Efficacy of oral vinorelbine (NVBo), capecitabine (X) and trastuzumab (H) triple combination (NVBoXH) in HER2-positive metastatic breast cancer (MBC): First results of an international phase II trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1052-1052 ◽  
Author(s):  
A. Chan ◽  
V. Ganju ◽  
D. Becquart ◽  
P. Conte ◽  
L. Petruzelka ◽  
...  
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Metastatic Breast ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
First Line ◽  
Her2 Positive ◽  
Eligibility Criteria ◽  
Oral Vinorelbine

1052 Background: Chemotherapy (CT) plus H is the standard first-line treatment for HER2-positive MBC. H plus vinorelbine is an active and well-tolerated regimen in this setting. The all-oral combination of NVBo and X also appears active and well-tolerated in MBC. We report efficacy and safety results from the first 34 patients (pts) included in an international trial evaluating NVBoXH in HER2-positive MBC. Methods: In this multicenter trial, main eligibility criteria included: HER2-positive disease (IHC 3+ or FISH+), documented measurable MBC previously untreated by CT, relapse 6 months after completing neoadjuvant or adjuvant CT, Karnofsky PS = 70, age =18 years. Pts received 3-weekly cycles of NVBo 60 mg/m2 (cycle 1) escalating to 80 mg/m2 (from cycle 2) days 1 and 8; × 1,000 mg/m2 bid (750 if = 65 years) days 1–14; H 4 mg/kg day 1 as a loading dose then 2 mg/kg i.v. weekly starting on day 8. Treatment was continued until progression or unacceptable toxicity. Primary endpoint is overall response rate. Results: Baseline characteristics: median age 54 years (20% = 65); prior (neo)adjuvant CT 21 pts (62%); type of CT: anthracycline 52%, anthracycline + taxane 29%, CMF 14%, taxane 5%; visceral involvement 29 pts (85%), >2 metastatic sites 13 pts (38%). Treatment administered: median 8 cycles, median relative dose intensity: NVBo 77%, X 81%, H 95%; NVBo dose escalation to 80 mg/m2 in 91% of pts. Safety (n=34, G3/4 NCI CTC v2 adverse events): neutropenia 22 pts (65%), diarrhea 4 pts (12%), febrile neutropenia 3 pts (9%), vomiting 3 pts (9%), hand-foot syndrome 3 pts (9%), asthenia 3 pts (9%), infection without neutropenia 2 pts (6%), LVEF decline 2 pts (6%), stomatitis 1 pt (3%), nausea 1 pt (3%), constipation 1 pt (3%). Efficacy (n=31 evaluable pts): objective response rate (RECIST) 71% (95% CI [52–86]), CR 13%, PR 58%, SD 23%, PD 6%, disease control (CR+PR+ SD for =6 months) 84%. Progression-free survival, overall survival and duration of response data are not yet mature. Conclusions: This is the first trial, in pts with HER2-positive MBC, to show high efficacy with first-line NVBoXH therapy. This regimen can be safely administered in this pt population. No significant financial relationships to disclose.

An international phase II study of an all-oral combination of oral vinorelbine (NVBo) and capecitabine (X) in HER2-negative metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1056-1056 ◽  
Author(s):  
N. Tubiana-Mathieu ◽  
P. Bougnoux ◽  
D. Becquart ◽  
A. Chan ◽  
F. Majois ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Safety Data ◽  
Metastatic Breast ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Eligibility Criteria ◽  
Good Tolerability ◽  
Oral Vinorelbine

