First-line pembrolizumab plus chemotherapy versus chemotherapy alone for advanced esophageal cancer: 5-year extended follow-up in the Japanese subgroup of KEYNOTE-590.

Brief Report: First-line Pembrolizumab in Metastatic Non-Small Cell Lung Cancer Habouring MET Exon 14 Skipping Mutation and PD-L1 ≥50% (GFPC 01-20 Study)

In the global phase 3 KEYNOTE-966 study (NCT04003636), pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group) showed a statistically significant, clinically meaningful improvement in overall survival (OS) versus placebo plus gemcitabine and cisplatin (placebo group) without any new safety signals in participants with advanced biliary tract cancer (BTC). This analysis focused on the subgroup of participants from KEYNOTE-966 enrolled in China. Adults with previously untreated advanced BTC were randomly assigned (1:1) to receive pembrolizumab 200mg or placebo intravenously every 3weeks plus gemcitabine 1000mg/m2 and cisplatin 25mg/m2 intravenously on days 1 and 8 of every 3-week cycle. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR), all per RECIST v1.1 by blinded independent central review, and safety. One hundred fifty-eight participants were enrolled in China (75, pembrolizumab group; 83, placebo group). Median time from randomization to data cutoff (December 15, 2022) was 20.5 (range, 15.0-28.8)months. Median OS was 14.1 (95% CI, 10.4-17.7)months in the pembrolizumab group versus 9.9 (95% CI, 8.6-13.0)months in the placebo group (HR, 0.74; 95% CI, 0.51-1.08); median PFS was 5.6 (95% CI, 3.2-7.4)months versus 5.7 (95% CI, 4.4-6.9; HR, 0.83 [95% CI, 0.58-1.19])months; ORR was 36.0% (95% CI, 25.2-47.9) versus 28.9% (95% CI, 19.5-39.9); median DOR was 10.2 (range, 1.2+ to 20.6)months versus 5.7 (range, 1.4+ to 18.2)months. Grade 3 or 4 treatment-related adverse events occurred in 53 participants (71.6%) in the pembrolizumab group versus 58 (70.7%) in the placebo group; no treatment-related grade 5 events occurred. Consistent with the KEYNOTE-966 global population, first-line pembrolizumab plus gemcitabine and cisplatin provided a numeric improvement in OS versus placebo plus gemcitabine and cisplatin and no new safety signals in participants enrolled in China. ClinicalTrials.gov identifier-NCT04003636.

BackgroundFirst-line pembrolizumab plus lenvatinib showed durable responses in participants with advanced non–clear cell renal cell carcinoma (nccRCC) in the single-arm, phase 2 KEYNOTE-B61 study (NCT04704219). Responses were observed across subtypes including papillary, chromophobe, and unclassified histologies. We present results from KEYNOTE-B61 with approximately 18 months of additional follow-up from the previous analysis.MethodsAdults with previously untreated, advanced nccRCC and measurable disease per RECIST v1.1 received pembrolizumab 400 mg intravenously every 6 weeks for up to 18 cycles (approximately 2 years) plus lenvatinib 20 mg by mouth once daily until intolerable toxicity, progressive disease, or participant withdrawal. The primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, overall survival (OS), and safety and tolerability. Histologic subtypes were determined by investigator assessment and retrospectively reviewed by central pathology.ResultsOverall, 158 participants received pembrolizumab plus lenvatinib. Median study follow-up (time from first dose to the data cutoff date of January 27, 2025) was 41.6 months (range, 35.4-46.4). Of 158 participants, 93 (58.9%) had papillary, 29 (18.4%) had chromophobe, and 20 (12.7%) had unclassified histologies, and 16 (10.1%) had translocation (n = 6), medullary (n = 1), or other (n = 9) histologic subtypes. As of the data cutoff date, 121 of 158 participants (76.6%) had discontinued treatment, most commonly due to disease progression (n = 81, 51.3%). A total of 61 of 158 participants (38.6%) received subsequent anticancer therapy, most commonly cabozantinib (n = 38, 24.1%). In all participants, ORR was 50.6% (n = 80; 95% CI, 42.6-58.7), with 16 complete responses and 64 partial responses. ORR was generally consistent across histologic subtypes, including chromophobe (33.3%) and papillary (52.9%). Median DOR was 23.5 months (range, 1.5+ to 40.2+); 34.6% of responders remained in response for ≥36 months per Kaplan-Meier estimates. In all participants, median PFS was 17.9 months (95% CI, 15.0-21.1); the 24- and 36-month PFS rates were 39.2% and 26.4%, respectively. Median OS was 41.5 months (95% CI, 32.8 to not reached [NR]); the 24- and 36-month OS rates were 66.5% and 53.7%, respectively. Based on histologic subtype, median PFS was 18.2 months (95% CI, 15.0-21.0) for participants with papillary nccRCC and 11.3 months (95% CI, 6.7-29.0) for participants with chromophobe nccRCC (table). Median OS was 37.5 months (95% CI, 27.1-NR) and NR (95% CI, 21.7-NR) for papillary and chromophobe histology, respectively. Grade 3 or 4 treatment-related adverse events occurred in 95 participants (60.1%) and most commonly included (≥5%) hypertension (25.9%), proteinuria (7.6%), diarrhea (6.3%), and weight decreased (6.3%). No deaths due to treatment-related adverse events occurred.Table.ConclusionsAfter a minimum of 3 years of follow-up, pembrolizumab plus lenvatinib continued to demonstrate durable responses and promising survival outcomes in the first-line setting for advanced nccRCC. With additional follow-up, 3 additional complete responses from the previous data cutoff were observed. No new safety signals have been reported with extended follow-up. Results from KEYNOTE-B61 support the use of pembrolizumab plus lenvatinib as a first-line treatment option for patients with nccRCC regardless of histology.

