First-line Treatment For Patients Research Articles

Afatinib (Afa) + bevacizumab (Bev) versus afatinib alone as first-line treatment of patients with EGFR-mutated advanced non-squamous NSCLC: Primary analysis of the multicenter, randomized, phase II study—AfaBev-CS study.

9112 Background: Adding Bev to erlotinib prolonged PFS in NEJ026 and CTONG1509 trials, but limited data are available adding Bev to a second-generation EGFR-tyrosine kinase inhibitor. AfaBev-CS is a Japanese no-profit, randomized, open-label, multicenter phase II trial of Afa plus Bev vs Afa alone as first-line treatment for EGFR-mutated advanced NSCLC. Methods: This study enrolled untreated pts of advanced non-squamous NSCLC harboring EGFR sensitizing mutation (Del19 or L858R) and without symptomatic brain metastases. 100 eligible pts were randomized in a 1:1 ratio to receive either Afa (30 mg, daily) plus Bev (15 mg/kg, every 3 weeks) (AfaBev arm) or Afa (40 mg, daily) monotherapy (Afa arm), and stratified according to stage, EGFR mutation status and institution. The primary endpoint was PFS and the secondary endpoints were OS, tumor response and time to treatment failure. The sample size was set in terms of feasibility. The power is greater than 50% under the assumptions of a median PFS of 12 months for the Afa arm and HR of 0.6 for the AfaBev arm, with an accrual of 2.5 years and a minimum planned follow-up period of 2 years with the type 1 error of 0.05 (two-sided). Results: Between August 2017 and September 2019, 100 pts were enrolled (each arm, 50 pts). At a median follow-up of 31.3 months for all randomized pts, total 69 events occurred. Median PFS was 16.3 months for AfaBev arm and 16.1 months for Afa arm, with a hazard ratio (HR) of 0.865 (95%CI, 0.539 – 1.388; loglank p = 0.5476). In subgroup analysis, pts < 70 years old (HR 0.347) and pts with brain metastasis (HR 0.353) showed better trend of PFS in AfaBev arm. On the other hand, pts ≥ 70 years old (HR 1.738) and pts without brain metastasis (HR 1.196) did not show better trend in AfaBev arm. In terms of OS, result was immature because number of events was still small. Objective response rate was 77.6% in AfaBev arm and 72.0% in Afa arm. Severe adverse events were observed in 11 pts for each arm. Grade 3 or more diarrhea, hypertension, rash acneiform, paronychia and stomatitis were frequently observed in AfaBev arm. Pneumonitis was not observed for AfaBev arm and observed in 3 (6.0%) for Afa arm, and grade 3 in one patient. Conclusions: This study failed to show the efficacy of AfaBev arm for improving PFS in untreated pts with EGFR mutated non-squamous NSCLC. In pts < 70 years old, Afa plus Bev might be promising. Clinical trial information: jRCTs061180006.

O-1 Outcomes by primary tumour location in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study

The double-blind, phase 3 TOPAZ-1 study (NCT03875235) evaluated the efficacy and safety of durvalumab plus gemcitabine and cisplatin (GemCis) as first-line treatment for patients with advanced biliary tract cancer (BTC; Oh D-Y et al. J Clin Oncol 2022;40[suppl 4]. Abs 378). Durvalumab plus GemCis significantly improved overall survival (OS) versus placebo plus GemCis and represents a potential new first-line treatment option. In BTC, primary tumour location (intrahepatic or extrahepatic cholangiocarcinoma [IHCC/EHCC], or gallbladder cancer [GBC]) may impact risk factors, prognoses, and response to treatment.

Aumolertinib plus apatinib versus aumolertinib as first-line treatment in patients with EGFR mutation–positive locally advanced or metastatic non–small cell lung cancer (NSCLC).

TPS9151 Background: Currently, EGFR-TKIs are widely accepted as the standard treatment for EGFR-mutant advanced NSCLC; however, acquired resistance is inevitable. Preclinical and clinical evidence has demonstrated that dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutant advanced NSCLC population to overcome the resistance to EGFR-TKIs. Aumolertinib (HS-10296) is a novel, third-generation EGFR-TKI approved in China to treat EGFR mutation positive non-small cell lung cancer. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for NSCLC. Here, we aimed to evaluate the safety and anticancer activity of aumolertinib alone/with apatinib for advanced/metastatic NSCLC patients with EGFR mutation. Methods: The phase III, multicenter, randomized, open-label, controlled study is evaluating the efficacy and safety of aumolertinib plus apatinib versus aumolertinib alone as first line therapy in adult patients with EGFR+ NSCLC. Adult patients with histologically confirmed stage IIIB/IV NSCLC harboring EGFR mutations without prior EGFR TKI treatment are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 300 patients, which will be randomized (1:1) to receive oral aumolertinib once daily 110 mg or adding apatinib 250 mg a day until assessed progressive disease(PD)，stratified by EGFR mutation (Ex19del /L858R/others) and distant metastases sites (brain/liver/others). The primary endpoint is progression free survival assessed by investigators using Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints are disease control rate, duration of response, overall survival and safety. Adverse effects were graded per CTCAE v.4.03. This trial is registered as ChiCTR2100047453. Results: Recruiting. Conclusions: Recruiting. Clinical trial information: ChiCTR2100047453.

Randomized study to investigate a switch maintenance concept with 5-FU plus bevacizumab after FOLFIRI plus cetuximab induction treatment versus continued treatment with FOLFIRI plus cetuximab: Report of a secondary endpoint of the phase-III FIRE-4 study (AIO KRK-0114).

