Comparison of Efficacy and Safety of a Bevacizumab Biosimilar, in Combination with Chemotherapies, in Nonresectable Metastatic Colorectal Cancer and in Advanced Nonsquamous Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study.

Ranjith K.The objective of this study was to compare the efficacy, safety, pharmacokinetics, and immunogenicity of a proposed bevacizumab biosimilar (DRL_BZ) with the innovator Avastin (reference medicinal product [RMP]) in patients with nonresectable metastatic colorectal cancer (mCRC) over a period of 9 months and advanced nonsquamous non-small cell lung cancer (NSCLC) over 6 months. The study was planned as a randomized, double-blind trial. In part A, a total of 117 mCRC patients were intended to receive 5 mg/kg of bevacizumab every 2 weeks along with mFOLFOX6 chemotherapy for a maximum of 18 cycles. In part B, 60 NSCLC patients were to receive 15 mg/kg of bevacizumab every 3 weeks along with pemetrexed and carboplatin for the initial four cycles, followed by pemetrexed for another four cycles. The primary endpoint was the progression-free survival rate at 6 months (PFS6) in both subparts. The anticipated sample size was 106 evaluable mCRC patients to achieve 85% statistical power for concluding noninferiority with a margin of half the difference (18.8%) between DRL_BZ and Avastin, along with a pilot study involving 60 evaluable NSCLC patients. Safety comparison included assessing adverse events (AEs), infusion reactions, and lab abnormalities. Immunogenicity comparison involved the incidence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs). Pharmacokinetic comparison was planned after the first and fourth dosing cycles of treatment in 24 NSCLC patients. The PFS6 for mCRC patients treated with DRL_BZ and RMP was 57.8% and 50% respectively, with a difference in efficacy of 7.8 (-8.7, 23.7). The PFS9 was 31.1% and 22.9%, with a difference of 8.2% (-6.9%, 22.9%). The objective response rate (ORR) for DRL_BZ and RMP was 28.8% and 22.4%, while the disease control rate (DCR) was 44.2% and 37.9% respectively. For NSCLC patients, the PFS6 was 44% and 45%, showing a difference of -1.0 (-4.2, 22.1). The ORR was 41.4% and 48.1%, and the DCR was 62.1% and 63%. The frequency, type, and severity of AEs were similar in both indications. Blood levels during the first and fourth dosing cycles exhibited comparable values. All NSCLC patients tested negative for ADA, while no mCRC patients on DRL_BZ tested positive for ADA. Low incidences of ADA (8%) and NAbs (4.0%) were reported in patients on RMP. Overall, the efficacy, safety, immunogenicity, and pharmacokinetic parameters of DRL_BZ and RMP were found to be comparable. Clinical Trial Registration For BZ-01-002: CTRI/2016/01/006481.

Efficacy and safety of maintenance therapy with pamiparib versus placebo for advanced gastric cancer responding to first-line platinum-based chemotherapy: Phase 2 study results.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved for the treatment of various solid tumors. In gastric cancer, genes commonly harbor mutations in the homologous recombination DNA repair pathway, potentially increasing sensitivity to PARPi. Pamiparib (BGB-290) is a small molecule inhibitor of PARP1 and PARP2. METHODS: The PARALLEL-303 study (NCT03427814) investigated the efficacy and safety of pamiparib 60 mg orally (PO) twice daily (BID) versus placebo PO BID as maintenance therapy in patients with inoperable locally advanced or metastatic gastric cancer that responded to platinum-based first-line chemotherapy. The primary endpoint of this double-blind, randomized, global phase 2 study was progression-free survival (PFS) (RECIST version 1.1; per investigator assessment). Secondary endpoints included overall survival (OS) and safety. RESULTS: In total, 136 patients were randomized 1:1 to receive pamiparib (n = 71) or placebo (n = 65). Median PFS was numerically longer with pamiparib versus placebo but did not reach statistical significance (3.7 months [95% confidence interval (CI): 1.9, 5.3] vs. 2.1 months [95% CI: 1.9, 3.8]; hazard ratio 0.8 [95% CI: 0.5, 1.2]; p = 0.1428). Median OS was 10.2 months (95% CI: 8.7, 16.3) in the pamiparib arm versus 12.0 months (95% CI: 8.2, not estimable) in the placebo arm. Overall, 8 patients (11.3%) in the pamiparib arm and 2 patients (3.1%) in the placebo arm experienced ≥1 TEAE leading to treatment discontinuation. CONCLUSIONS: Maintenance pamiparib did not meet statistical significance for superiority versus placebo for PFS, but was well tolerated with few treatment discontinuations; no unexpected safety signals were identified.

Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3.

BACKGROUND: EMPOWER-Lung 3, a randomized 2:1 phase 3 trial, showed clinically meaningful and statistically significant overall survival improvement with cemiplimab plus platinum-doublet chemotherapy versus placebo plus chemotherapy for first-line treatment of advanced non-small cell lung cancer. This study evaluated patient-reported outcomes (PROs). METHODS: PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks) for the first six doses, and then at start of every three cycles, using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30) and Quality of Life-Lung Cancer Module (QLQ-LC13) questionnaires. Prespecified analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis performed for global health status/quality of life (GHS/QoL) and all scales from the questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and proportional hazards model. RESULTS: A total of 312 patients were assigned to receive cemiplimab plus platinum-doublet chemotherapy and 154 to receive placebo plus chemotherapy; 391 (83.9%) were male and the median age was 63.0 years (range, 25-84). For pain symptoms (EORTC QLQ-C30), a statistically significant overall improvement from baseline (-4.98, 95% confidence interval [CI] -8.36 to -1.60, p = .004) and a statistically significant delay in TTD (hazard ratio, 0.39; 95% CI, 0.26-0.60, p < .0001) favoring cemiplimab plus chemotherapy were observed. Statistically significant delays in TTD, all favoring cemiplimab plus chemotherapy, were also observed in functioning and symptom scales. A significant overall improvement from baseline in GHS/QoL was seen for cemiplimab plus chemotherapy compared with nonsignificant overall change from baseline for placebo plus chemotherapy (1.69, 95% CI, 0.20-3.19 vs. 1.08, 95% CI, -1.34 to 3.51; between arms, p = .673). No analyses yielded statistically significant PRO results favoring placebo plus chemotherapy for any QLQ-C30 or QLQ-LC13 scale. CONCLUSION: Cemiplimab plus chemotherapy resulted in significant overall improvement in pain symptoms and delayed TTD in cancer-related and lung cancer-specific symptoms and functions.

Tislelizumab Versus Docetaxel in Patients With Previously Treated Advanced NSCLC (RATIONALE-303): A Phase 3, Open-Label, Randomized Controlled Trial.

INTRODUCTION: The phase 3 RATIONALE-303 trial (NCT03358875) investigated the efficacy and safety of tislelizumab versus docetaxel in pretreated patients with advanced NSCLC. Here, we report the efficacy and safety results and describe the exploratory biomarker analyses. METHODS: A total of 805 patients aged more than or equal to 18 years with locally advanced or metastatic squamous or nonsquamous NSCLC were randomized 2:1 to intravenous tislelizumab 200 mg or docetaxel 75 mg/m2 every 3 weeks. Co-primary end points were overall survival (OS) in the intent-to-treat (ITT) and programmed death-ligand 1 (PD-L1) tumor cell expression greater than or equal to 25% populations. The exploratory biomarker analyses included PD-L1 expression, tumor mutation burden, and gene expression profile. RESULTS: At the prespecified interim analysis (August 10, 2020), the co-primary end point of OS in the ITT population was met, with a statistically significant and clinically meaningful improvement in OS with tislelizumab versus docetaxel (median 17.2 versus 11.9 mo, respectively; hazard ratio [HR] = 0.64, p < 0.0001). At the final analysis (July 15, 2021), the other co-primary end point of OS in the PD-L1 tumor cell greater than or equal to 25% population was further met (median 19.3 versus 11.5 mo, respectively; HR = 0.53, p < 0.0001), and OS continued to improve in the ITT population (median 16.9 versus 11.9 mo, respectively, HR = 0.66). Exploratory biomarker analyses revealed the potential association of NOTCH1-4 mutations with improved tislelizumab efficacy for both OS and progression-free survival, whereas tissue tumor mutation burden correlated with progression-free survival benefit, but not OS benefit. No new safety signals were identified. CONCLUSIONS: Tislelizumab was found to have a significantly improved and long-term clinical benefit in OS versus docetaxel in pretreated patients with advanced NSCLC, regardless of PD-L1 expression.