4049 Background: In the randomized, double-blind, placebo-controlled, multicenter, phase 3 KEYNOTE-590 study (NCT03189719), pembrolizumab + chemotherapy provided superior OS, PFS, and ORR versus chemotherapy with a manageable safety profile in patients with untreated locally advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric junction (EGJ) adenocarcinoma. We present results from the subgroup of patients enrolled in China. Methods: Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo Q3W for ≤35 cycles (̃2 years) + chemotherapy (cisplatin 80 mg/m2 Q3W [d1; 6 doses] + 5-FU 800 mg/m2 on d1-d5 Q3W). Randomization was stratified by region, histology, and ECOG performance status. Primary end points were OS in patients with ESCC PD-L1 combined positive score (CPS) ≥10 tumors and OS and PFS (RECIST v1.1; by investigator) in ESCC, PD-L1 CPS ≥10, and all patients; ORR (RECIST v1.1; by investigator) in all patients was the key secondary end point. Data cutoff was July 2, 2020. Results: Of 749 patients enrolled, 106 (14.2%) enrolled in China (51 in pembrolizumab + chemotherapy arm; 55 in chemotherapy arm); 88.7% were male and 49.1% had PD-L1 CPS ≥10. In Chinese patients, ECOG performance status 1 (81.1% vs 59.8%) and ESCC (98.1% vs 73.2%) were more prevalent than they were in all patients enrolled in the study. Additionally, in Chinese patients (pembrolizumab + chemotherapy vs chemotherapy), median OS was 10.5 months versus 8.0 months (HR, 0.51; 95% CI, 0.32-0.81), median PFS was 6.2 months versus 4.6 months (HR, 0.60; 95% CI, 0.39-0.92), ORR was 37.3% versus 20.0%, and median DOR (range) was 6.4 months (2.2+ to 18.9+) versus 4.0 months (1.5+ to 16.6+). Grade 3 or 4 treatment-related adverse events (TRAEs) were reported in 74.5% of patients in the pembrolizumab + chemotherapy arm and 66.7% in the chemotherapy arm; no grade 5 events were reported. Eight patients (15.7%) in the pembrolizumab + chemotherapy arm and 3 patients (5.6%) in the chemotherapy arm discontinued because of TRAEs. Immune-mediated AEs (defined for the safety profile of pembrolizumab as events with potentially treatment-related immunologic causes) were reported in 21.6% of patients in the pembrolizumab + chemotherapy arm and 13.0% in the chemotherapy arm; most were grade 1 or 2 and were manageable with interruption or discontinuation of study drug or standard medical therapy. Conclusions: In Chinese patients with advanced esophageal or EGJ cancer, pembrolizumab + chemotherapy improved OS, PFS, and ORR versus chemotherapy as first-line therapy, and safety was manageable. These findings were consistent with those in the global study population. Clinical trial information: NCT03189719.