3519 Background: FIRE-4 (AIO KRK-0114) is performed in RAS-wild-type (wt) mCRC patients. This randomized study tests the efficacy of early switch maintenance during 1st-line therapy (part 1) and re-challenge with cetuximab (part 2) in later-line treatment. In part 1, all patients received first-line induction treatment with FOLFIRI plus cetuximab (FOLFIRI/Cet). In arm A, patients were randomized to continue FOLFIRI/Cet until progression or intolerable toxicity. In arm B, patients received FOLFIRI/Cet for 8-12 cycles, after which maintenance therapy with Fluoropyrimidin plus bevacizumab was applied. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab during maintenance therapy may prolong PFS. Methods: Within this randomized, controlled, open-label phase-III study, patients received FOLFIRI (irinotecan plus 5-FU/FA) plus cetuximab every two weeks at the standard dosing schedule. In arm A, FOLFIRI plus cetuximab was continued every 2 weeks until progression or intolerable toxicity. De- and re-escalation was allowed according to the local standard of care. In arm B, patients received 8 cycles of FOLFIRI plus cetuximab (in case of tumor response) or 12 cycles (in case of stable disease) followed by maintenance with Fluoropyrimidin plus bevacizumab (5mg/kg) every two weeks until disease progression or intolerable toxicity. Overall survival after second randomization (part 2) is evaluated as a primary endpoint. Here, we report PFS in first-line (part 1) as a secondary study endpoint of the study. Other secondary endpoints included ORR, OS, safety, and tolerability. Results: From August 2015 to January 2021, 672 patients were randomized and 656 patients were assigned to treatment in 120 German and 10 Austrian centers (327 arm A and 329 in arm B). PFS was comparable between both treatment arms (10.7 vs 11.3 months, HR 0.92 (95% CI: 0.76-1.10), p = 0.36). ORR in evaluable patients was not different and reached 75.7% and 72.3% with a DCR of 94.6% vs. 92.5% in the respective arms. Preliminary OS (≤40% of OS events recorded) was also similar between both arms (HR 1.030; p = 0.81). Updated results will be presented at the meeting. No new or unexpected toxicities were observed. Conclusion: Switch from FOLFIRI cetuximab to maintenance therapy with 5-FU plus bevacizumab did not induce superior efficacy (PFS, ORR, OS) compared to continued application of cetuximab. The results suggest that early switch maintenance from cetuximab to bevacizumab is not effective to postpone disease progression during targeted therapy. FIRE-4 confirms the efficacy of FOLFIRI plus cetuximab as first-line treatment of patients with RAS wild-type mCRC. Clinical trial information: NCT02934529.

FoRT 05-BEAT: A phase II randomized trial comparing atezolizumab versus atezolizumab + bevacizumab as first-line treatment in patients with PD-L1 high advanced/metastatic NSCLC.

TPS9145 Background: Several ongoing phase III studies are evaluating the efficacy of first-line atezolizumab in combination with chemotherapy in patients with non small-cell lung cancer (NSCLC). Among angiogenesis inhibitors, bevacizumab is approved as first-line therapy in combination with chemotherapy or in combination with erlotinib in patients with NSCLC harboring activating EGFR mutations. Recent evidence (Wallin 2016) suggests that the combination of atezolizumab and bevacizumab increases intra-tumoral CD8+T cells, suggesting that dual VEGF and PD-L1 inhibition improves antigen-specific T-cell migration. In addition, preliminary clinical data suggested a strong synergistic effects of bevacizumab with immune checkpoint inhibitors. There is therefore a strong rationale for investigating the combination of atezolizumab and bevacizumab in patients with advanced/metastatic NSCLC. The FoRT 05-BEAT is a multicenter, Italian, phase II, randomized study comparing atezolizumab monotherapy versus the combination of atezolizumab and bevacizumab in patients with chemo-naive metastatic NSCLC and high levels of PD-L1 expression. Methods: The trial was conducted in 35 Italian centers: chemotherapy naive metastatic NSCLC patients, with high levels of PD-L1 expression (PD-L1 TPS ≥50% or TC/IC 3 scoring) were randomly assigned to atezolizumab monotherapy (1200 mg every 3 weeks) or to the combination of atezolizumab (1200 mg every 3 weeks) and bevacizumab (15 mg/kg every 3 weeks).The primary endpoint is overall survival (OS) rate at 18 months. Secondary endpoints include response rate (RR), PFS, OS according to presence of bone and/or hepatic metastases. Safety considerations will be considered. Exploratory analysis of predictive biomarker on tumor tissue and blood samples has been planned. Sample size has been calculated assuming a 18 months OS of 50% in the atezolizumab arm. Therefore, a total of 186 patients is needed to detect an absolute improvement of 20%, thus obtaining a 18mOS of 70% in the combination arm, with a power of 80% at a significance level of 5%. Taking into account the percentage of patients lost-to-follow-up, the sample size has been increased by 10% (N = 206 patients, 103 per arm). At the drafting of this abstract, 57 patients have already been enrolled (47 randomized). Clinical trial information: NCT03896074.

Trial in progress: A phase 2 study of sotorasib as first-line treatment in patients with stage IV non–small cell lung cancer (NSCLC) whose tumors harbor a KRAS p.G12C mutation (CodeBreaK 201).

