Teng Jin Ong

Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Gemcitabine/Cisplatin Alone or With Sorafenib for the First-Line Treatment of Advanced, Nonsquamous Non-Small-Cell Lung Cancer

PURPOSE This trial evaluated the efficacy and safety of sorafenib plus gemcitabine/cisplatin in chemotherapy-naive patients with unresectable stage IIIB to IV nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Between February 2007 and March 2009, 904 patients were randomly assigned to daily sorafenib (400 mg twice a day) or matching placebo plus gemcitabine (1,250 mg/m(2) per day on days 1 and 8) and cisplatin (75 mg/m(2) on day 1) for up to six 21-day cycles. Because of safety findings from the Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC (ESCAPE) trial, patients with squamous cell histology were withdrawn from the trial in February 2008 and excluded from analysis. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS) and time-to-progression (TTP). RESULTS The primary analysis population consisted of 772 patients (sorafenib, 385; placebo, 387); the two groups had similar demographic and baseline characteristics. Median OS was similar in the sorafenib and placebo groups (12.4 v 12.5 months; hazard ratio [HR], 0.98; P = .401). By investigator assessment, sorafenib improved median PFS (6.0 v 5.5 months; HR, 0.83; P = .008) and TTP (6.1 v 5.5 months; HR, 0.73; P < .001). Grade 3 to 4 drug-related adverse events more than two-fold higher in the sorafenib group included hand-foot skin reaction (8.6% v 0.3%), fatigue (7.3% v 3.6%), rash (5.7% v 0.5%), and hypertension (4.2% v 1.8%). No unexpected toxicities were observed. CONCLUSION This study did not meet its primary end point of improved OS when sorafenib was added to first-line gemcitabine/cisplatin in patients with advanced nonsquamous NSCLC. Identification of predictive biomarkers is warranted in future trials of sorafenib.

Monotherapy Administration of Sorafenib in Patients with Non-Small Cell Lung Cancer (MISSION) Trial: A Phase III, Multicenter, Placebo-Controlled Trial of Sorafenib in Patients with Relapsed or Refractory Predominantly Nonsquamous Non-Small-Cell Lung Cancer after 2 or 3 Previous Treatment Regimens

INTRODUCTION Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC). METHODS The phase III, multinational, double-blind, placebo-controlled MISSION trial randomized patients with advanced relapsed/refractory NSCLC, following 2 or 3 prior treatment regimens, to sorafenib 400 mg bid (n=353) or matching placebo (n=353) plus best supportive care. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and time-to-progression (TTP). EGFR and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening. RESULTS Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 months; hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.84-1.17, p=0.47). Median PFS (2.8 versus 1.4 mo; HR 0.61; 95% CI 0.51-0.72, p<0.0001) and TTP (2.9 versus 1.4 months; HR 0.54; 95% CI 0.45-0.65, p<0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with EGFR mutations, OS (13.9 versus 6.5 months; HR 0.48; 95% CI 0.30-0.76, p=0.002) and PFS (2.7 versus 1.4 months; HR 0.27; 95% CI 0.16-0.46, p<0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea and fatigue, consistent with the safety profile of sorafenib. CONCLUSIONS Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.Introduction: Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non–small-cell lung cancer (NSCLC). Methods: The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn–small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening. Results: Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84–1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51–0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45–0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30–0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16–0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib. Conclusions: Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.

Survival, quality-adjusted survival, and other clinical end points in older advanced non-small-cell lung cancer patients treated with albumin-bound paclitaxel

Background:This analysis compared the quality-adjusted survival and clinical outcomes of albumin-bound paclitaxel+carboplatin (nab-PC) vs solvent-based paclitaxel+carboplatin (sb-PC) as first-line therapy in advanced non-small-cell lung cancer (NSCLC) in older patients.Methods:Using age-based subgroup data from a randomised Phase-3 clinical trial, nab-PC and sb-PC were compared with respect to overall response rate (ORR), overall survival (OS), progression-free survival (PFS), quality of life (QoL), safety/toxicity, and quality-adjusted time without symptoms or toxicity (Q-TWiST) with ages ⩾60 and ⩾70 years as cut points.Results:Among patients aged ⩾60 years (N=546), nab-PC (N=265) significantly increased ORR and prolonged OS, despite a non-significant improvement in PFS, vs sb-PC (N=281). Nab-PC improved QoL and was associated with less neuropathy, arthralgia, and myalgia but resulted in more anaemia and thrombocytopenia. Nab-PC yielded significant Q-TWiST benefits (11.1 vs 9.8 months; 95% CI of gain: 0.2–2.6), with a relative Q-TWiST gain of 10.8% (ranging from 6.4% to 15.1% in threshold analysis). In the ⩾70 years age group, nab-PC showed similar, but non-significant, ORR, PFS, and Q-TWiST benefits and significantly improved OS and QoL.Conclusion:Nab-PC as first-line therapy in older patients with advanced NSCLC increased ORR, OS, and QoL and resulted in quality-adjusted survival gains compared with standard sb-PC.