464 Background: After a median follow-up of 41.6 months, data from the global phase 3 KEYNOTE-859 study (NCT03675737; N = 1579) continued to show that use of pembrolizumab (pembro) plus chemotherapy (chemo) improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), with manageable safety, versus placebo (pbo) plus chemo for patients (pts) with advanced HER2-negative G/GEJ adenocarcinoma. Here, we report updated results from the subgroup analysis of pts enrolled in Asia after an additional 11 months of follow-up from the first interim analysis. Methods: Eligible pts aged ≥18 years with locally advanced unresectable or metastatic HER2-negative G/GEJ adenocarcinoma, an ECOG performance status (PS) of 0 or 1, and measurable disease per RECIST v1.1 were randomly assigned 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles; all pts received investigator’s choice of chemo (FP or CAPOX). The primary end point was OS. Secondary end points included PFS, ORR, and DOR per RECIST v1.1 by blinded independent central review, and safety. Efficacy end points were evaluated in all randomly assigned pts (intention to treat). Results: A total of 525 pts (263, pembro plus chemo; 262, pbo plus chemo) were enrolled in KEYNOTE-859 in Asia. The median time from randomization to database cutoff (August 22, 2023) was 39.2 months (range, 26.0-56.8). The median OS was 17.3 months (95% CI, 14.8-19.5) for pembro plus chemo versus 13.0 months (95% CI, 11.8-14.4) for pbo plus chemo (HR, 0.75; 95% CI, 0.62-0.91). The median PFS was 8.4 months (95% CI, 7.1-9.6) for pembro plus chemo versus 5.8 months (95% CI, 5.6-6.9) for pbo plus chemo (HR, 0.72; 95% CI, 0.58-0.89). The ORR was 61.2% (95% CI, 55.0-67.1; 36, complete response [CR]; 125, partial response [PR]) for pembro plus chemo and 48.5% (95% CI, 42.3-54.7; 24, CR; 103, PR;) for pbo plus chemo. The median DOR was 10.0 months (range, 1.2+ to 50.8+) for pembro plus chemo and 5.8 months (range, 1.3+ to 44.3+) for pbo plus chemo; 28.9% and 23.3% of pts, respectively, had a response lasting ≥24 months. Grade 3-5 treatment-related adverse events (AEs) occurred in 155 pts (59.2%) in the pembro plus chemo group and 119 pts (45.4%) in the pbo plus chemo group. Treatment-related AEs led to death in 1 pt (0.4%) in the pembro plus chemo group (unknown cause) and 2 pts (0.8%) in the pbo plus chemo group (cerebral hemorrhage and abnormal liver function). Immune-mediated AEs and infusion reactions occurred in 85 pts (32.4%) in the pembro plus chemo group and 35 pts (13.4%) in the pbo plus chemo group. Conclusions: The addition of pembro to chemo improved OS, PFS, and ORR in pts with advanced HER2-negative G/GEJ adenocarcinoma from Asia enrolled in KEYNOTE-859, with no new safety signals. These results further support first-line pembro plus chemo as a treatment option for this population. Clinical trial information: NCT03675737 .

e16052 Background: Immunotherapy, particularly with anti-PD-1/PD-L1 antibodies, has shown therapeutic efficacy in various malignancies. Compared with chemotherapy, anti-PD-1 antibody monotherapy improved the median overall survival in advanced or metastatic esophageal cancer. The combination of an anti-PD-1/PD-L1 antibody with an angiogenesis inhibitor has shown efficacy in many cancers which including esophageal cancer. The purpose of this study is to investigate the efficacy and safety of anlotinib plus PD-1 inhibitors as chemo-free therapy during the treatment of esophageal cancer in the real world setting. Methods: This prospective, multicenter real-world study (NCT04966611) evaluated the efficacy and safety of anlotinib plus PD-1 inhibitors in the chemo-free therapy setting for advanced or metastatic esophageal cancer patients (pts). Primary endpoint was evaluation of PFS (progression-free survival), and secondary endpoints included ORR (objective response rate), DCR (disease control rate) and OS (overall survival). The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: Between May 2020 and Dec 2021, 50 pts were enrolled. 45 comprised the evaluable population. In the full analysis set, 44 had squamous cell and 1 patient had adenocarcinoma histology. 29 (64.4%) of 45 pts were male. 10 (22.2%) had an ECOG performance status of 0, 32 (71.1%) status of 1 and 3 (6.7%) status of 2. Twenty (44.4%) pts had distant metastases and 29(64.4%) pts had comorbidities. 15 pts had previously used anti-PD-1/PD-L1 antibody or vascular targeting drugs, of which 5 cases had combined the two drugs. Among all evaluable pts, 5(11.1%) pts received first-line, 27(60.0%) second-line and 13(28.9%) third & above line therapy. Among all pts, 1 patient achieved complete response (CR), 16 pts partial response (PR), 25 pts stable disease (SD), illustrating an ORR of 37.8% and a DCR of 93.3%. In the first line therapy, ORR was 60.0%, DCR was 100%.In the second line therapy, ORR was 37.0%, DCR was 96.3%. In the third & above line, ORR with 30.8%, DCR with 84.6% was observed. Median PFS was not reached. Treatment related adverse events (trAEs) were reported in 24 pts(53.3%). No patient had grade 3 or more trAEs. Conclusions: Anlotinib plus PD-1 inhibitors in chemo-free therapy for advanced or metastatic esophageal cancer was active and showed excellent tumor response and was generally well tolerated. Further investigation is required in a larger real-world cohort to validate the benefit of anlotinib plus PD-1 inhibitor in esophageal cancer. Clinical trial information: NCT04966611.