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized Clinical Trial.

Importance: Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. Objective: To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. Design, Setting, and Participants: This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Interventions: Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. Main Outcomes and Measures: The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Results: Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Conclusions and Relevance: Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT04063163.

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial.

First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 ( NCT03409614 ), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5-not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9-16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53-0.93; P = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies.

Randomized phase 3 study of the anti-disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan for second-line treatment of small cell lung cancer.

INTRODUCTION: Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior tolerability. Preclinical studies support disialoganglioside (GD2) as an SCLC target and the combination of dinutuximab, an anti-GD2 antibody, plus irinotecan in this setting. We tested dinutuximab/irinotecan versus irinotecan or topotecan as second-line therapy in relapsed/refractory (RR) SCLC. MATERIALS AND METHODS: Patients with RR SCLC and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:2:1 to receive dinutuximab 16-17.5 mg/m2 intravenous (IV)/irinotecan 350 mg/m2 IV (day 1), irinotecan 350 mg/m2 IV (day 1), or topotecan 1.5 mg/m2 IV (days 1-5) in 21-day cycles. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR; complete response [CR] + partial response [PR]), and clinical benefit rate (CBR; CR + PR + stable disease). Safety/tolerability were also assessed. RESULTS: A total of 471 patients were randomized to dinutuximab/irinotecan (n = 187), irinotecan (n = 190), or topotecan (n = 94). Age, sex, performance status, prior therapies, and metastatic disease sites were similar between groups. Survival and response rates were not improved for patients receiving dinutuximab/irinotecan versus those receiving irinotecan or topotecan (median OS 6.9 vs 7.0 vs 7.4 months [p = 0.3132]; median PFS 3.5 vs 3.0 vs 3.4 months [p = 0.3482]; ORR confirmed 17.1% vs 18.9% vs 20.2% [p = 0.8043]; and CBR 67.4% vs 58.9% vs 68.1% [p = 0.0989]), respectively. Grade 3/4 adverse events (≥5% receiving dinutuximab/irinotecan) included neutropenia, anemia, diarrhea, and asthenia. CONCLUSIONS: Dinutuximab/irinotecan treatment did not result in improved OS in RR SCLC versus irinotecan alone. Irinotecan administered every 21 days demonstrated comparable activity to topotecan administered daily × 5 every 21 days. CLINICALTRIALS: gov Identifier. NCT03098030.

Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Few prospective studies have compared poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors to chemotherapy for the treatment of BRCA1-mutated or BRCA2-mutated ovarian carcinoma. We aimed to assess rucaparib versus platinum-based and non-platinum-based chemotherapy in this setting. METHODS: In this open-label, randomised, controlled, phase 3 study (ARIEL4), conducted in 64 hospitals and cancer centres across 12 countries (Brazil, Canada, Czech Republic, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, the UK, and the USA), we recruited patients aged 18 years and older with BRCA1-mutated or BRCA2-mutated ovarian carcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had received two or more previous chemotherapy regimens. Eligible patients were randomly assigned (2:1), using an interactive response technology and block randomisation (block size of six) and stratified by progression-free interval after the most recent platinum-containing therapy, to oral rucaparib (600 mg twice daily) or chemotherapy (administered per institutional guidelines). Patients assigned to the chemotherapy group with platinum-resistant or partially platinum-sensitive disease were given paclitaxel (starting dose 60-80 mg/m2 on days 1, 8, and 15); those with fully platinum-sensitive disease received platinum-based chemotherapy (single-agent cisplatin or carboplatin, or platinum-doublet chemotherapy). Patients were treated in 21-day or 28-day cycles. The primary endpoint was investigator-assessed progression-free survival, assessed in the efficacy population (all randomly assigned patients with deleterious BRCA1 or BRCA2 mutations without reversion mutations), and then in the intention-to-treat population (all randomly assigned patients). Safety was assessed in all patients who received at least one dose of assigned study treatment. This study is registered with ClinicalTrials.gov, NCT02855944; enrolment is complete, and the study is ongoing. FINDINGS: Between March 1, 2017, and Sept 24, 2020, 930 patients were screened, of whom 349 eligible patients were randomly assigned to rucaparib (n=233) or chemotherapy (n=116). Median age was 58 years (IQR 52-64) and 332 (95%) patients were White. As of data cutoff (Sept 30, 2020), median follow-up was 25·0 months (IQR 13·8-32·5). In the efficacy population (220 patients in the rucaparib group; 105 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 7·3-9·1) in the rucaparib group versus 5·7 months (5·5-7·3) in the chemotherapy group (hazard ratio [HR] 0·64 [95% CI 0·49-0·84]; p=0·0010). In the intention-to-treat population (233 in the rucaparib group; 116 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 6·7-7·9) in the rucaparib group versus 5·7 months (5·5-6·7) in the chemotherapy group (HR 0·67 [95% CI 0·52-0·86]; p=0·0017). Most treatment-emergent adverse events were grade 1 or 2. The most common grade 3 or worse treatment-emergent adverse event was anaemia or decreased haemoglobin (in 52 [22%] of 232 patients in the rucaparib group vs six [5%] of 113 in the chemotherapy group). Serious treatment-emergent adverse events occurred in 62 (27%) patients in the rucaparib group versus 13 (12%) in the chemotherapy group; serious adverse events considered related to treatment by the investigator occurred in 32 (14%) patients in the rucaparib group and six (5%) in the chemotherapy group. Three deaths were considered to be potentially related to rucaparib (one due to cardiac disorder, one due to myelodysplastic syndrome, and one with an unconfirmed cause). INTERPRETATION: Results from the ARIEL4 study support rucaparib as an alternative treatment option to chemotherapy for patients with relapsed, BRCA1-mutated or BRCA2-mutated ovarian carcinoma. FUNDING: Clovis Oncology.