Quality of life (QoL) by response: An interim analysis of patients (pts) with squamous (SCC) NSCLC treated with nab-paclitaxel/carboplatin (nab-P/C) induction therapy in the phase III ABOUND.sqm study.

63 Background: The correlation of radiological response and pt-reported outcomes (PROs) in advanced NSCLC remains underreported. This interim analysis evaluated QoL by response (RECIST v1.1) in SCC NSCLC pts treated with nab-P/C during the induction part of the ABOUND.sqm study. METHODS In the ongoing phase III ABOUND.sqm study, pts with advanced SCC NSCLC are treated with first-line nab-P 100 mg/m2 d 1, 8, 15 and C AUC 6 mg•min/mL d 1 (21-d cycles) for 4 cycles (induction). Pts not progressing are randomized 2:1 to maintenance nab-P 100 mg/m2d 1 and 8 of each 21-d cycle + best supportive care (BSC) or BSC alone until progression. The primary endpoint is PFS from randomization to maintenance. QoL, an exploratory endpoint, was assessed with predefined PRO instruments, LCSS and EQ-5D-5L, on d 1 of each cycle. Pts with a radiological CR/ PR are considered responders (R) in this analysis (57% of evaluable pts). As the study is ongoing, this pre-planned analysis included QoL and tumor response data that were reported up to the cutoff date. RESULTS Baseline (BL) characteristics were similar for Rs (n = 73) and non-Rs (n = 55). Over 80% of pts completed BL + ≥ 1 post-BL PRO assessments. For LCSS, average total score and symptom burden index improved during induction chemotherapy; a higher percentage of Rs vs non-Rs had clinically meaningful improvements (≥ 10 mm [VAS]) from BL in composite LCSS cough, shortness of breath, & hemoptysis (56% vs 38%). Of pts reporting BL EQ-5D-5L dimension problem(s), a higher percentage of Rs vs non-Rs reported complete resolution at least once during treatment (Table). CONCLUSIONS These results indicate that Rs and non-Rs maintained/improved QoL during induction therapy with nab-P/C. Rs appeared to have greater improvements in LCSS and EQ-5D-5L. Radiological response translates into meaningful QoL improvement. CLINICAL TRIAL INFORMATION NCT02027428. [Table: see text].

nab-Paclitaxel–Based Therapy in Underserved Patient Populations: The ABOUND.PS2 Study in Patients With NSCLC and a Performance Status of 2

Introduction The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified nab-paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. Methods Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of nab-paclitaxel 100 mg/m2 days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction). Patients without progression received nab-paclitaxel monotherapy (100 mg/m2 days 1 and 8 q3w) until progression/unacceptable toxicity. Primary endpoint: percentage of patients discontinuing induction due to treatment-emergent adverse events (TEAEs). Results 11/40 treated patients (27.5%; 95% CI, 14.60–43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued nab-paclitaxel monotherapy. Median progression-free and overall survival were 4.4 (95% CI, 2.99–7.00) and 7.7 (95% CI, 4.93–13.17) months. Grade 3/4 TEAEs during induction included neutropenia (22.5%), anemia (17.5%), thrombocytopenia (5.0%), and peripheral neuropathy (2.5%). Conclusion This nab-paclitaxel–based regimen was tolerable in patients with advanced NSCLC and ECOG PS 2, with efficacy comparable to historical chemotherapy data.

nab-Paclitaxel/carboplatin in elderly patients with advanced squamous non-small cell lung cancer: a retrospective analysis of a Phase III trial