4524 Background: In the open-label, single-arm, phase 2 CheckMate 275 trial, objective response rate (ORR) for patients (pts) with metastatic urothelial carcinoma (mUC) with nivolumab (NIVO) was 20.4% with minimum follow-up of 21.3 mo. Here, we report updated efficacy and safety data with minimum follow-up of 33.7 mo. Methods: Pts with platinum-resistant locally advanced or metastatic urothelial carcinoma received NIVO 3 mg/kg until disease progression or unacceptable toxicity. The primary endpoint was ORR by blinded independent review committee (BIRC) by RECIST v1.1 (including duration of response [DOR]). Secondary endpoints included progression-free survival (PFS) by BIRC, overall survival (OS), and ORR per investigator. Efficacy was evaluated in all treated pts and by tumor PD-L1 expression. Safety and PFS by investigator were exploratory endpoints. Results: ORR by BIRC was 20.7% (95% CI 16.1–26.1) including 18 (7%) complete responses (CR; with 1 additional CR since the last report; Table). ORR per investigator was similar (24.8%). Median DOR by BIRC was 20.3 mo (95% CI 11.5–31.3). Of 56 pts with best overall response (BOR) of CR or partial response (PR), 59% had a DOR ≥12 mo. Median PFS (mPFS) was 1.9 mo per BIRC (95% CI 1.9–2.3; Table) and 2.0 mo per investigator (95% CI 1.9–2.5). Median OS (mOS) was 8.6 mo (95% CI 6.1–11.3; Table). 12, 24, and 36-mo OS rates were 40%, 30%, and 22%. While efficacy was numerically higher in pts with tumor PD-L1 expression ≥1%, efficacy was observed in all pts (Table). Any-grade treatment-related adverse events occurred in 69% of pts (grade 3–4, 25%), mostly (59%) within the first 3 mo of initiating therapy. Conclusions: With long-term follow-up from CheckMate 275, NIVO continues to provide durable antitumor activity in pts with mUC. No new safety signals were noted. Clinical trial information: NCT02387996. [Table: see text]

IntroductionResults of the global, randomized, phase 3 KEYNOTE-859 study (N = 1579) showed that first-line pembrolizumab plus chemotherapy produced a statistically significant and clinically meaningful improvement in overall survival (OS) with manageable toxicity versus placebo plus chemotherapy in patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)–negative gastric or gastroesophageal junction cancer. This subgroup analysis was conducted to investigate outcomes in patients enrolled in mainland China.MethodsAdults with previously untreated advanced or metastatic HER2-negative gastric cancer or gastroesophageal junction adenocarcinoma were randomly assigned (1:1) to receive pembrolizumab or placebo with fluoropyrimidine- and platinum-containing chemotherapy. The primary outcome was OS. Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR), all assessed per RECIST v1.1 by blinded independent central review, and safety.ResultsOverall, 236 patients were enrolled in mainland China (126 pembrolizumab plus chemotherapy; 110 placebo plus chemotherapy). Median time from randomization to database cutoff (October 3, 2022) was 24.7 months (range 15.3–38.9). Median OS was 15.9 months (95% confidence interval [CI] 13.2–19.2) for pembrolizumab plus chemotherapy versus 12.2 months (95% CI 10.6–14.1) for placebo plus chemotherapy (hazard ratio [HR], 0.68; 95% CI 0.50–0.91). Median PFS was 8.1 months (95% CI 6.9–9.6) for pembrolizumab plus chemotherapy versus 5.7 months (95% CI 4.5–6.5) for placebo plus chemotherapy (HR, 0.65; 95% CI 0.48–0.88). ORR was 69.0% for pembrolizumab plus chemotherapy versus 45.5% for placebo plus chemotherapy; median DOR was 8.2 months (range 1.2+ to 34.6+) versus 5.5 months (range 1.3+ to 31.2+), respectively. Grade 3–5 treatment-related adverse events occurred in 82 patients (65.6%) treated with pembrolizumab plus chemotherapy and 54 patients (49.1%) treated with placebo plus chemotherapy.ConclusionConsistent with efficacy in the overall population from KEYNOTE-859, first-line pembrolizumab plus chemotherapy showed improved efficacy, versus placebo plus chemotherapy, and manageable safety in patients enrolled in mainland China.Trial RegistrationClinicaltrials.gov: NCT03675737.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-024-03069-4.

