxa0=xa0259) with concurrent cisplatin and radiation (arm B; nxa0=xa0256) in patients with LACC (stages IIB to IVA) (Duenas-Gonzalez et al., 2011). In this study, PFS at 3xa0years (primary objective) was significantly improved in arm A vs arm B (74.4% vs 65.0%; pxa0=xa00.029), as were overall PFS (log-rank pxa0=xa00.0227; hazard ratio [HR], 0.68; 95% CI, 0.49–0.95) and OS (log-rank pxa0=xa00.0224; HR, 0.68; 95% CI, 0.49–0.95) (Duenas-Gonzalez et al., 2011). Grade 3 and 4 toxicities were more frequent in arm A vs arm B (86.5% vs 46.3%; pxa0<xa00.001). n nPhippen et al. (2012) used a modified Markov model to compare the cost-effectiveness of the two regimens based on the studys published 5-year OS and treatment-related toxicity rates, and reported that the gemcitabine regimen was a cost-effective treatment for LACC compared with standard cisplatin chemoradiation. The mean cost was US

1381PDGefitinib with or without pemetrexed in nonsquamous (NS) non-small cell lung cancer (NSCLC) with EGFR mutation (mut): Final overall survival (OS) results from a randomized phase II study

60,974 for the gemcitabine regimen and US