Efficacy and Safety of Bevacizumab Biosimilar FKB238 Versus Originator Bevacizumab: Results from AVANA, a Phase III Trial in Patients with Non-Squamous Non-Small-Cell Lung Cancer (non-sq-NSCLC).

BACKGROUND: Bevacizumab is an antiangiogenic recombinant humanized monoclonal antibody that inhibits tumor growth. FKB238, a bevacizumab biosimilar, has analytical pharmacokinetic and safety profiles similar to those of bevacizumab. OBJECTIVE: This phase III trial (NCT02810457) compared the efficacy and safety of FKB238 with that of bevacizumab in patients with advanced/recurrent non-squamous non-small-cell lung cancer (non-sq-NSCLC). METHODS: This global, multicenter, double-blind, parallel, randomized, comparative clinical trial enrolled and randomized patients with advanced/recurrent non-sq-NSCLC to receive intravenous infusions of either FKB238 15 mg/kg or bevacizumab 15 mg/kg. All patients received intravenous infusions of paclitaxel 200 mg/m2 and carboplatin (area under the curve 6.0) immediately prior to investigational products for 4-6 cycles. FKB238 and bevacizumab were administered on day 1 of each 21-day cycle until objective progressive disease by RECIST version 1.1 or other discontinuation criteria were met. The primary efficacy endpoint was overall response rate (ORR), including complete and partial response and based on blinded independent central review assessment. Other efficacy determinations included progression-free survival (PFS), overall survival (OS), and immunogenicity. Adverse events and severity were reported. RESULTS: The ORR for the intent-to-treat (ITT) population (N = 731) was 51.6% in the FKB238 arm (N = 364) and 53.7% in the bevacizumab arm (N = 367). The FKB238:bevacizumab ORR ratio (ITT population) was 0.96 (90% confidence interval [CI] 0.86-1.08), and the difference in ORR (per-protocol set) between FKB238 and bevacizumab was - 0.02 (95% CI - 0.09 to 0.06). Both CIs fell within the prespecified equivalence margins. Estimated median PFS was 7.72 and 7.62 months in the FKB238 and bevacizumab arms, respectively (hazard ratio 0.97; 95% CI 0.82-1.16). Treatment-emergent adverse events (TEAEs) were reported for 94.2% and 95.1% of patients in the FKB238 and bevacizumab arms, respectively. Grade 3 or higher TEAEs were reported for 53.6% and 55.5% of patients in the FKB238 and bevacizumab arms, respectively. Serious TEAEs were reported for 25.1% and 26.0% of patients treated with FKB238 and bevacizumab, respectively. CONCLUSIONS: Efficacy equivalence was demonstrated between the two drugs, and safety profiles were similar. There were no meaningful differences in efficacy and safety between FKB238 or bevacizumab in patients with non-sq-NSCLC. TRIAL REGISTRATION NUMBER: NCT02810457.