Linvoseltamab in Patients with Relapsed/Refractory Multiple Myeloma: Longer Follow-up and Selected High-Risk Subgroup Analyses of the Linker-MM1 Study

Dear Editor, Uncommon mutations in exons 18-21 of the epidermal growth factor receptor (EGFR) gene account for 10%–15% of all EGFR mutations when considered as a whole group [1, 2]. However, each variant confers heterogeneous clinical outcomes to different generations of EGFR tyrosine kinase inhibitors (TKIs) with G719X, L861Q, and/or S768I showing adequate sensitivity to EGFR inhibition [1-3]. Osimertinib, based on its superior survival outcomes, has become the preferred first-line treatment for patients diagnosed with advanced non-small cell lung cancer (NSCLC) harboring common EGFR mutations [4]; however, its efficacy in patients harboring G719X, S768I, and/or L861Q mutations was comparable or even inferior to Afatinib [5]. Afatinib, a second-generation EGFR-TKI, has received approval for extended clinical indication in treating previously untreated patients with metastatic NSCLC harboring G719X, L861Q, and/or S768I based on the findings from the pooled analysis of three clinical trials (LUX-Lung 2/3/6) [2]. The real-world clinical efficacy of Afatinib for treating this patient subset has been consistently demonstrated by two large retrospective studies [6, 7]. In China, chemotherapy remains a standard first-line treatment for this patient subset, with Afatinib available only as an off-label treatment option. Mefatinib is a novel, second-generation EGFR-TKI with promising clinical efficacy and safety for patients with common EGFR mutations [8]. Here, we report the results of the phase II open-label, single-arm, multicenter study investigating the efficacy and safety of Mefatinib as first-line therapy for patients with NSCLC harboring uncommon EGFR mutations (ChiCTR2000029058). Details of the study methods are provided in the Supplementary Materials. The pre-planned sample size was 50; however, patient recruitment was discontinued due to slow recruitment. Figure 1A illustrates the study flow diagram. Of the 32 patients screened between March 2019 and October 2019, 21 treatment-naïve patients with stage IIIB–IV NSCLC detected with at least 1 EGFR G719X, S768I, and/or L861Q mutations based on a central lab next-generation sequencing (Burning Rock Biotech, Guangzhou, China) analysis of tissue or malignant effusion samples were included in the study. Supplementary Table S1 summarizes the baseline characteristics of this cohort. First-line Mefatinib therapy is associated with a high ORR and longer PFS in patients with stage IIIB–IV NSCLC harboring EGFR G719X, S768I, and/or L861Q mutations (n = 21). (A). Study flow chart. (B). Waterfall plot illustrating the best percentage change in target lesion size after Mefatinib therapy (relative to baseline). Measurable lesions were assessed at baseline and after 1 cycle of Mefatinib therapy based on RECIST version 1.1. Tumor shrinkage of 30% from baseline is evaluated as partial response. An increase of > 20% from baseline was evaluated as progressive disease. Color denotes the EGFR mutation of each patient. (C). Table summarizing the treatment and survival outcomes of the cohort and subgroups of uncommon EGFR mutation types. Treatment outcomes were presented as the number of cases and the corresponding percentage of patients whose disease was evaluated as a partial response or stable disease. PFS was calculated for all patients, whereas the duration of response was only calculated among Mefatinib responders. (D–E). Kaplan-Meier curves illustrating the PFS (D) and OS (E) of 21 patients with uncommon EGFR mutations who received Mefatinib as first-line therapy. Gray shadow represents 95% CI. The dotted line indicates the median survival. Tick marks denote censored events. The risk table below the plot shows the number of events/patients included in the survival analysis per time point. Abbreviations: CI, confidence intervals; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria of Solid Tumors. All 21 patients received Mefatinib at a daily oral dose of 80 mg as first-line therapy. The primary endpoint was objective response rate (ORR) by the investigator's assessment. Tumor shrinkage was observed in 20 patients (Figure 1B). Figure 1C summarizes the clinical outcomes of the cohort and subgroups of uncommon EGFR mutation types. ORR of the cohort was 85.7% (95% confidence intervals [CI]: 63.7-97.0). The respective ORR and median progression-free survival (PFS) was 94.1% and 20.6 months for patients with G719X (n = 17), 75.0% and 18.7 months for patients with L861Q (n = 4), and 71.4% and 20.6 months for patients with S768I (n = 7). At the data cutoff date (December 31, 2021), the median duration of follow-up was 26.7 (range: 2.3-32.8) months. The median PFS was 20.6 months (95% CI: 8.3–NR) (Figure 1D). At 3 months and 6 months, 90.5% (n = 19) and 85.7% (n = 18) of patients remained progression-free; while 57.1% (n = 12) remained progression-free at 12 months. No patient died while receiving Mefatinib, with all patients alive at 12 months. The overall survival (OS) data remains immature (Figure 1E). Based on these findings, Mefatinib had generally comparable ORR but had better PFS outcomes than those reported for Afatinib and Osimertinib [2, 5, 6, 9]; however, these comparisons should be considered with caution due to the difference in sample size and overall treatment history of the patients. As summarized in Supplementary Table S2, the ORR and PFS with different EGFR-TKIs were heterogeneous for the three subtypes of uncommon EGFR mutations, but the long-term efficacy of Mefatinib was demonstrated by its durable disease control and promising OS benefit. The results of our current study were also consistent with the efficacy of first-line Mefatinib therapy in patients with common EGFR mutations [8]. Our previous phase II study reported an ORR of 84.9%, DCR of 97.2%, median PFS of 15.4 months, and median OS of 31.6 months with common EGFR mutations with consistent long-term efficacy regardless of EGFR mutation subtypes (i.e., L858R, common and uncommon 19del), and concurrent TP53 mutation status [8]. Together, our current clinical findings suggest that Mefatinib is active across common and uncommon EGFR subtypes. Based on its promising benefit for survival outcomes, Mefatinib may potentially serve as a best-in-class EGFR-TKI for uncommon