TPS9150 Background: Chemo-immunotherapy regimens represent a standard of care for the first-line treatment of metastatic NSCLC, yet clinical outcomes in patients bearing tumors that lack PD-L1 expression [PD-L1 Tumor Proportion Score (TPS) < 1%)] or harbor a serine/threonine kinase 11 ( STK11) mutation remain poor. Sotorasib is a selective, irreversible small molecule KRASG12C inhibitor that is approved for the treatment of patients with locally advanced or metastatic KRAS p.G12C-mutated NSCLC following failure of at least one prior line of systemic therapy and has previously demonstrated robust antitumor activity in subgroups of KRAS p.G12C mutant NSCLC with PD-L1 TPS <1% and/or STK11 co-mutations. We hypothesized that sotorasib may represent an effective first-line therapy for subgroups of NSCLC patients who may have suboptimal chemo-immunotherapy outcomes and a high unmet clinical need. Methods: This phase 2, open-label, global study is designed to evaluate the efficacy and safety of sotorasib (960 mg or 240 mg daily) as first-line treatment in approximately 170 patients with KRAS p.G12C-mutated, metastatic NSCLC with PD-L1 TPS <1% as determined by immunohistochemical assay and/or presence of STK11 mutation as determined by next-generation sequencing (NGS). Key eligibility criteria include patients with untreated metastatic NSCLC without active brain metastases. Patients will be stratified by known presence of STK11 mutation. The primary endpoint is objective response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints include disease control, duration of response, time to response, progression-free survival per RECIST 1.1, overall survival, safety and tolerability, and pharmacokinetic profile. Enrollment began in January 2022 and is ongoing. Contact Amgen Medical Information for more information. Clinical trial information: NCT04933695.

Phase 2 trial of enoblituzumab plus retifanlimab or tebotelimab in first-line treatment of patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

TPS6102 Background: Head and neck cancer accounts for ̃900,000 cases and over 400,000 annual deaths worldwide as of 2021. Pts with R/M SCCHN have a poor prognosis with median overall survival <1 year. Programmed death (PD)-protein 1 (PD-1) and PD-ligand 1 (PD-L1) blockade has shown antitumor activity in advanced SCCHN. Enoblituzumab (MGA271) is an investigational monoclonal antibody (mAb) that binds B7-homolog 3 (B7-H3) with enhanced binding to the activating Fc gamma receptor CD16A, particularly the low-affinity allele CD16A-158. B7-H3 is overexpressed in many cancers, including SCCHN, but not in most normal tissues. Retifanlimab (MGA012, INCMGA00012) is an investigational anti-PD-1 mAb, blocking binding of PD-L1 or PD-ligand 2 (PD-L2) to PD-1. Tebotelimab (MGD013) is an investigational, Fc-bearing bispecific, tetravalent DART® molecule designed to bind PD-1 and lymphocyte activation gene 3, inhibiting their interaction with PD-L1 or PD-L2 and major histocompatibility complex class II. In vitro data suggest that both retifanlimab and tebotelimab have potential to sustain enoblituzumab-mediated immune activation and antitumor activity (Obara G, et al. Ann Oncol. 2021;32[suppl 5]:S814). Combination of enoblituzumab with retifanlimab or tebotelimab sustained the ability of natural killer cells and CD8+ T cells to produce interferon gamma upon restimulation. Both retifanlimab and tebotelimab enhanced enoblituzumab-dependent cytotoxicity targeting B7-H3–expressing tumor cells. In a phase 1/2 study, the combination of enoblituzumab with pembrolizumab was well tolerated (Aggarwal C, et al. J Immunother Cancer. 2022 [under review]). The overall response rate in anti-PD-1/PD-L1–naïve pts with SCCHN (post platinum) was 33% (6/18), including 1 confirmed complete and 5 confirmed partial responses, warranting further development of this combination in R/M SCCHN. Methods: This is an open-label, nonrandomized study in first-line treatment of pts with R/M SCCHN. Approximately 50 pts with PD-L1 combined positive score (CPS) ≥1 will receive enoblituzumab 15 mg/kg plus retifanlimab 375 mg and 30 pts with CPS <1 will receive enoblituzumab 15 mg/kg plus tebotelimab 600 mg. Dosing is once every 3 weeks with tumor assessment at the end of Cycle 2 and every 3 cycles thereafter. Pts with no prior systemic therapy for R/M SCCHN are eligible. Pts who completed systemic therapy >6 months before the study, if given as part of multimodal treatment for locally advanced disease, are eligible. In the tebotelimab cohort, safety data will be reviewed for dose-limiting toxicities through Cycle 2 Day 7 on the first 12 pts (2 mini cohorts of 6 pts each). All pts will be followed for survival after the last dose of study drug. The first pt was enrolled in March 2021, and 28 pts are on treatment as of January 19, 2022. Clinical trial information: NCT04634825.

SO-17 A randomized, open-label, multicenter, phase III study of high-dose vitamin C plus FOLFOX +/- bevacizumab versus FOLFOX +/- bevacizumab as first-line treatment in patients with unresectable metastatic colorectal cancer