New Therapies and Biomarkers: Are We Ready for Personalized Treatment in Small Cell Lung Cancer?

Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a 5-year survival rate of less than 7%. In contrast to non-small cell lung cancer, SCLC has long been treated as a homogeneous disease without personalized treatment options. In recent years, the incorporation of immunotherapy into the treatment paradigm has brought moderate benefit to patients with SCLC; however, more effective therapies are urgently needed. In this article, we describe the current treatment standards and emerging therapeutic approaches for the treatment of SCLC. We also discuss promising biomarkers in SCLC and the recently discovered four subtypes of SCLC, each with its unique therapeutic vulnerability. Lastly, we discuss the advances in radiation therapy for the treatment of SCLC.

Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued. FINDINGS: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure). INTERPRETATION: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.

Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a subgroup analysis from the phase 3 TAGS study.

BACKGROUND: Patients with advanced gastroesophageal junction cancer (GEJC) have poor survival outcomes, and GEJC-specific data from trials evaluating agents in gastric cancers (GCs) as a whole are lacking. Trifluridine/tipiracil (FTD/TPI) was approved for previously treated metastatic GC or GEJC (mGC/mGEJC) based on results of the phase 3 TAGS trial. Subgroup analyses by primary tumor type (GC or GEJC) in TAGS are reported here. METHODS: Pa tients with mGC/mGEJC treated with ≥ 2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI or placebo, plus best supportive care. A pre-planned sub-analysis was performed to evaluate efficacy and safety outcomes by primary tumor type (GEJC or GC). RESULTS: Of 507 randomized patients, 145 (29%) had GEJC and 360 (71%) had GC as the primary disease site. Baseline characteristics were generally similar between the GEJC and GC subgroups, except that more patients in the GEJC subgroup had received ≥ 3 prior regimens (72 vs. 59% in the GC subgroup). Survival benefit with FTD/TPI was observed in both subgroups. The overall survival hazard ratio for FTD/TPI vs placebo was 0.75 (95% CI 0.50-1.11) and 0.67 (95% CI 0.52-0.87) in the GEJC and GC subgroups, respectively. Grade ≥ 3 adverse events of any cause were reported in 75 (77%) and 192 (81%) FTD/TPI-treated patients in the GEJC and GC subgroups, respectively. No new safety concerns were noted with FTD/TPI. CONCLUSION: As in patients with GC, FTD/TPI showed an efficacy benefit in patients with GEJC in the TAGS trial, along with demonstrating a manageable safety profile.

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum-etoposide) showed a significant improvement in overall survival versus platinum-etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide alone. METHODS: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum-etoposide, durvalumab plus platinum-etoposide, or platinum-etoposide alone. In all groups, patients received etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m2 on day 1 of each cycle. Patients in the platinum-etoposide group received up to six cycles of platinum-etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum-etoposide versus platinum-etoposide and for durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. FINDINGS: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum-etoposide, 268 to durvalumab plus platinum-etoposide, and 269 to platinum-etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3-27·9). Durvalumab plus tremelimumab plus platinum-etoposide was not associated with a significant improvement in overall survival versus platinum-etoposide (hazard ratio [HR] 0·82 [95% CI 0·68-1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6-12·0) versus 10·5 months (9·3-11·2). Durvalumab plus platinum-etoposide showed sustained improvement in overall survival versus platinum-etoposide (HR 0·75 [95% CI 0·62-0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3-14·7) versus 10·5 months (9·3-11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum-etoposide group, and 88 [33%] of 266 patients in the platinum-etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 85 (32%) in the durvalumab plus platinum-etoposide group, and 97 (36%) in the platinum-etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum-etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum-etoposide group (pancytopenia and thrombocytopenia [n=1 each]). INTERPRETATION: First-line durvalumab plus platinum-etoposide showed sustained overall survival improvement versus platinum-etoposide but the addition of tremelimumab to durvalumab plus platinum-etoposide did not significantly improve outcomes versus platinum-etoposide. These results support the use of durvalumab plus platinum-etoposide as a new standard of care for the first-line treatment of ES-SCLC. FUNDING: AstraZeneca.

Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100.