1056 Background: Oral chemotherapy (CT) is attractive for patients (pts) with MBC. The all-oral regimen of NVBo and X is active with good tolerability in MBC. We report efficacy and safety data from an international phase II study of NVBo plus X. Methods: Main eligibility criteria included: measurable HER2-negative, CT-naive MBC, relapse ≥6 months after completing (neo)adjuvant CT, Karnofsky PS ≥70%, age ≥18 years. Study treatment: 3-weekly cycles of NVBo 60 mg/m2 (cycle 1) or 80 mg/m2 (from cycle 2) d1 and d8, plus X 1,000 (750 if ≥ 65 years) mg/m2 twice-daily d1–14. Treatment was continued until progression or unacceptable toxicity. Results: 55 pts were enrolled: median age: 58.5 years (41% ≥65); prior (neo)adjuvant CT in 63%; type of CT: anthracycline 67%, anthracycline + taxane 18%, CMF 15%; visceral involvement in 78%; >2 metastatic sites in 46%. Median 6 cycles; median relative dose intensity: NVBo 88%, X 87%; NVBo dose escalated to 80 mg/m2 in 94% of pts. G3/4 NCI CTC v2 adverse events (n=54): neutropenia 44% of pts, vomiting 9%, febrile neutropenia 7%, stomatitis 7%, asthenia 7%, infection with G3/4 neutropenia 4%, nausea 4%, diarrhea 4%, hand-foot syndrome 4%, thrombosis/embolism 4%. Efficacy (n=48 evaluable pts): objective response rate (RECIST) 44% (95% CI [29–59]), CR 2%, PR 42%, SD 35%, PD 21%, disease control (CR+PR+SD ≥6 months) 56%. Median time to objective response was 2.9 months. Because of short follow-up, progression-free survival, overall survival and duration of response data are not yet available. Conclusion: The all-oral combination of NVBo and X is an effective and well-tolerated first-line therapy for MBC. Based on these results and the high convenience of oral CT, evaluation of this regimen vs i.v. combinations in a randomized trial is ongoing. [Table: see text]

Randomized Phase II Trial of First-Line Trastuzumab Plus Docetaxel and Capecitabine Compared With Trastuzumab Plus Docetaxel inHER2-Positive Metastatic Breast Cancer

2010 ◽  
Vol 28 (6) ◽  
pp. 976-983 ◽  
Author(s):  
Andrew M. Wardley ◽  
Xavier Pivot ◽  
Flavia Morales-Vasquez ◽  
Luis M. Zetina ◽  
Maria de Fátima Dias Gaui ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Response Rate ◽  
Performance Status ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
First Line ◽  
Her2 Positive ◽  
Grade 3

PurposeTo evaluate trastuzumab (H) and docetaxel (T) with or without capecitabine (X) as first-line combination therapy for human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer.Patients and MethodsPatients with HER2-positive locally advanced or metastatic breast cancer were randomly assigned to H (8 mg/kg loading; 6 mg/kg every 3 weeks) plus T (75 mg/m2in HTX arm, 100 mg/m2in HT arm, every 3 weeks) with or without X (950 mg/m2twice per day on days 1 to 14 every 3 weeks). The primary end point was overall response rate (ORR).ResultsIn 222 patients, median follow-up was approximately 24 months. ORR was high with both regimens (70.5% with HTX; 72.7% with HT; P = .717); complete response rate was 23.2% with HTX compared with 16.4% with HT. HTX demonstrated significantly longer progression-free survival: median 17.9 months compared with 12.8 months with HT (hazard ratio, 0.72; P = .045), which translates to a gain of around 5 months. Two-year survival probability was 75% with HTX compared with 66% with HT. Febrile neutropenia (27% v 15%) and grade 3/4 neutropenia (77% v 54%) incidences were higher with HT than HTX. Treatment-related grade 3 hand-foot syndrome (17% v < 1%) and grade 3/4 diarrhea (11% v 4%) occurred more commonly with HTX than HT. One case of congestive heart failure occurred in each arm.ConclusionHTX is an effective and feasible first-line therapy for HER2-positive locally advanced or metastatic breast cancer, although it should be reserved for patients with good performance status who are not receiving long-term steroids.

scholarly journals Efficacy and Safety of Anti-HER2 Agents in Combination With Chemotherapy for Metastatic HER2-Positive Breast Cancer Patient: A Network Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaohui Zhang ◽  
Junsheng Leng ◽  
Yidong Zhou ◽  
Feng Mao ◽  
Yan Lin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Meta Analysis ◽  
Objective Response ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Breast Cancers ◽  
First Line ◽  
Her2 Positive ◽  
The Cochrane Library