Previous studies showed that intravenously high dose vitamin C probably have anti-cancer effect. Preclinical study found that high dose vitamin C selectively killed human colorectal cancer cells harboring KRAS or BRAF mutations. Our phase I dose-escalation and expansion study has shown that high dose (up to 1.5g/kg) intravenous vitamin C with FOLFOX or FOLFIRI is well tolerated in patients with colorectal or gastric cancer. This is a randomized, open-label, phase III study, enrolled patients with unresectable metastatic colorectal cancer (mCRC), normal G6PD status and no prior treatment. Patients with mCRC were randomized 1:1 into one of two groups. Patients in the control group were treated with FOLFOX with or without bevacizumab every 2 weeks. Patients in the experimental group were treated with vitamin C intravenously (1.5g/kg/day, d1-3) plus FOLFOX with or without bevacizumab every 2 weeks. Randomization was stratified by the location of primary site (left- or right-sided) and treatment with bevacizumab (with or without). The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate, assessment of treatment-related adverse events (TRAEs), and PFS and OS in RAS or BRAF mutant patients. Between July 2017 and December 2019, 442 patients were randomized 1:1 into the control group (chemotherapy only) and the experimental group (chemotherapy plus high-dose vitamin C) respectively. After a median follow-up of 24.5 months (95% confidence interval [CI], 23.4 to 27.2 months), chemotherapy plus high dose vitamin C was not superior to chemotherapy only group in terms of PFS (8.6 vs 8.3 months; hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.70-1.05, P = 0.1). An overall response, as evaluated with Response Evaluation Criteria in Solid Tumors version 1.1, was observed in 44.3% of the patients in the experimental group and 42.1% in the control group. In the prespecified subgroup analysis, patients with RAS mutation (HR = 0.67, 95%CI, 0.50-0.91) showed significantly improved PFS in the experimental group than in the control group. Patients with RAS mutation showed longer PFS in the experimental group than in the control group (9.2 vs 7.8 months, P = 0.01). TRAEs of grade 3 or higher occurred in 33.5% of the patients in the experimental group, as compared with 30.3% in the control group. High-dose vitamin C plus FOLFOX with or without bevacizumab failed to show superior PFS than FOLFOX with or without bevacizumab in patients with mCRC as first-line treatment, but showed some benefit in patients with RAS mutation.

Drug-Related Pneumonitis Induced by Osimertinib as First-Line Treatment for Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Real-World Setting

Osimertinib has demonstrated impressive efficacy as a first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive (m+) lung cancer. Drug-related pneumonitis (DRP) is a potentially lethal complication of osimertinib treatment, but reliable real-world data currently are lacking. What is the prevalence of osimertinib-induced DRP in first-line settings? What are the characteristics, clinical impact, and risk factors of osimertinib-induced DRP? We conducted a retrospective multicenter cohort study of patients who received osimertinib as a first-line treatment for advanced EGFR m+ non-small cell lung cancer (NSCLC) between August 2018 and December 2019. All chest CT scans and clinical information during osimertinib exposure were collected until June 2020. The primary end point was DRP incidence identified through central review. A total of 452 patients from 18 institutions were evaluated. Eighty patients (18%) had a diagnosis of DRP (all grades), and 21 patients (4.6%) had a diagnosis of grade 3 or more DRP. Among the patients with DRP, 46%were identified as having transient asymptomatic pulmonary opacity (TAPO). Regarding the CT scan patterns, organizing pneumonia, simple pulmonary eosinophilia, hypersensitivity pneumonia, diffuse alveolar damage, and nonspecific interstitial pneumonia were found in 30, 21, 18, 9, and two patients (38%, 26%, 23%, 11%, and 3%), respectively. In multivariate analysis, smoking history was identified as an independent risk factor for DRP (hazard ratio, 1.72; 95%CI, 1.01-2.89; P= .046). In the 3-month landmark analysis, DRP was associated with poor treatment efficacy; however, the presence of TAPO did not affect treatment efficacy negatively. For osimertinib treatment in first-line settings, the frequency of DRP was considerably elevated to 18 %, and half of these patients exhibited TAPO features.

TACTI-003: A randomized phase IIb study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab as first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma.

TPS6099 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein targeting a subset of MHC class II molecules that mediate antigen presenting cell (APC) and CD8 T-cell activation. Data from a non-randomized, phase II trial of efti plus pembrolizumab (TACTI-002) showed encouraging antitumor activity and manageable safety when given as second-line treatment of patients with recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC). TACTI-003 (NCT04811027) is a multicenter, open label, randomized phase IIb trial to investigate efti plus pembrolizumab in the first-line setting for RM-HNSCC. Methods: A total of 154 patients (pts) are currently being recruited into two cohorts (A+B). In cohort A, pts with tumors that are CPS≥1 will be randomly assigned 1:1 to receive either efti (30 mg subcutaneously Q2W for initial 6 months, thereafter Q3W) plus pembrolizumab (400 mg intravenously Q6W) for up to two years or pembrolizumab alone. Randomization will be stratified by CPS (1-19 vs. ≥ 20) and ECOG PS (0 vs. 1). Pts with tumors that are CPS < 1 will receive efti plus pembrolizumab (cohort B). Imaging will be performed every 9 weeks. The primary endpoint (EP) is objective response rate (ORR) by RECIST1.1. Secondary EPs include overall survival, ORR according to iRECIST, time to and duration of response, disease control rate, progression-free survival, occurrence of anti-efti -specific antibodies, safety, and quality of life. Exploratory endpoints comprise biomarkers. The study has been approved by relevant competent authorities, ethic committees and IRBs. Clinical trial information: NCT04811027.

Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Analysis of progression after first subsequent therapy in KEYNOTE-426.

