CNS Protective Effect of Selpercatinib in First-Line RET Fusion-Positive Advanced Non-Small Cell Lung Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Although the CNS activity of selpercatinib in patients with RET fusion-positive non-small cell lung cancer (NSCLC) has been previously described, the ability of potent RET inhibition to prevent new CNS metastases from developing has been challenging to measure without randomized data. Serial CNS scans were studied from LIBRETTO-431, a randomized phase III trial of selpercatinib versus platinum/pemetrexed ± pembrolizumab whose primary results have been previously disclosed. Intracranial outcomes were assessed by neuroradiologic blinded independent central review in patients with baseline and ≥1 postbaseline CNS scans. Of the 192 patients within the intention-to-treat pembrolizumab population with baseline CNS scans, 150 patients were without baseline CNS metastases. The cumulative incidence of CNS progression in these patients was reduced with selpercatinib versus chemotherapy + pembrolizumab (cause-specific hazard ratio [HR], 0.17 [95% CI, 0.04 to 0.69]). The HR for intracranial progression-free survival (PFS) was 0.46 (95% CI, 0.18 to 1.18). Among the 42 patients with baseline CNS metastases, similar trends were observed in the cumulative incidence of CNS progression (cause-specific HR, 0.61 [95% CI, 0.19 to 1.92]) and intracranial PFS (HR, 0.74 [95% CI, 0.28 to 1.97]). These data demonstrate that selpercatinib effectively treats existing CNS disease and prevents or delays the formation of new CNS metastases. These results reinforce the importance of identifying RET fusions in first-line patients with NSCLC and treating with selpercatinib.

First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC.

BACKGROUND: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study. METHODS: In a randomized phase 3 trial, we evaluated the efficacy and safety of first-line selpercatinib as compared with control treatment that consisted of platinum-based chemotherapy with or without pembrolizumab at the investigator's discretion. The primary end point was progression-free survival assessed by blinded independent central review in both the intention-to-treat-pembrolizumab population (i.e., patients whose physicians had planned to treat them with pembrolizumab in the event that they were assigned to the control group) and the overall intention-to-treat population. Crossover from the control group to the selpercatinib group was allowed if disease progression as assessed by blinded independent central review occurred during receipt of control treatment. RESULTS: In total, 212 patients underwent randomization in the intention-to-treat-pembrolizumab population. At the time of the preplanned interim efficacy analysis, median progression-free survival was 24.8 months (95% confidence interval [CI], 16.9 to not estimable) with selpercatinib and 11.2 months (95% CI, 8.8 to 16.8) with control treatment (hazard ratio for progression or death, 0.46; 95% CI, 0.31 to 0.70; P<0.001). The percentage of patients with an objective response was 84% (95% CI, 76 to 90) with selpercatinib and 65% (95% CI, 54 to 75) with control treatment. The cause-specific hazard ratio for the time to progression affecting the central nervous system was 0.28 (95% CI, 0.12 to 0.68). Efficacy results in the overall intention-to-treat population (261 patients) were similar to those in the intention-to-treat-pembrolizumab population. The adverse events that occurred with selpercatinib and control treatment were consistent with those previously reported. CONCLUSIONS: Treatment with selpercatinib led to significantly longer progression-free survival than platinum-based chemotherapy with or without pembrolizumab among patients with advanced RET fusion-positive NSCLC. (Funded by Eli Lilly and others; ClinicalTrials.gov number, NCT04194944.).

Clinical outcomes of ramucirumab plus docetaxel in the treatment of patients with non-small cell lung cancer after immunotherapy: a systematic literature review.