Background Limited data on elderly patients with squamous advanced non-small cell lung cancer (NSCLC) preclude optimal treatment. Here, we report the outcomes of a retrospective analysis of a subset of patients ≥70 years with squamous histology from the Phase III trial that evaluated nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. Patients and methods Patients with stage IIIB/IV NSCLC received (1:1) nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 or paclitaxel 200 mg/m2 on day 1, both with carboplatin area under the curve 6 mg×min/mL on day 1 every 3 weeks. The primary endpoint was independently assessed overall response rate as per the Response Evaluation Criteria in Solid Tumors v1.0. Secondary endpoints included progression-free survival, overall survival, and safety. Results Sixty-five patients ≥70 years with squamous histology were included (nab-paclitaxel/carboplatin, n=35; paclitaxel/carboplatin, n=30). nab-Paclitaxel/carboplatin vs paclitaxel/carboplatin, respectively, resulted in an overall response rate of 46% vs 20% (response rate ratio, 2.29, P=0.029) and a median overall survival of 16.9 vs 8.6 months (hazard ratio, 0.50, P=0.018). No difference was observed in median progression-free survival (5.7 months for both). Incidences of grade 3/4 neutropenia (50% vs 63%), leukopenia (29% vs 37%), fatigue (3% vs 13%), and peripheral neuropathy (3% vs 13%) were lower, but those of thrombocytopenia (21% vs 10%) and anemia (21% vs 7%) were higher with nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. Conclusion nab-Paclitaxel/carboplatin was efficacious and tolerable in patients ≥70 years with squamous NSCLC. These results build upon prior analyses, indicating that nab-paclitaxel/carboplatin is effective for this difficult-to-treat patient subgroup.

Quality-adjusted Outcomes Stratified by Response in Patients With Advanced Non–Small-cell Lung Cancer Receiving First-line nab-Paclitaxel/Carboplatin or Paclitaxel/Carboplatin

Micro‐Abstract: In the present analysis of quality‐adjusted outcomes from a phase III trial of nab‐paclitaxel/carboplatin versus paclitaxel/carboplatin to treat advanced non–small‐cell lung cancer, the progression‐free survival, overall survival, and quality‐adjusted time without symptoms or toxicity duration were significantly longer for patients with a tumor response (early or late) compared with those without. These results support the use of the tumor response as a surrogate for long‐term outcomes. Background: First‐line nab‐paclitaxel/carboplatin was associated with a significantly improved overall response rate (primary endpoint) versus paclitaxel/carboplatin in a phase III trial of advanced non–small‐cell lung cancer (NSCLC). We report the results of an analysis evaluating the correlation of response and the time to response with survival and quality‐adjusted outcomes. Patients and Methods: Using a landmark approach, progression‐free survival (PFS), overall survival (OS), and quality‐adjusted time without symptoms or toxicity (Q‐TWiST) were compared between patients with a confirmed partial or complete response at or before 6 weeks (≤ 6‐week responders) and those without (≤ 6‐week nonresponders). The outcomes were also analyzed in two 12‐week landmark analyses: ≤ 12‐week responders versus ≤ 12‐week nonresponders and early responders (≤ 6 weeks) versus late responders (6–12 weeks) versus ≤ 12‐week nonresponders. Results: The median OS and PFS for the ≤ 6‐week responders versus ≤ 6‐week nonresponders were 14.5 versus 10.3 months (P < .001) and 5.5 versus 4.5 months (P = .002), respectively. The ≤ 6‐week responders gained 2.1 months of mean Q‐TWiST. The median OS and PFS for the ≤ 12‐week responders versus ≤ 12‐week nonresponders were 16.3 versus 8.4 months and 5.3 versus 2.8 months (both P < .001), respectively, and the ≤ 12‐week responders gained 3.2 months of mean Q‐TWiST. The median OS was 13.1, 16.6, and 8.4 months (P < .001), the median PFS was 4.1, 6.7, and 2.8 months (P < .001), and the mean Q‐TWiST was 10.2, 11.7, and 7.8 months for the early responders, late responders, and ≤ 12‐week nonresponders, respectively. Both early and late responders had significantly longer Q‐TWiST compared with the ≤ 12‐week nonresponders (difference, +2.4 and +3.9 months, respectively; P < .05). Conclusion: These results underscore response as an important surrogate for assessment of long‐term treatment outcomes in advanced NSCLC.

nab-paclitaxel/carboplatin induction in squamous NSCLC: Longitudinal quality of life while on chemotherapy