4513 Background: The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) met its primary and key secondary end points of improved OS, PFS, and ORR with pembro + axi versus sunitinib as first-line treatment for patients with advanced ccRCC. Extended follow-up (42.8-mo median follow-up) continued to show the superior efficacy of pembro + axi versus sunitinib in this patient population. We describe the results of PFS2 for all randomly assigned patients and across IMDC risk categories. Methods: Treatment-naive patients with advanced ccRCC, Karnofsky Performance Status Scale score ≥70% and measurable disease per RECIST v1.1 were randomly assigned 1:1 to receive pembro 200 mg IV every 3 weeks for up to 35 doses (̃2 y) + axi 5 mg orally twice daily or sunitinib 50 mg orally once daily on a 4-wk on/2-wk off schedule. The end point of this exploratory analysis was PFS2, defined as time from randomization to progression after first subsequent therapy or any-cause death. The Kaplan-Meier method was used to estimate PFS2 and hazard ratios were estimated using a Cox regression model. Results: Of 861 patients, 432 were assigned to receive pembro + axi; 429, to sunitinib. Median time from randomization to the database cutoff date (January 11, 2021) was 42.8 mo (range, 35.6-50.6). Overall, 47.2% of patients (204/432) in the pembro + axi arm and 65.5% of patients (281/429) in the sunitinib arm received ≥1 line of subsequent anticancer therapy. For patients who received subsequent therapy, anti–PD-1/PD-L1 agents were the first subsequent treatment for 11.3% of patients (23/204) in the pembro + axi arm and 54.8% of patients (154/281) in the sunitinib arm. In the pembro + axi arm, 82.8% of patients (169/204) received a VEGF/VEGFR inhibitor as first subsequent therapy, as did 43.4% (122/281) in the sunitinib arm. PFS2 results are displayed in the Table. Conclusions: In this exploratory analysis, PFS2 was longer for patients randomized to pembro + axi compared to sunitinib. Results were consistent across IMDC risk groups. These data support use of pembro + axi for the first-line treatment of patients with advanced ccRCC. Clinical trial information: NCT02853331. [Table: see text]

CPGJ602 plus mFOLFOX6 as first-line treatment for patients with KRAS/NRAS/BRAF wild-type metastatic colorectal cancer: A randomized phase II study.

3574 Background: CPGJ602 is a recombinant anti-EGFR human-mouse chimeric monoclonal antibody. CPGJ602 plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) may have efficacy in KRAS/NRAS/BRAF wild-type metastatic colorectal cancer. Methods: In this open-label, randomized trial, patients who had received no previous treatment were randomly assigned (2:2:1) to receive CPGJ60（325mg/m2, q2w) plus mFOLFOX6 (biweekly group), CPGJ602 (400 mg/m 2 initial dose followed by 250 mg/m2 /week thereafter) plus mFOLFOX6 (weekly group) or cetuximab (400 mg/m2 initial dose followed by 250 mg/m2 /week thereafter) plus mFOLFOX6 (cetuximab group). All subjects received treatment up to 16 weeks. The primary endpoint was the best overall response (BOR) at 16 weeks. The second endpoints were DCR, DOR, PFS, safety. Results: As of Dec 30, 2021, 76 patients were enrolled (30 in biweekly group, 32 in weekly group and 14 in control group). The best overall response achieved at 16 weeks was 76.7% (23/30, 95% CI 60.3% - 92.0%),78.1% (25/32, 95% CI 62.5% - 92.5%) and 78.6% (11/14, 95% CI 49.2% - 95.3%) in the biweekly group, weekly group and cetuximab group, respectively. The confirmed overall response rate at 16 weeks was 60%(18/30), 71.9%(23/32) and 57.1%(8/14) in the biweekly group, weekly group and cetuximab group, respectively. The PFS rates at 16 weeks were 81.5% (95% CI 57.7% -92.6%), 96.8% (95% CI 79.2%-99.5%), 81.3% (95% CI 41.5%- 95.2%) in the biweekly group, weekly group and cetuximab group, respectively. The most common adverse events were a decreased neutrophil count (60%，78.1% and 71.4% in the biweekly group, weekly group and cetuximab group respectively), decreased white-cell count (53.3%, 78.1% and 71.4% respectively), decreased platelet count (40.0%, 40.6% and 42.9% respectively), and elevated serum aspartate aminotransferase (43.3%, 37.5% and 35.7% respectively). Conclusions: CPGJ602 plus mFOLFOX6 could be an option for KRAS/NRAS/BRAF wild-type metastatic colorectal cancer. Clinical trial information: NCT04466254.

Dosage of joint mobilisation for the management of rotator cuff-related shoulder pain: protocol for a scoping review

IntroductionRotator cuff-related shoulder pain is the most common diagnosis of shoulder pain, which ranks as the third most common musculoskeletal disorder. The first-line treatment for patients with rotator cuff-related shoulder...

P-68 Regorafenib monotherapy as second-line treatment of patients with RAS-mutant advanced colorectal cancer (STREAM): An academic, multicenter, single-arm, two-stage, phase 2 study