PURPOSE: The role of maintenance therapy for gastric (GC) or gastroesophageal junction cancer (GEJC) is unclear. We investigated avelumab (anti-programmed death ligand-1 [PD-L1]) maintenance after first-line induction chemotherapy for GC/GEJC. PATIENTS AND METHODS: JAVELIN Gastric 100 was a global, open-label, phase III trial. Eligible patients had untreated, unresectable, human epidermal growth factor receptor 2-negative, locally advanced or metastatic GC or GEJC. Patients without progressive disease after 12 weeks of first-line chemotherapy with oxaliplatin plus a fluoropyrimidine were randomly assigned 1:1 to avelumab 10 mg/kg every 2 weeks or continued chemotherapy, stratified by region (Asia v non-Asia). The primary end point was overall survival (OS) after induction chemotherapy in all randomly assigned patients or the PD-L1-positive randomly assigned population (≥ 1% of tumor cells; 73-10 assay). RESULTS: A total of 805 patients received induction; 499 were randomly assigned to avelumab (n = 249) or continued chemotherapy (n = 250). Median OS was 10.4 months (95% CI, 9.1 to 12.0 months) versus 10.9 months (95% CI, 9.6 to 12.4 months) and 24-month OS rate was 22.1% versus 15.5% with avelumab versus chemotherapy, respectively (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; P = .1779). In the PD-L1-positive population (n = 54), the HR for OS was 1.13 (95% CI, 0.57 to 2.23; P = .6352). In an exploratory analysis of the PD-L1-positive population, defined as combined positive score ≥ 1 (22C3 assay; n = 137), median OS was 14.9 months (95% CI, 8.7 to 17.3 months) with avelumab versus 11.6 months (95% CI, 8.4 to 12.6 months) with chemotherapy (unstratified HR, 0.72; 95% CI, 0.49 to 1.05). With avelumab and chemotherapy, treatment-related adverse events (TRAEs) occurred in 149 (61.3%) and 184 (77.3%) patients, including grade ≥ 3 TRAEs in 31 (12.8%) and 78 (32.8%) patients, respectively. CONCLUSION: JAVELIN Gastric 100 did not demonstrate superior OS with avelumab maintenance versus continued chemotherapy in patients with advanced GC or GEJC overall or in a prespecified PD-L1-positive population.

Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study.

OBJECTIVES: In the phase III CASPIAN study, first-line durvalumab plus etoposide in combination with either cisplatin or carboplatin (EP) significantly improved overall survival (primary endpoint) versus EP alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) at the interim analysis. Here we report patient-reported outcomes (PROs). MATERIALS AND METHODS: Treatment-naïve patients with ES-SCLC received 4 cycles of durvalumab plus EP every 3 weeks followed by maintenance durvalumab every 4 weeks until progression, or up to 6 cycles of EP every 3 weeks. PROs, assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13), were prespecified secondary endpoints. Changes from baseline to disease progression or 12 months in prespecified key disease-related symptoms (cough, dyspnea, chest pain, fatigue, appetite loss) were analyzed with a mixed model for repeated measures. Time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization was analyzed. RESULTS: In the durvalumab plus EP and EP arms, 261 and 260 patients were PRO-evaluable. Patients in both arms experienced numerically reduced symptom burden over 12 months or until progression for key symptoms. For the improvements from baseline in appetite loss, the between-arm difference was statistically significant, favoring durvalumab plus EP (difference, -4.5; 99% CI: -9.04, -0.04; nominal p = 0.009). Patients experienced longer TTD with durvalumab plus EP versus EP for all symptoms (hazard ratio [95% CI] for key symptoms: cough 0.78 [0.600‒1.026]; dyspnea 0.79 [0.625‒1.006]; chest pain 0.76 [0.575‒0.996]; fatigue 0.82 [0.653‒1.027]; appetite loss 0.70 [0.542‒0.899]), functioning, and global health status/QoL. CONCLUSION: Addition of durvalumab to first-line EP maintained QoL and delayed worsening of patient-reported symptoms, functioning, and global health status/QoL compared with EP.

Health-related quality of life associated with trifluridine/tipiracil in heavily pretreated metastatic gastric cancer: results from TAGS.