Introduction: In the REVEL trial, ramucirumab plus docetaxel demonstrated significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) compared with placebo plus docetaxel for treatment of metastatic non-small cell lung cancer (NSCLC) that progressed during or after platinum-based chemotherapy. Since the approval of ramucirumab plus docetaxel, immune checkpoint inhibitors (ICIs), either as single agents or in combination with chemotherapy, have become the standard of care for first-line treatment of patients with advanced NSCLC. However, efficacy and safety data for ramucirumab plus docetaxel after prior ICI treatment from randomized controlled clinical studies are lacking. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic literature review was performed. Electronic databases and select international oncology conference proceedings were searched. Studies published between 01 January 2014 and 01 July 2022, which evaluated 2 efficacy outcomes (and included at least 1 time-to-event endpoint) or safety outcomes of ramucirumab plus docetaxel in NSCLC that progressed after prior ICI treatment, were identified. Twelve studies were included in the analysis. Two treatment groups were selected: ramucirumab plus docetaxel after prior ICI ± chemotherapy (RAM + DTX ICI pre-treated) and ramucirumab plus docetaxel after prior chemotherapy only (RAM + DTX ICI naïve). OS, PFS, ORR, disease control rate (DCR), and safety data were extracted and descriptively summarized across both treatment groups. Results: The pooled weighted median PFS and median OS were 5.7 months (95% confidence interval [CI]: 3.9-6.8) and 11.2 months (95% CI: 7.5-17.5), respectively, in the RAM + DTX ICI pre-treated group and 3.8 months (95% CI: 2.3-4.1) and 13.5 months (95% CI: 8-24.0), respectively, in the RAM + DTX ICI naïve group. The ORR and DCR ranged from 20.9% to 60.0% and from 62.4% to 90.0%, respectively, in the RAM + DTX ICI pre-treated group and from 17.7% to 20.0% and from 57.1% to 75.0%, respectively, in the RAM + DTX ICI naïve group. The safety profile across studies was consistent between both treatment groups, and no new safety signals were reported. Conclusions: Cumulatively, these results support the combination of ramucirumab plus docetaxel as an effective and safe subsequent therapy for the treatment of patients with metastatic NSCLC with disease progression irrespective of previous ICI treatment.

Efficacy and Tolerability of Ramucirumab Plus Erlotinib in Taiwanese Patients with Untreated, Epidermal Growth Factor Receptor-Mutated, Stage IV Non-small Cell Lung Cancer in the RELAY Study.

BACKGROUND: In RELAY, a randomized, double-blind, phase III trial investigating the efficacy and safety of ramucirumab+erlotinib (RAM+ERL) or ERL+placebo (PBO) in patients with untreated, stage IV, epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), RAM+ERL demonstrated superior progression-free survival (PFS) versus PBO+ERL, with no new safety signals. OBJECTIVE: The aim of this paper was to report efficacy and tolerability findings for the Taiwanese participants of RELAY. PATIENTS AND METHODS: Patients were randomized 1:1 to RAM+ERL or ERL+PBO. Primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate (ORR), duration of response (DoR) and tolerability. Data for the current analysis are reported descriptively. RESULTS: In RELAY, 56 Taiwanese patients were enrolled; 26 received RAM+ERL, 30 received ERL+PBO. The demographic profile of the Taiwanese subgroup was consistent with that of the overall RELAY population. Median PFS for RAM+ERL/ERL+PBO, respectively, was 22.05 months/13.40 months (unstratified hazard ratio 0.4; 95% confidence interval 0.2-0.9); ORR was 92%/60%; median DoR was 18.2 months/12.7 months. All patients experienced one or more treatment-emergent adverse events (TEAEs); those most commonly reported were diarrhea and dermatitis acneiform (58% each) for RAM+ERL and diarrhea (70%) and paronychia (63%) for PBO+ERL. Grade ≥  3 TEAEs were experienced by 62%/30% of RAM+ERL/PBO+ERL patients, respectively, and included dermatitis acneiform (19%/7%), hypertension (12%/7%), and pneumonia (12%/0%). CONCLUSIONS: PFS for the Taiwanese participants of RELAY receiving RAM+ERL versus ERL+PBO was consistent with that in the overall RELAY population. These results, together with no new safety signals and a manageable safety profile, may support first-line use of RAM+ERL in Taiwanese patients with untreated EGFR-mutant stage IV NSCLC. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02411448.

Patient Characteristics, Testing and Treatment Patterns, and Outcomes in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multinational, Real-World Study.