Therapeutic options after first-line treatment in patients with RAS mutant metastatic colorectal cancer (mCRC) are limited by poor clinical outcomes and lack of activity of anti-epidermal growth factor receptor drugs. Maintaining angiogenesis inhibition and switching the chemotherapy backbone represents the current therapeutic strategy of second-line mCRC therapy. Regorafenib, an oral broad-spectrum multikinase inhibitor targeting angiogenesis, has been shown to prolong overall survival (OS) and is approved after progression on chemotherapy. STREAM trial was an academic, multicentric, phase 2, single-arm, Simon’s two-stage design, aimed to establish the activity of regorafenib, defined as the rate of patients alive and progression free after 6months from study entry (6mo-PFS) in patients with RAS mutant mCRC, after progression on fluoropyrimidine, oxaliplatin and bevacizumab.Setting α and β errors at 0.10, defining a 6mo-PFS rate of 30% as p0 and 50% as p1, to consider the study positive ≧8 patients without progression at 6mo, were needed in the first stage (N=22) and ≧18 in the overall population (N=46). Regorafenib was administered orally at the approved schedule of 160mg day1-21 q28. Secondary endpoints were the evaluation of toxicity, objective response rate (ORR), progression-free survival (PFS), OS. Early metabolic response assessed by PET-CT scan after 2 weeks of treatment was an exploratory endpoint. Translational analyses are ongoing and will be presented at a later stage. Between November 2015, and December 2020, 46 patients were enrolled. median age was 67ys; 80.4% had ECOG performance status 0, 32.6% single organ involvement, 26% lung-limited disease. The study did not meet its predefined primary endpoint. Eight of the first 22 patients and 14 in the overall population were 6mo-PFS, as compared to the 18 required by the study protocol. At a median follow-up of 50.2 months (95%CI=24.2-56.3), ORR was 10.9%, Disease Control Rate (DCR) was 54.6%, median (m)PFS was 3.6mo (95%CI=1.9-6.7).Despite the short mPFS, regorafenib did not preclude a subsequent treatment: mPFS2 (from study entry to progression to subsequent treatment line) was 13.3mo (95%CI=8.4-19.7) and mOS was 18.9mo (95%CI=10.3-35.3). No unexpected toxicity was reported. Grade≥3 AEs occurred in 18 patients(39.1%), mostly hand foot syndrome(13%), fatigue and bilirubin increase(6.5%). Early metabolic response with PET/CT was not associated with ORR, mPFS and mOS. Baseline metabolic assessment, not predictive of ORR and mPFS, was significantly associated with mOS. A subgroup of patients, with single organ involvement, mostly lung-limited disease, low baseline PET-CT parameters, a low rate of early progression in first line (<6months=21.4%) and a long mPFS2 (23.3mo 95%CI=13.3-39.9), reported a long disease control with regorafenib: ORR=35.7%; mPFS=10.2mo (95%CI =8.6-13.5), mOS=38.8mo (95%CI=23.9-NR). Conversely, patients with higher radiological and metabolic burden of disease, higher rate of early progression in first-line (<6months=56.3%) and a shorter mPFS2 (8.4mo CI95%=6.1-13.3), reported unfavorable outcomes. Despite the study did not meet its primary endpoint, treatment with regorafenib had no unexpected toxicity and did not preclude efficacy of subsequent treatments. A subgroup of patients characterized by good prognostic features (limited disease, lung metastasis and low metabolic burden) had clinical benefit with regorafenib. Appropriate patients selection might guide the clinical development of regorafenib in an earlier setting, ensuring a chemotherapy-free interval in the treatment sequence.

Patient-reported outcomes for the phase 3 TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer.

4070 Background: TOPAZ-1 (NCT03875235) is a randomized, double-blind, global, Phase 3 study evaluating the efficacy and safety of durvalumab (D) in combination with (+) gemcitabine and cisplatin (GC) as first-line treatment for patients (pts) with advanced biliary tract cancer (BTC).1 D + GC significantly improved overall survival (OS) versus placebo (PBO) + GC and represents a new treatment option. Methods: A pre-planned secondary objective of TOPAZ-1 was to assess pt-reported outcomes (PROs) for pts receiving D + GC versus PBO + GC. Pts with BTC were randomized 1:1 to D (1500 mg) or PBO, + G (1000 mg/m2) and C (25 mg/m2), for up to 8 cycles, followed by D or PBO monotherapy until disease progression, unacceptable toxicity, or other discontinuation criteria were met. PROs were assessed with the European Organisation for Research and Treatment of Cancer 30-item Quality of Life (QoL) Questionnaire, EORTC QLQ-C30 (C30), and the BTC 21-item module, EORTC QLQ-BIL21 (BIL21). Time to deterioration (TTD) was the primary assessment of PROs; defined as the time from randomization to the date of the first pre-specified, clinically meaningful deterioration (e.g. disease progression). The PRO analysis set included all pts from the full analysis set who completed a questionnaire. Results: Compliance rates for PROs were high at baseline (&gt;81%) and remained high (majority &gt;70% over 28 cycles) for both treatment groups. Baseline scores were comparable between treatment groups. Addition of D was well tolerated, with no significant difference in TTD in D + GC versus PBO + GC for pt-reported symptoms or functioning using either C30 or BIL21 (Table), or Global Health Status/QoL (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.69–1.12; p=0.279). Conclusions: Addition of D to GC improved OS (Oh D-Y, et al. J Clin Oncol 2022;40(suppl 4). Abs 378) and was well tolerated with no difference in TTD of QoL for pts, supporting D + GC as a new treatment option for pts with BTC. Clinical trial information: NCT03875235. [Table: see text]

Switch of Nocturnal Non-Invasive Positive Pressure Ventilation (NPPV) in Obstructive Sleep Apnea (OSA).

Background. Continuous positive airway pressure (CPAP) is considered the first-line treatment for patients with OSA, but Bilevel-PAP (BiPAP) therapy is a recognized option for noncompliant/unresponsive patients to CPAP. The present study was designed to evaluate the role of ResMed VAuto in the management of two different issues raised because of the Philips recall: the treatment of naïve noncompliant/unresponsive patients to CPAP (Group A) and the switch to VAuto for patients already on treatment with Philips Auto-BiPAP (Group B). Methods. Sixty-four patients who required auto-BiPAP treatment from August to December 2021 were included in the study. The efficacy of each mode of PAP therapy was compared between the two groups of patients. Results. Group A showed a statistically significant improvement in the apnea–hypopnea index (AHI) (7.4 ± 8.5 events·h−1 vs. 15.2 ± 12.1 events·h−1, p < 0.001), and oxygen desaturation index (ODI) (9.4 ± 8.9 events·h−1 vs. 15.2 ± 8.8 events·h−1, p = 0.029) during VAuto in comparison to CPAP, respectively. Conversely, a similar trend was found for patients in Group B for global AHI, but a statistically significant reduction was just found in supine AHI and ODI. In group B, an AHI <5 events·h−1 was found in 89.3% during VAuto in comparison to 82.1% with Philips Auto-BiPAP (p = ns). The levels of IPAPmax and EPAPmin were not statistically different between the two devices (p = 0.69 and p = 0.36, respectively). Conclusion. Bilevel ventilation in VAuto mode is effective in the clinical management of two different issues derived from the Philips recall. The switching between two different auto-BiPAP devices can be performed easily and successfully.