BackgroundThe presence of anti-HER2 agents, such as trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1), significantly improved the prognosis of metastatic HER2-positive (HER2+) breast cancers (BC). However, drug resistance and disease progression are still common. In order to further improve the treatment efficacy, new clinical trials about anti-HER2 agents in combination with chemotherapy are growing rapidly. We conducted the network meta-analysis to synthesize evidences of clinical trials to identify the best therapy for metastatic HER2+ BC.MethodsA systematic search of randomized controlled trials regarding anti-HER2 agents in combination with chemotherapy for advanced or metastatic breast cancers up to May 2020 was conducted in Embase, PubMed, and the Cochrane Library. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR), and safety. Bayesian network meta-analysis was conducted to synthesize the results and rank the therapies.ResultsTwenty-six studies, including 16 studies for first-line treatments and 10 studies for second- or later-line treatments were included in the network meta-analysis. For first-line studies, the THP (taxanes + trastuzumab + pertuzumab) regimen exhibited the highest probability to be the optimal treatment in all efficacy outcomes and moderate safety. For second- or later-line studies, the T-DM1 and XHTuC (capecitabine + trastuzumab + tucatinib) regimens ranked top two in all efficacy outcomes according to the surface under the cumulative ranking (SUCRA) results. T-DM1 ranked first in PFS and OS whereas XHTuC ranked first in ORR. The safety outcomes of T-DM1 and XHTuC were acceptable.ConclusionsTHP was still the optimal first-line treatment for metastatic HER2+ BC. T-DM1 and XHTuC were recommended for second-line treatments.Systematic Review RegistrationINPLASY.com, identifier (INPLASY202090086).

scholarly journals Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of HER2-positive breast cancer with brain metastases (TRIO-US B-09)

2018 ◽  
Vol 10 ◽  
pp. 175883591880733 ◽  
Author(s):  
Sara Hurvitz ◽  
Rashi Singh ◽  
Brad Adams ◽  
Julie A. Taguchi ◽  
David Chan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Response Rate ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
Metastatic Breast ◽  
Study Drug ◽  
Progression Free Survival ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Breast Cancer Brain Metastasis

Background: Improving outcomes for patients with human epidermal growth factor 2-positive (HER2+) central nervous system (CNS) metastases remains an unmet clinical need. This trial evaluated a novel combination of everolimus, lapatinib and capecitabine for this disease. Methods: Patients with trastuzumab-pretreated, HER2+ breast cancer brain metastasis without prior therapy with a mammalian target of rapamycin (mTOR) inhibitor were eligible. Patients received lapatinib and everolimus daily (continuously) and capecitabine twice daily (d1–14) in 21-d cycles. The primary endpoint was the 12-week CNS objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), best CNS ORR and extra-CNS ORR. Results: A total of 19 participants were enrolled and treated with ⩾1 dose of the study drug. The median age was 58.5 years, the median number of therapies for metastatic breast cancer was 2.5 (0–11). Pretrial, 74% of participants had received prior lapatinib, capecitabine or both. A total of 63% had received previous CNS radiation or surgical resection and CNS radiation. The maximum tolerated doses were lapatinib at 1000 mg, everolimus at 10 mg, and capecitabine at 1000 mg/m2. Phase II proceeded with capecitabine at 750 mg/m2 due to better tolerability. The most common grade 3/4 adverse events were mucositis (16%), diarrhea, fatigue, and hypokalemia (11% each). Of 11 participants evaluable for 12-week CNS ORR, 3 (27%) had partial response and 7 (64%) had stable disease. The best CNS ORR in eligible participants was 28% (5/18). The median PFS and OS were 6.2 and 24.2 months, respectively. Conclusions: This novel triplet combination of lapatinib, everolimus, and capecitabine is well tolerated and yielded a 27% response rate in the CNS at 12 weeks in heavily pretreated participants. Larger studies are warranted to further evaluate this regimen. Trial registration: ClinicalTrials.gov: NCT01783756. Registered 05 February 2013, https://clinicaltrials.gov/ct2/show/NCT01783756

scholarly journals Oral vinorelbine and capecitabine as first-line therapy in metastatic breast cancer: a retrospective analysis