EGFR mutations. Furthermore, first-line Mefatinib therapy demonstrated a manageable toxicity profile. Grade 3 treatment-related adverse events (TRAEs) primarily involved gastrointestinal and skin disorders, including diarrhea (n = 8), rash (n = 5), and oral mucositis (n = 1) (Supplementary Table S3). All patients reported at least 1 TRAE, but no unexpected and Grade 4-5 TRAEs were observed (Supplementary Table S4). Intolerable grade 1-3 toxicities were observed in 57.1% (12/21), which were managed by treatment interruption and/or dose modifications (Supplementary Table S5). In vitro assays have also demonstrated that treatment with Mefatinib or Afatinib effectively inhibited the proliferation of cell lines expressing G719S, S768I, or L861Q (Supplementary Figure S1, Supplementary Table S6). An unpublished pharmacokinetic dose-escalation study demonstrated a Mefatinib exposure (measured as the area under the plasma concentration-time curve over the time interval from 0 to 24 hr post-dose [AUC0-24]) of 4393 ng·h/mL for 80 mg Mefatinib. The AUC0-24 observed for Mefatinib was much higher than the reported AUC0-24 of 498 ng·h/mL for Afatinib 40 mg daily [10], which may explain the better clinical efficacy observed with Mefatinib therapy. The main limitation of this study is its small cohort, which severely limits further subgroup analysis. Our study on patients with common EGFR mutations found that a lower 60 mg dose had comparable efficacy but was more tolerable than the higher 80 mg dose [8]; however, Mefatinib was only administered at one dose level due to the small cohort of our study. The rarity of G719X, S768I, and/or L861Q mutations severely limited patient recruitment. Although patient recruitment was initiated in multiple institutions, the uncertainty in clinical outcomes associated with investigational drugs and the availability of approved treatment options might have influenced the treatment decisions of some patients. The third limitation is the absence of an assessment of Mefatinib's efficacy in the central nervous system (CNS) for patients with uncommon EGFR mutation. All patients enrolled in this study were not detected with CNS metastasis at initial diagnosis. Our earlier observation on the efficacy of first-line Mefatinib in NSCLC patients harboring common EGFR mutations with CNS metastasis at baseline [8] raises the possibility of Mefatinib's CNS activity in patients with uncommon EGFR mutations; however, clinical data is needed to support this speculation. In conclusion, our study provides preliminary clinical evidence that first-line Mefatinib therapy was effective, provides durable PFS, and has a manageable toxicity profile in patients with stage IIIB–IV NSCLC harboring EGFR G719X, S768I, and/or L861Q mutations. This study did not reach the planned accrual; hence, clinical evidence from a larger cohort is needed to establish Mefatinib efficacy in this patient subset. Based on these encouraging clinical and survival outcomes from a small cohort, Mefatinib could potentially serve as an alternative treatment regimen to target both common and uncommon EGFR mutations in advanced NSCLC. Yong Song and Kai Wang contributed to the study design. Pingli Wang, Liming Cao, Panwen Tian, Shengxiang Ren, Liyun Miao, Chengzhi Zhou, Yun Fan, Yuping Li, Dongqing Lv, Xin Zhao, Yong Song, and Kai Wang provided study participants. All authors contributed to data analysis and data interpretation, manuscript revision and editing. All authors reviewed and approved the final version of the manuscript. The corresponding authors take full responsibility for the credibility of the descriptions of data presented in this work. Funding for the study was provided by Hangzhou Zhongmei Huadong Pharmaceutical Company. Medical writing support was provided by Dr. Analyn Lizaso, funded by Hangzhou Zhongmei Huadong Pharmaceutical Company. The authors would like to thank all the patients and their families for their participation and cooperation and the clinical study teams who were part of the study. Mei Yang, Chaonan Zhu, Bing Yu, and June Xu are employees of Hangzhou Zhongmei Huadong Pharmaceutical Company. All the other authors declare no conflict of interest. This study was funded by Hangzhou Zhongmei Huadong Pharmaceutical Company. The study protocol was approved by the institutional ethics board of The Second Affiliated Hospital Zhejiang University School of Medicine (Approval number: 2018-0216) and the ethics board of the other participating centers. Written informed consent was obtained from all study participants. Not applicable. This phase II study on Mefatinib was registered on the Chinese Clinical Trial Registry (ChiCTR2000029058). The data that supports the findings of this study are available from the corresponding authors upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

At present, albumin-bound paclitaxel combined with platinum is the standard first-line treatment option for advanced esophageal cancer (EC). However, following a hospitalization surge, clinicians may prefer to use albumin-bound paclitaxel as a single dose. The present study aimed to investigate the survival of patients with advanced EC when treated with single or fractionated doses of albumin-bound paclitaxel. We collected survival data of patients with advanced first-line EC who had used albumin-bound paclitaxel with or without other treatment regimens from January 2018 to September 2023 at the Harbin Medical University Cancer Hospital and the Shanxi Province Cancer Hospital. The patients were divided into two groups according to the frequency and dose of albumin-bound paclitaxel administration, namely the abraxane fractional administration group (A group, 27 patients) and the abraxane single administration group (B group, 182 patients). The median progression-free survival (PFS) was 9.0 months in both groups (p = 0.35), and the median overall survival (OS) was 21.0 months in A group and 18.0 months in B group (p = 0.61). The objective response rate was 37% in A group and 25% in B group (p = 0.314), and the disease control rate was 89% in A group and 83% in B group (p = 0.580). The incidence of grade 3 or higher treatment-related adverse events was 15% in both groups. Albumin-bound paclitaxel treatments showed no statistically significant differences in the PFS or OS. They were considered safe, whether administered as a single dose or in fractionated doses.