Regional subgroup analysis of the phase 3 TOPAZ-1 study of durvalumab (D) plus gemcitabine and cisplatin (GC) in advanced biliary tract cancer (BTC).

4075 Background: TOPAZ-1 (NCT03875235) is a randomized, double-blind, global, Phase 3 study evaluating the efficacy and safety of D + GC as first-line treatment for patients (pts) with advanced BTC. D + GC significantly improved overall survival (OS) versus placebo (PBO) + GC (Oh D-Y, et al. J Clin Oncol 2022;40[suppl 4]. Abs 378). Methods: A pre-specified subgroup analysis was performed for efficacy outcomes including OS for pts enrolled in Asia (China, Hong Kong, India, Japan, South Korea, Taiwan, Thailand) or the rest of the world (RoW; Europe [Bulgaria, France, Italy, Poland, Russia, Turkey, United Kingdom], North America [NA; USA], and South America [SA; Argentina, Chile]). Post hoc country level analyses were also performed to better characterize outcomes in different countries and regions. Pts with BTC were randomized 1:1 to D (1500 mg once every 3 weeks [Q3W]) or PBO, + G (1000 mg/m2) and C (25 mg/m2) on Days 1 and 8, Q3W, for up to 8 cycles, followed by D (1500 mg Q4W) or PBO monotherapy until disease progression or unacceptable toxicity. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from a Cox proportional hazards model. Results: Pt numbers were balanced across regions (Asia, n=374 [54.6%]; RoW, n=311 [45.4%]). Baseline characteristics were balanced between regions with the exception of modest differences in important pre-defined prognostic factors, including disease status: recurrent disease (Asia 23%; RoW 14.5%), ECOG performance status 1 (Asia 59.1%; RoW 41.2%), and metastatic disease (Asia 89.3%; RoW 82%). In the PBO arm, more pts in Asia received subsequent anti-cancer therapies than pts in RoW (53.6% vs 43.9%). Median duration of follow-up in censored pts was about 2 months (mo) longer in Asia versus RoW (14.8 vs 13.0 mo in D + GC; 13.8 vs 12.1 mo in PBO + GC). Regional level analysis (Table) showed outcomes were similar and approximated the overall population for Asia, Europe, and NA. Grade 3/4 adverse events were similar for Asia (D + GC 78.5%; PBO + GC 78.6%) and RoW (D + GC 72.7%; PBO + GC 76.7%). Conclusions: Despite some regional differences in prognostic characteristics, OS trends favored D + GC versus PBO + GC for pts enrolled in both Asia and RoW, supporting the use of D + GC as a potential new treatment option for all pts with BTC. Country-specific and regional outcomes continue to be explored. Clinical trial information: NCT03875235. [Table: see text]

P-285 Q-TWiST analysis for pembrolizumab plus chemotherapy versus chemotherapy as first-line treatment for patients with advanced esophageal cancer in the KEYNOTE-590 study

In the phase 3 KEYNOTE-590 study (NCT03189719), first-line pembrolizumab plus chemotherapy provided statistically significant and clinically meaningful improvement in OS and PFS, maintained HRQoL, and was associated with a manageable safety profile versus chemotherapy in patients with locally advanced, unresectable or metastatic esophageal cancer or Siewert type 1 gastro-esophageal junction adenocarcinoma. The objective of this analysis was to assess Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) among patients receiving pembrolizumab + chemotherapy or chemotherapy in the KEYNOTE-590 study. Q-TWiST analysis divided survival time into 3 health states: time with grade 3+ toxicity before disease progression or death (TOX), time without symptoms or toxicities before progression (TWiST), and time from disease progression (REL). Q-TWiST was calculated as the restricted mean time spent in each health state, weighted by a health-state utility for that particular state, combined. Average utility weights for each health state were based on the pooled EQ-5D health utility score using base case utility weights of Utility[TWiST], 1.0; Utility[TOX], 0.5; and Utility[REL], 0.5. Treatment difference 95% CIs were generated using the non-parametric bootstrapping method. Data are reported for all randomized patients and patients with PD-L1 combined positive score (CPS) ≥10. Relative gains in Q-TWiST of ≥10% and ≥15% have been established as “clinically important” and “clearly clinically important,” respectively, in the literature. Data cutoff, July 2, 2020. In all patients at month 33, patients receiving pembrolizumab + chemotherapy had a 1.51 month (95% CI, 0.10-2.95) longer restricted mean time in TWiST (5.95 vs 4.44 months), 1.59 month (95% CI, 0.76-2.43) longer restricted mean time in TOX (3.71 vs 2.12 months), and a 0.01 month (95% CI, -1.93-1.85) shorter restricted mean time in REL (6.16 vs 6.18 months) versus chemotherapy. For the restricted mean Q-TWIST in all patients, the difference between the pembrolizumab + chemotherapy and chemotherapy arms favored the pembrolizumab + chemotherapy arm by 2.30 months (95% CI, 1.27-3.40; 10.89 vs 8.59 months) at month 33, representing a 18.1% relative Q-TWiST gain. In patients with PD-L1 CPS ≥10, those receiving pembrolizumab + chemotherapy had a 2.24 month (95% CI, 0.08-4.44) longer restricted mean time in TWiST (6.35 vs 4.11 months), 2.16 month (95% CI, 0.82-3.52) longer restricted mean time in TOX (4.39 vs 2.23 months), and a 0.19 month (95% CI, -2.44-2.99) longer restricted mean time in REL (5.98 vs 5.80 months) versus chemotherapy. For the restricted mean Q-TWIST in patients with PD-L1 CPS ≥10, the difference between the pembrolizumab + chemotherapy and chemotherapy arms favored the pembrolizumab + chemotherapy arm by 3.41 months (95% CI, 1.92-4.84; 11.54 vs 8.13 months) at month 33, representing a 28.1% relative Q-TWiST gain. Pembrolizumab + chemotherapy demonstrated clinically meaningful improvement in quality-adjusted survival based on Q-TWIST analyses compared with chemotherapy in patients with advanced esophageal cancer.