INTRODUCTION: Treatment landscape for advanced/metastatic NSCLC (aNSCLC) has evolved considerably over the past few decades with the advent of targeted therapies for epidermal growth factor receptor-mutated (EGFRm+) aNSCLC treatment. This study described real-world patient and disease characteristics, treatment and practice patterns, and clinical, economic, and patient-reported outcomes (PROs) in patients with EGFRm+ aNSCLC. METHODS: Data were derived from the Adelphi NSCLC Disease Specific Programme™ (DSP™), a point-in-time survey conducted between July and December 2020. The survey included oncologists and pulmonologists, and their consulting patients (with physician-confirmed EGFRm+ aNSCLC) from nine countries: the US, Brazil, the UK, Italy, France, Spain, Germany, Japan, and Taiwan. All analyses were descriptive. RESULTS: Overall, 542 physicians reported data for 2857 patients (mean age 65.6 years), and most patients were female (56.0%), white (61.0%), and had stage IV disease at initial diagnosis (76.0%), and adenocarcinoma histology (89.0%). Most patients received EGFR-tyrosine kinase inhibitors (TKI) therapy in first- (91.0%), second- (74.0%), and third-line (67.0%). The most common tumor samples and methods for EGFR detection were EGFR-specific mutation detection tests (44.0%) and core needle biopsy (56.0%). Median time to next treatment was 14.0 (IQR 8.0-22.0) months and disease progression was the main physician-reported reason for early discontinuation. The most common physician-reported disease symptoms were cough (51.0%), fatigue (37.0%), and dyspnea (33.0%). In patients assessed for PROs, mean EQ-5D-5L index and FACT-L health utility scores were 0.71 and 83.5, respectively. On average, patients lost 10.6 h of work/week for approximately 29.2 weeks due to EGFRm+ aNSCLC. CONCLUSION: This real-world multinational data set showed that most patients with EGFRm+ aNSCLC were treated per the country relevant clinical guidelines, with progression as the main reason for early treatment discontinuation. For the included countries, these findings may offer a useful benchmark for decision makers to determine future allocation of healthcare resources for patients with EGFRm+ aNSCLC.

Current perspectives on the management of patients with advanced RET-driven thyroid cancer in Europe.

The incidence of thyroid cancer is increasing worldwide with the disease burden in Europe second only to that in Asia. In the last several decades, molecular pathways central to the pathogenesis of thyroid cancer have revealed a spectrum of targetable kinases/kinase receptors and oncogenic drivers characteristic of each histologic subtype, such as differentiated thyroid cancer, including papillary, follicular, and medullary thyroid cancer. Oncogenic alterations identified include B-Raf proto-oncogene (BRAF) fusions and mutations, neurotrophic tyrosine receptor kinase (NTRK) gene fusions, and rearranged during transfection (RET) receptor tyrosine kinase fusion and mutations. Multikinase inhibitors (MKIs) targeting RET in addition to multiple other kinases, such as sorafenib, lenvatinib and cabozantinib, have shown favourable activity in advanced radioiodine-refractory differentiated thyroid cancer or RET-altered medullary thyroid cancer; however, the clinical utility of MKI RET inhibition is limited by off-target toxicity resulting in high rates of dose reduction and drug discontinuation. Newer and selective RET inhibitors, selpercatinib and pralsetinib, have demonstrated potent efficacy and favourable toxicity profiles in clinical trials in the treatment of RET-driven advanced thyroid cancer and are now a therapeutic option in some clinical settings. Importantly, the optimal benefits of available specific targeted treatments for advanced RET-driven thyroid cancer require genetic testing. Prior to the initiation of systemic therapy, and in treatment-naïve patients, RET inhibitors may be offered as first-line therapy if a RET alteration is found, supported by a multidisciplinary team approach.

RET Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape.

The objective of this narrative review is to summarize the efficacy and safety of available therapies for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), including in patients with central nervous system (CNS) metastases. Background information is provided on RET rearrangements in NSCLC and the molecular testing options available as well as an overview of clinical guidelines for molecular testing, which recommend broad molecular testing, including for RET rearrangements. The efficacy and safety of potential treatments for RET fusion-positive NSCLC, including multikinase inhibitors, RET-selective inhibitors, pemetrexed-based therapy, and immunotherapies are reviewed from Phase I/II and `real-world' studies, alongside an overview of primary and secondary resistance mechanisms. The RET-selective inhibitors, selpercatinib and pralsetinib, are preferred first-line therapy options for patients with RET fusion-positive metastatic NSCLC and are recommended as subsequent therapy if RET inhibitors have not been used in the first-line setting.

Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial.

PURPOSE: Selpercatinib, a first-in-class, highly selective, and potent CNS-active RET kinase inhibitor, is currently approved for the treatment of patients with RET fusion-positive non-small-cell lung cancer (NSCLC). We provide a registrational data set update in more than double (n = 316) of the original reported population (n = 144) and better characterization of long-term efficacy and safety. METHODS: Patients were enrolled to LIBRETTO-001, a phase I/II, single-arm, open-label study of selpercatinib in patients with RET-altered cancers. An analysis of patients with RET fusion-positive NSCLC, including 69 treatment-naive and 247 with prior platinum-based chemotherapy, was performed. The primary end point was objective response rate (ORR; RECIST v1.1, independent review committee). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival, and safety. RESULTS: In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92); 6% achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0 to could not be evaluated); 40% of responses were ongoing at the data cutoff (median follow-up of 20.3 months). The median PFS was 22.0 months; 35% of patients were alive and progression-free at the data cutoff (median follow-up of 21.9 months). In platinum-based chemotherapy pretreated patients, the ORR was 61% (95% CI, 55 to 67); 7% achieved CRs. The median DoR was 28.6 months (95% CI, 20.4 to could not be evaluated); 49% of responses were ongoing (median follow-up of 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and progression-free (median follow-up of 24.7 months). Of 26 patients with measurable baseline CNS metastasis by the independent review committee, the intracranial ORR was 85% (95% CI, 65 to 96); 27% were CRs. In the full safety population (n = 796), the median treatment duration was 36.1 months. The safety profile of selpercatinib was consistent with previous reports. CONCLUSION: In a large cohort with extended follow-up, selpercatinib continued to demonstrate durable and robust responses, including intracranial activity, in previously treated and treatment-naive patients with RET fusion-positive NSCLC.

Efficacy and safety of first-line therapies in EGFR-mutated advanced non-small-cell lung cancer: a network meta-analysis.

Aim: To evaluate the comparative efficacy and safety of identified first-line therapies for patients with EGFR mutation-positive (EGFRm+) advanced non-small-cell lung cancer (NSCLC), with a focus on ramucirumab + erlotinib. Methods: In the absence of head-to-head studies, a Bayesian network meta-analysis was conducted using randomized clinical trial data to evaluate first-line systemic therapies with erlotinib/gefitinib as the reference treatment. Results: For progression-free survival, ramucirumab + erlotinib was comparable to osimertinib and dacomitinib in the primary analysis. Conclusion: The analysis showed ramucirumab + erlotinib efficacy to be comparable to best-in-class treatment options for previously untreated patients with EGFRm+ advanced NSCLC. Registration information: PROSPERO ID: CRD42020136247.

Overall Treatment Strategy for Patients With Metastatic NSCLC With Activating EGFR Mutations.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR-activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21_L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G, and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed.

A Randomized Phase 2 Study of Gefitinib With or Without Pemetrexed as First-line Treatment in Nonsquamous NSCLC With EGFR Mutation: Final Overall Survival and Biomarker Analysis.

INTRODUCTION: Clinical studies have shown that a combination of a tyrosine kinase inhibitor (TKI) and pemetrexed overcame acquired resistance to epidermal growth factor receptor (EGFR) TKI in NSCLC. Previously, pemetrexed+gefintib (P+G) had improved progression-free survival (PFS) compared with gefitinib. We present OS, updated PFS, biomarker analysis, and safety of P+G versus gefitinib. METHODS: This was a phase 2, multicenter, randomized study conducted in East Asian patients with advanced nonsquamous NSCLC with EGFR mutations. Patients were randomized (2:1) to receive P+G (500 mg/m2 intravenously 3-weekly + 250 mg/day orally) or gefitinib. RESULTS: In total, 191 patients (P+G, n=126; gefitinib, n=65) comprised the intent-to-treat and safety populations. Median OS was 43.4 months in P+G versus 36.8 months in gefitinib arm; adjusted HR 0.77 (95% CI, 0.5-1.2); one-sided P=0.105. Median PFS was significantly longer in the P+G (16.2 months) versus gefitinib arm (11.1 months); adjusted HR 0.67 (95% CI, 0.5-0.9); one-sided P=0.009. In the P+G and gefitinib arms, median PFS was 22.6 and 11.0 months, respectively, in patients with low thymidylate synthase (TS) expression, and 12.6 and 9.9 months, respectively, in patients with high TS expression. Common second-line post-discontinuation systemic therapies were EGFR-TKIs and chemotherapy. Most patients experienced at least one adverse event. CONCLUSIONS: Addition of pemetrexed to EGFR TKI gefitinib resulted in significantly improved PFS and numerically longer OS compared with gefitinib in treatment-naïve patients with EGFR-mutated advanced nonsquamous NSCLC. Low TS expression appeared to be a good predictor for treatment outcomes.