Introduction: In the phase 3 KEYNOTE-048 trial (NCT02358031) in R/M HNSCC, first-line pembrolizumab (P) monotherapy vs EXTREME (E; chemotherapy [C] + cetuximab) improved overall survival (OS) in PD-L1 combined positive score (CPS) ≥20 and CPS ≥1 populations and led to noninferior OS in the total population with favorable safety; first-line P+C vs E had superior OS in CPS ≥20, CPS ≥1, and total populations with comparable safety. Outcomes in CPS <1 and CPS 1-19 subgroups were not prospectively defined end points; we present a post hoc analysis in these subgroups. Methods: Patients with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to P, P+C, or E. Progression-free survival (PFS), objective response rate (ORR), and duration of response were assessed by RECIST v1.1 per blinded independent central review. OS and PFS were estimated by the Kaplan-Meier method. Hazard ratios and 95% CIs were based on a Cox regression model with Efron's method of tie handling, with treatment as a covariate. Data cutoff was Feb 25, 2019. Results: Baseline characteristics of the CPS <1, CPS 1-19, and CPS ≥20 subgroups were similar to those of the total population. In the CPS <1 subgroup, the HR (95% CI) for OS was 1.51 (0.96-2.37) for P (n = 44) vs E (n = 45) and 1.21 (0.76-1.94) for P+C (n = 39) vs E (n = 43) (Table). In the CPS 1-19 subgroup, HR (95% CI) for OS showed a slight advantage of P (n = 124) vs E (n =133) (0.86 [0.66-1.12]) and favored P+C (n = 116) vs E (n = 125) (0.71 [0.54-0.94]). Conclusions: There was overall evidence of increased efficacy with increasing PD-L1 expression. In the CPS 1-19 subgroup, P+C vs E results were consistent with treatment benefit. Analysis of the CPS <1 subgroup was limited by small patient numbers. Future exploratory analyses of tumor mutational burden and inflamed signatures could further evaluate predictors of benefit in patients with low PD-L1-expressing HNSCC. Table.Efficacy in subgroups of patients with PD-L1 CPS <1, CPS 1-19, and CPS ≥20CPS subgroupTreatmentMedian OS, moOS HR12-mo OS rate, %Median PFS, moPFS HRORR, nMedian DOR, mo(95% CI)(95% CI)(95% CI)(95% CI)(95% CI)(%)(range)<1Pembrolizumab7.91.5138.62.14.3122.6n = 44(4.7-13.6)(0.96-2.37)(24.5-52.6)(1.9-2.3)(2.63-7.08)(4.5)(2.2-3.0)<1EXTREME11.3_48.96.2_197.8n = 45(9.1-15.9)(33.7-62.4)(5.1-7.6)(42.2)(2.0-38.6+)<1Pembrolizumab + Chemotherapy11.31.2141.04.71.46125.7n = 39(9.5-14.0)(0.76-1.94)(25.7-55.8)(3.4-6.2)(0.93-2.30)(30.8)(2.6-20.6+)<1EXTREME10.7_46.56.2_174.3n = 43(8.5-15.9)(31.2-60.4)(5.0-7.3)(39.5)(2.0-31.2+)1-19Pembrolizumab10.80.8644.02.21.2518NRn = 124(9.0-12.6)(0.66-1.12)(35.1-52.5)(2.1-2.9)(0.96-1.61)(14.5)(1.5+-38.9+)1-19EXTREME10.1_42.44.9_455.0n = 133(8.7-12.1)(33.9-50.7)(3.8-6.0)(33.8)(1.4+-38.7+)1-19Pembrolizumab + Chemotherapy12.70.7152.64.90.93345.6n = 116(9.4-15.3)(0.54-0.94)(43.1-61.2)(4.2-5.3)(0.71-1.21)(29.3)(1.6+-25.6+)1-19EXTREME9.9_41.14.9_424.6n = 125(8.6-11.5)(32.4-49.6)(3.7-6.0)(33.6)(1.4+-31.4+)≥20Pembrolizumab14.80.5856.43.40.993122.6n = 133(11.5-20.6)(0.44-0.78)(47.5-64.3)(3.2-3.8)(0.76-1.29)(23.3)(2.7-43.0+)≥20EXTREME10.7_44.95.3_444.2n = 122(8.8-12.8)(35.9-53.4)(4.8-6.3)(36.1)(1.2+-31.5+)≥20Pembrolizumab + Chemotherapy14.70.6057.15.80.76547.1n = 126(10.3-19.3)(0.45-0.82)(48.0-65.2)(4.7-7.6)(0.58-1.01)(42.9)(2.1+-39.0+)≥20EXTREME11.0_46.15.3_424.2n = 110(9.2-13.0)(36.6-55.1)(4.9-6.3)(38.2)(1.2+-31.5+) Citation Format: Barbara Burtness, Danny Rischin, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G. Hughes, Ricard Mesia, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Joy Ge, Ramona Swaby, Burak Gumuscu, Kevin Harrington. Efficacy of first-line (1L) pembrolizumab by PD-L1 combined positive score <1, 1-19, and ≥20 in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): KEYNOTE-048 subgroup analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-258.