2021 ◽  
Author(s):  
Maria Rosaria Valerio ◽  
Pietro Spadaro ◽  
Concetta Arcanà ◽  
Nicolò Borsellino ◽  
Calogero Cipolla ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Retrospective Analysis ◽  
Triple Negative ◽  
Response Rate ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Complete Response ◽  
Advanced Breast ◽  
First Line ◽  
Oral Vinorelbine

A retrospective analysis of 70 patients with triple-negative or hormone-resistant advanced breast carcinoma who had not previously received chemotherapy was carried out. Patients received oral vinorelbine 60 mg/m2 on day 1 and 8, plus capecitabine 1000 mg/m2 bid for 14 consecutive days every 3 weeks. Overall response rate was 53% with a 9% complete response rate. Stable disease was recorded in 27% of the cases. Median progression-free survival was 7.9 months and median overall survival was 29.2 months. Toxicity was generally mild and easily manageable. These data demonstrate that this combination is feasible, safe and active as first-line treatment of triple-negative fully hormone-resistant advanced breast carcinoma patients.

scholarly journals Phase II study of metronomic treatment with daily oral vinorelbine as first-line chemotherapy in patients with advanced/metastatic HR+/HER2− breast cancer resistant to endocrine therapy: VinoMetro—AGO-B-046

2021 ◽  
Author(s):  
Slavomir Krajnak ◽  
Thomas Decker ◽  
Lukas Schollenberger ◽  
Christian Rosé ◽  
Christian Ruckes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
First Line ◽  
Open Label ◽  
Oral Vinorelbine ◽  
Her2 Breast Cancer ◽  
Line Chemotherapy

Abstract Purpose Metronomic chemotherapy (MCT) is an increasingly used treatment option in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced/metastatic breast cancer (MBC) after failure of endocrine-based therapies. Methods VinoMetro was a multicentre, open-label, single-arm, phase II study of metronomic oral vinorelbine (VRL; 30 mg/day) as a first-line chemotherapy (CT) in patients with HR+/HER2− MBC after endocrine failure. The primary endpoint was the clinical benefit rate (CBR) at 24 weeks. Results Between January 2017 and April 2019, nine patients were enrolled. The CBR was 22.2% (90% confidence interval [CI] 4.1–55.0), p = 0.211. The median progression-free survival (PFS) was 12.0 weeks (95% CI 11.3–12.7). Grade 3–4 adverse events (AEs) occurred in 22.2% of patients. One patient died of febrile neutropenia. Conclusion VinoMetro (AGO-B-046) was closed early after nine patients and occurrence of one grade 5 toxicity in agreement with the lead institutional review board (IRB). Metronomic dosing of oral VRL in HR+/HER2− MBC as first-line CT after failure of endocrine therapies showed only limited benefit in this population. Trial registration number and date of registration ClinicalTrials.gov Identifier: NCT03007992; December 15, 2016.

scholarly journals The Efficacy of Ramucirumab in the Treatment of Gastric or Gastroesophageal Junction Cancer: A Meta-Analysis of RCTs

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Hongqiong Yang ◽  
Yaojun Zhou ◽  
Liangzhi Wang ◽  
Tianyi Gu ◽  
Mengjia Lv ◽  
...  
Keyword(s):  
Response Rate ◽  
Meta Analysis ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
First Line ◽  
Free Survival ◽  
Gastroesophageal Junction Cancer ◽  
Line Chemotherapy

Five electronic databases were searched for eligible records. Outcomes were presented and analyzed according to the objective response rate (ORR), progression-free survival (PFS) rate, and overall survival (OS) rate. Five records involving 2,024 participants were included in the study. The pooled analysis of OS and PFS were longer with ramucirumab (RAM) therapy than without RAM for OS (odds ratio OR = 0.90 , 95% confidence interval CI = 0.82 – 1.00 , p = 0.05 ) and PFS ( OR = 0.74 , 95 % CI = 0.57 – 0.96 , p = 0.02 ). Moreover, compared with the current first-line chemotherapy, the OS ( OR = 0.93 , 95 % CI = 0.83 – 1.04 , p = 0.19 ) and PFS ( OR = 0.82 , 95 % CI = 0.64 – 1.06 , p = 0.13 ) results were not significantly higher with RAM. The ORRs of the patients in the RAM therapy groups were significantly higher than those in the groups without RAM ( OR = 1.40 , 95 % CI = 1.14 – 1.73 , p = 0.001 ).