BACKGROUND: In TAGS, an international, double-blind, phase 3 trial, trifluridine/tipiracil significantly improved overall survival and progression-free survival compared with placebo in heavily pretreated metastatic gastric cancer patients. This paper reports pre-specified quality of life (QoL) outcomes for TAGS. METHODS: Patients were randomized 2:1 to trifluridine/tipiracil (35 mg/m2 twice daily on days 1-5 and 8-12 of each 28-day cycle) plus best supportive care (BSC) or placebo plus BSC. QoL was evaluated at baseline and at each treatment cycle, using the EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires; results were considered valid for analysis only if ≥ 10% of patients completed the questionnaires. Key QoL outcomes were mean changes from baseline and time to deterioration in QoL. A post hoc analysis assessed the association between QoL and time to deterioration of Eastern Cooperative Oncology Group performance score (ECOG PS) to ≥ 2. RESULTS: Of 507 randomized patients, 496 had baseline QoL data available. The analysis cut-off was 6 cycles for trifluridine/tipiracil and 3 cycles for placebo. In both treatment groups, there were no clinically significant deteriorations in the mean QLQ-C30 Global Health Status (GHS) score, or in most subscale scores. In a sensitivity analysis including death and disease progression as events, there was a trend towards trifluridine/tipiracil reducing the risk of deterioration of QoL scores compared with placebo. Deterioration in the GHS score was associated with deterioration in ECOG PS. CONCLUSION: QoL was maintained in TAGS, and there was a trend towards trifluridine/tipiracil reducing the risk of QoL deterioration compared with placebo. Trial registration ClinicalTrials.gov number: NCT02500043.

Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC. METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. FUNDING: AstraZeneca.

Maintenance avelumab versus continuation of first-line chemotherapy in gastric cancer: JAVELIN Gastric 100 study design.

Avelumab is a human anti-PD-L1 IgG1 monoclonal antibody that has shown antitumor activity in early phase studies in advanced/metastatic gastric/gastroesophageal junction cancer, including as first-line maintenance therapy. Here, we describe the design of JAVELIN Gastric 100 (NCT02625610), an open-label, Phase III trial. A total of 499 patients with locally advanced/metastatic HER2- gastric/gastroesophageal junction cancer adenocarcinoma, who had achieved at least stable disease following 12 weeks of first-line oxaliplatin/fluoropyrimidine chemotherapy, have been randomized 1:1 to receive avelumab maintenance therapy or continue chemotherapy. The primary objective is to demonstrate superior overall survival in all randomized patients or in the PD-L1+ population. Secondary objectives are to demonstrate superiority for progression-free survival and objective response rate, compare quality of life measures, and determine safety.

Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Trifluridine/tipiracil showed activity and was well tolerated in a phase 2 study of pretreated patients with advanced gastric cancer done in Japan. We investigated whether the treatment was efficacious compared with placebo in a global population. METHODS: TAGS was a randomised, double-blind, placebo-controlled, phase 3 trial done in 110 academic hospitals in 17 countries. Patients aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression were eligible for inclusion. Patients were randomly assigned (2:1) via dynamic randomisation from a centralised interactive voice-response system to receive either oral trifluridine/tipiracil (35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days) plus best supportive care or placebo plus best supportive care. Participants were allocated to groups by study-site personnel. Randomisation was stratified by region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no). Both patients and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT02500043. The trial, including follow-up of all participants, has been completed. FINDINGS: Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group. Median overall survival was 5·7 months (95% CI 4·8-6·2) in the trifluridine/tipiracil group and 3·6 months (3·1-4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56-0·85]; one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of any cause occurred in 267 (80%) patients in the trifluridine/tipiracil group and 97 (58%) in the placebo group. The most frequent grade 3 or worse adverse events of any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the trifluridine/tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) in the placebo group. Serious adverse events of any cause were reported in 143 (43%) patients in the trifluridine/tipiracil group and 70 (42%) in the placebo group. One treatment-related death was reported in each group (because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of toxic hepatitis in the placebo group). INTERPRETATION: Trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer. Trifluridine/tipiracil could be a new treatment option in this population who represent a high unmet medical need. FUNDING: Taiho Oncology and Taiho Pharmaceutical.

Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. OBJECTIVE: To determine if continuous blockade of EGFR by Sym004 has survival benefit. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator's choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-type KRAS exon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. INTERVENTIONS: Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator's choice of treatment (arm C). MAIN OUTCOMES AND MEASURES: Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. RESULTS: A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n = 160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). CONCLUSIONS AND RELEVANCE: Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2013-003829-29.