Background Longitudinal data on the impact of treatment on quality of life (QoL) in advanced non-small cell lung cancer (NSCLC) are limited. In this palliative setting, treatment that does not deteriorate QoL is key. Here we report longitudinal QoL in patients with squamous NSCLC, receiving ≤4 cycles of nab-paclitaxel/carboplatin combination chemotherapy. Methods Patients received nab-paclitaxel 100 mg/m2 days 1, 8, 15 + carboplatin area under the curve 6 mg•min/mL day 1 (q3w) for four cycles. QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) at baseline and each cycle (day 1). Results Two-hundred and six lesion-response-evaluable patients completed baseline + ≥1 postbaseline QoL assessment and were QoL evaluable. LCSS average total score and symptom burden index improved from baseline throughout four cycles. In the LCSS pulmonary symptoms score, 46% of patients reported clinically meaningful improvement (≥10 mm visual analog scale) from baseline. Individual EQ-5D-5L dimensions remained stable/improved in ≥83% of patients; ≈33% reported complete resolution of baseline problems at least once during four cycles. Generally, responders (unconfirmed complete/partial response) had higher scores vs nonresponders. Conclusion In patients with squamous NSCLC, four cycles of nab-paclitaxel/carboplatin demonstrated clinically meaningful QoL improvements, with greater benefits in responders vs nonresponders.

P1.47: ABOUND.sqm QoL by Response: Interim Analysis of Squamous NSCLC Pts Treated With nab-Paclitaxel/Carboplatin Induction Therapy: Track: Advanced NSCLC.

Method: The primary objective of part 1 is to evaluate dose-limiting toxicities (DLTs). Patients (pts) treated with 2 cycles of nivo with chemotherapy (CT) and remained on study for 14 additional calendar days or who discontinued due to DLT prior to completing 2 cycles of nivo were considered DLT evaluable. Treatment arms could expanded in Part 2 to further assess safety, tolerability, and antitumor activity. The lung arms, C and D, were initiated sequentially in part 1 of the study. In Arm C, treatment-naive pts with stage IIIB/IV NSCLC received 4 cycles of nab-P 100 mg/m on days 1, 8, and 15 plus C AUC 6 on day 1 of a 21 day cycle in combination with nivolumab 5 mg/kg on day 15 starting at cycle 1. Enrollment for Arm D starts after Arm C is deemed safe to expand. The same regimen will be given in Arm D; however, nivolumab will be given starting cycle 3. In both NSCLC arms, nivo monotherapy begins at cycle 5.

Quality of life (QoL) in patients (pts) with squamous (SCC) NSCLC treated with nab-paclitaxel with carboplatin (nab-P/C) induction therapy: Interim analysis of the phase III ABOUND.sqm study.

64 Background: Recent data on QoL in pts with advanced NSCLC treated with platinum-doublets are limited. This interim analysis evaluated QoL in pts with SCC NSCLC treated with nab-P/C during the induction part of the ABOUND.sqm study. METHODS In the ongoing phase III ABOUND.sqm study, pts with advanced SCC NSCLC are treated with first-line nab-P 100 mg/m2 d 1, 8, 15 and C AUC 6 mg•min/mL d 1 (21-d cycles) for 4 cycles (induction). Pts not progressing after 4 cycles are randomized 2:1 to maintenance nab-P 100 mg/m2d 1 and 8 of each 21-d cycle + best supportive care (BSC) or BSC alone until progression. The primary endpoint is PFS from randomization to maintenance. QoL, an exploratory endpoint, was assessed using predefined PRO instruments, LCSS and EQ-5D-5L, on d 1 of each cycle. As the study is ongoing, this pre-planned analysis included data for QoL that were reported up to the cutoff date. RESULTS Of 128 pts included in this interim analysis, > 80% completed baseline (BL) + ≥ 1 post-BL PRO assessments. The median age was 68 years, 65% were male, and 99% had an ECOG PS of 0-1. Overall, the symptom burden index and average total score of the LCSS PRO were improved during induction therapy with nab-P/C; ≈ 50% of pts had clinically meaningful improvements (≥ 10 mm [VAS]) from BL in the composite LCSS items of cough, shortness of breath, and hemoptysis. More than 80% of pts maintained or improved each dimension of the EQ-5D-5L from BL, and a substantial proportion reported complete resolution of ≥ 1 specific dimension problem during induction (33%-48%; Table). No unusual safety signals were observed. CONCLUSIONS This interim analysis demonstrates that QoL was maintained or improved in pts with SCC NSCLC during nab-P/C induction therapy. For pts who reported problems in EQ-5D-5L dimensions at BL, many achieved complete resolution at least once during chemotherapy. CLINICAL TRIAL INFORMATION NCT02027428. [Table: see text].