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.

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.

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.

PURPOSE: To 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. PATIENTS AND METHODS: Chemotherapy-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). RESULTS: PFS 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. CONCLUSION: P+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.

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.

AIM: 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. METHODS: A subgroup analysis was performed for all patients randomized from China (n = 61), Taiwan (n = 25), and Korea (n = 11). RESULTS: Baseline characteristics were balanced between treatment arms for East Asian patients. In the 97 randomized East Asian patients, median overall survival was 26.8 months for the pemetrexed-cisplatin arm and 36.3 months for the etoposide-cisplatin arm (hazard ratio: 1.23; 95% confidence interval: 0.70-2.14; P = 0.469). Median progression-free survival was 10.0 months for the pemetrexed-cisplatin arm and 7.6 months for the etoposide-cisplatin arm (hazard ratio: 0.97; 95% confidence interval: 0.61-1.54; P = 0.890). The objective response rate was 47.7% in the pemetrexed-cisplatin arm and 34.0% in the etoposide-cisplatin arm (P = 0.167). In the 90 treated East Asian patients, the overall incidence of drug-related grade 3-4 treatment-emergent adverse events was significantly lower in the pemetrexed-cisplatin arm versus the etoposide-cisplatin arm (61.4% vs 91.3%; P = 0.001). CONCLUSION: For East Asian patients, pemetrexed-cisplatin combined with thoracic radiation therapy, followed by consolidation pemetrexed, did not improve overall survival but did have a good safety profile with a trend for improved progression-free survival and objective response rate compared to standard chemoradiotherapy for stage III unresectable nonsquamous non-small cell lung cancer.

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.

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.

BACKGROUND: The 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. PATIENTS AND METHODS: Chemotherapy-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. RESULTS: In 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. CONCLUSION: In 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.

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.

Outcomes of pediatric glioblastoma treated with adjuvant chemoradiation with temozolomide and correlation with prognostic factors.

BACKGROUND: Pediatric glioblastoma (pGBM) patients are underrepresented in major trials for this disease. We aimed to explore the outcome of pGBM patients treated with concurrent and adjuvant temozolomide (TMZ). MATERIALS AND METHODS: 23 patients of pGBM treated from 2004 to 2010 were included in this retrospective analysis. Adjuvant therapy included conformal radiation 60 gray at 2 gray/fraction daily over 6 weeks with concurrent TMZ 75 mg/m(2) followed by six cycles of adjuvant TMZ 150-200 mg/m(2) (day 1-5) every 4 weeks. Kaplan-Meier estimates of overall survival (OS) were determined. Univariate analysis with log-rank test was used to determine the impact of prognostic variables on survival. RESULTS: Median age at presentation was 11.5 years (range: 7-19 years) and M:F ratio was 15:8. All patients underwent maximal safe surgical resection; 13 gross total resection and 10 sub-total resection. At a median follow-up of 18 months (range: 2.1-126 months), the estimated median OS was 41.9 months. The estimated median OS for patients receiving only concurrent TMZ was 8 months while that for patients receiving concurrent and adjuvant TMZ was 41.9 months (P = 0.081). Estimated median OS for patients who did not complete six cycles of adjuvant TMZ was 9.5 months versus not reached for those who completed at least six cycles (P = 0.0005). Other prognostic factors did not correlate with survival. CONCLUSIONS: Our study shows the benefit of TMZ for pGBM patients. Both concurrent and adjuvant TMZ seem to be important for superior OS in this group of patients.