Randomized Phase II Trial of the Efficacy and Safety of Trastuzumab Combined With Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer Administered As First-Line Treatment: The M77001 Study Group

2005 ◽  
Vol 23 (19) ◽  
pp. 4265-4274 ◽  
Author(s):  
Michel Marty ◽  
Francesco Cognetti ◽  
Dominique Maraninchi ◽  
Ray Snyder ◽  
Louis Mauriac ◽  
...  
Keyword(s):  
Disease Progression ◽  
Response Rate ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
First Line ◽  
Her2 Positive ◽  
Symptomatic Heart Failure ◽  
Time To Treatment Failure ◽  
Epidermal Growth ◽  
First Line Treatment

Purpose This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer (MBC). Patients and Methods Patients were randomly assigned to six cycles of docetaxel 100 mg/m2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. Results A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen more commonly with the combination (32%) than with docetaxel alone (22%), and there was a slightly higher incidence of febrile neutropenia in the combination arm (23% v 17%). One patient in the combination arm experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression, while being treated with an investigational anthracycline for 4 months. Conclusion Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity.

Effects of adding necitumumab to first-line chemotherapy in patients with stage IV non-small-cell lung cancer: Meta-analysis

2019 ◽  
Vol 26 (6) ◽  
pp. 1331-1342
Author(s):  
Irena Ilic ◽  
Sandra Sipetic ◽  
Jovan Grujicic ◽  
Milena Ilic
Keyword(s):  
Overall Survival ◽  
Objective Response Rate ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Meta Analysis ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival

Introduction Almost half of patients with non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage. Our aim was to assess the effects of adding necitumumab to chemotherapy in patients with stage IV NSCLC. Material and methods A comprehensive literature search was performed according to pre-specified inclusion and exclusion criteria. Data on overall survival, progression-free survival, objective response rate and adverse events were extracted. A meta-analysis was performed to obtain pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) for time-to-event data and pooled odds ratio (OR) with 95% CI for dichotomous outcomes. Results The meta-analysis included four randomized clinical trials with 2074 patients. The pooled results showed significant improvement for overall survival (HR = 0.87 (95% CI 0.79–0.95), p = 0.004) when necitumumab was added to chemotherapy in patients with advanced NSCLC. No statistically significant improvement was noted for progression-free survival and objective response rate (HR = 0.83 (95% CI 0.69–1.01), p = 0.06 and OR = 1.46 (95% CI 0.90–2.38), p = 0.13, respectively). Subgroup analysis showed that in patients with non-squamous NSCLC, there was no benefit in overall survival and objective response rate. Patients with advanced NSCLC who received necitumumab were at the highest odds of developing a skin rash (OR = 14.50 (95% CI 3.16–66.43), p = 0.0006) and hypomagnesaemia (OR = 2.77 (95% CI 2.23–3.45), p < 0.00001), while the OR for any grade ≥3 adverse event was 1.55 (95% CI 1.28–1.87, p < 0.00001). Conclusions The addition of necitumumab to standard chemotherapy in a first-line setting in patients with stage IV NSCLC results in a statistically significant improvement in overall survival, while the results were not significant for progression-free survival and objective response rate.

scholarly journals Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial

2020 ◽  
Vol 38 (27) ◽  
pp. 3138-3149 ◽  
Author(s):  
Cristina Saura ◽  
Mafalda Oliveira ◽  
Yin-Hsun Feng ◽  
Ming-Shen Dai ◽  
Shang-Wen Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Her2 Positive ◽  
End Points ◽  
Cns Disease

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

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