Mefatinib as first-line treatment of patients with advanced non–small cell lung cancer harboring rare EGFR mutations.

9102 Background: Mefatinib is a novel, second-generation, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI). A Phase Ib/II study has showed promising efficacy in patients with advanced EGFR (19del/L858R) mutant non-small cell lung cancer (NSCLC). This study is aimed to assess the efficacy and safety of mefatinib as first-line therapy for advanced rare EGFR mutations (G719X/S768I/L861Q) NSCLC. Methods: In this phase II study, we enrolled patients with stage IIIB-IV lung adenocarcinoma with at least one mutation in G719X, L861Q, and S768I who hadn¡¯t received front-line anticancer therapy. Other concurrent EGFR mutations were allowed with the exception of Ex19del, L858R, and exon 20 insertions. Eligible patients were treated with mefatinib 80 mg orally once daily. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 criteria. Results: A total of 21 patients (median age 57.6, 47.62% male) have been enrolled, 80.95% with G719X, 33.3% S768I, and 19.05% L861Q. Six (28.57%) patients had concurrent mutations of G719X and S768I, and one (4.76%) patient had co-mutations of G719X and L861Q. As of data cut-off (Jan, 6, 2022), median follow-up was 25.1 months. Among the 21 efficacy evaluable patients, ORR was 85.71% (95% CI, 63.66-96.95) with a duration of response (DOR) of 22.2 months (95% CI, 8.4-NA). Disease control rate (DCR) was 100% (95% CI, 83.89-100.00). Median progression-free survival (mPFS) was 20.6 months (95% CI, 8.3-NA). Median overall survival (OS) was not reached.. The most common treatment-related adverse events (TRAEs) were rash (20, 95.24%), diarrhea (19, 90.48%), stomatitis (15, 71.43%), and pandactilitis (9, 42.86%). Grade 3 TRAEs were reported in 47.63% patients. Common Grade 3 TRAEs (¡Ý5%) included diarrhea (8, 38.10%) and rash (5, 23.81%). No ¡ÝGrade 4 TRAE or treatment-related SAE reported. 33.33% (n=7) of patients experienced dose reduction due to AEs (mainly diarrhea and rash). All TRAEs were reversible and remained stable or recovered without sequelae after dose reduction. None of the patients discontinued treatment or died due to TRAE. Conclusions: Mefatinib has shown promising anti-tumor activity and a favorable safety profile in patients with advanced NSCLC harboring rare EGFR mutations. Clinical trial information: CTR20190110. [Table: see text]

Influence of KDR Genetic Variation on the Effectiveness and Safety of Bevacizumab in the First-Line Treatment for Patients with Advanced Colorectal Cancer.

ObjectiveBevacizumab is usually considered a first-line anti-tumor therapy, which inhibits tumor growth by downregulating the vascular endothelial growth factor (VEGF) that further silences the activity of the kinase insert region receptor (KDR) gene. In the current study, we investigated the treatment response of bevacizumab in advanced colorectal cancer (CRC) patients bearing 889 C>T mutation in the KDR gene.MethodsA total of 135 advanced CRC patients were treated with bevacizumab along with chemotherapy at the seventh medical center of the People’s Liberation Army general hospital from January 2012 to June 2021 and were analyzed retrospectively. The KDR genotyping and mRNA expression analyses were performed in 57 patients.ResultsThe KDR genotyping revealed 97 (71.85%) cases with CC genotype, 34 (25.19%) cases with CT, and 4 (2.96%) cases with TT genotype, while the minor allele frequency of 889 C>T was found as 0.16. The median progression-free survival (PFS) of the patients with CT/TT genotype and CC genotype was found to be 6.1 and 9.7 months, respectively (P = 0.009). The median overall survival (OS) of the two genotypes was 13.7 and 19.7 (P = 0.025), respectively. Multivariable Cox regression analysis of PFS, CT/TT genotype was found to be an independent factor for PFS (odds ratio (OR) = 1.88, P = 0.023). Additionally, the mRNA expression of KDR in 57 biopsies taken from patients with CT/TT genotypes was significantly higher than that of patients with CC genotype (P < 0.001). Additionally, in terms of safety, 55 patients experienced grade 2 or higher fatigue (incidence rate 40.74%) after receiving bevacizumab along with chemotherapy.ConclusionThe 889 C>T mutation in KDR gene affects the KDR expression in colorectal cancer patients, thereby affecting the effectiveness of bevacizumab therapy.