Esophageal cancer is the sixth leading cause of carcinoma-associated death and the seventh most clinically diagnosed carcinoma globally, accounting for 544 076 new deaths and 604 127 new cases in year 2020.1 About half of the esophageal cancer cases are diagnosed in China, with 70% of the cases at advanced stages where the opportunity for surgery has been lost. Although chemoradiation can prolong overall survival and improve the locally controlled rate of esophageal cancer, the prognosis of advanced esophageal carcinoma has not significantly improved for a long time. Recently, immune checkpoint inhibitor (ICI) immunotherapy, a new cancer treatment choice, has provided a promising treatment method for a variety of malignant carcinomas and has greatly improved the survival of patients with malignant melanoma, lung cancer, cervical cancer, bladder cancer, and other carcinomas. Several clinical trials have evaluated the treatment efficacy and safety of the ICI pembrolizumab for second-line treatment of advanced esophageal cancer.2-4 In a multiple cohort, a phase IB clinical study of cases with programmed death ligand-1 (PD-L1)-positive advanced esophageal cancer (KEYNOTE-028), patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until confirmed disease progression or intolerable toxicity.3 The results indicated that the objective response rate (ORR) was 28% with a median maintained response of 15 months and median overall survival (OS) and progression-free survival (PFS) of 7 and 1.8 months, respectively. Severe adverse events or death were not recorded in pembrolizumab group. KEYNOTE-028 preliminarily demonstrated the efficacy and safety of pembrolizumab in second-line treatment of advanced esophageal cancer. A phase II clinical study to evaluate the efficacy and safety of pembrolizumab for second-line treatment of advanced esophageal cancer (KEYNOTE-180) further confirmed the potential benefits of pembrolizumab with durable antitumor activity and manageable safety in patients with pretreated advanced esophageal cancer.4 More reliable evidence from a phase III clinical trial (KEYNOTE-181) confirmed pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients of PD-L1 combined positive score (CPS) ≥10, with fewer treatment-related adverse events. In our view, this series of clinical trials from phase I to phase III provide reliable evidence of the efficacy and safety of pembrolizumab as a second-line treatment of advanced esophageal cancer cases with PD-L1 CPS ≥10. However, survival advantages were not found for cases of PDL-1 CPS <10, adenocarcinoma, female, and extra-Asia cases.2 Therefore whether the nonsuperior results for the aforementioned cases are for pembrolizumab itself or a small sample size of subgroup analysis needs further investigation from larger sample size clinical trials.

5536 Background: The anlotinib (a novel multi-target TKI, inhibiting tumor angiogenesis and proliferative signaling) plus sintilimab (an antibody against PD-1) in patients with advanced cervical cancer trial was a multicenter, single-arm, phase II study (ChiCTR1900023015) that showed promising activity. The results of this trial have been previously reported and here we present updated survival data after a median follow-up of 13.0 months. Methods: Pts who have received at least once platinum-based chemotherapy, recurrent advanced cervical cancer, PD-L1 for CPS≥1, ECOG 0-1 were considered eligible for enrollment. Anlotinib was taken orally (10mg, qd, d1-14, 21 days per cycle), and sintilimab was administered intravenously (200mg, q3w, d1). The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS), safety and biomarkers. Results: Between December 2019 and December 2020, 42 patients with a median age of 53 years (range 36 to 67 years) were enrolled and received study treatment (ITT population and safety population). The data cutoff date was February 10, 2022. The patients were followed up for median duration of 13.0 months (range 0.03 to 24.8 months). In the ITT population, 2 (4.8%) patients achieved CR and 21 (50%) attained PR, the confirmed ORR was 54.8% (95% CI 38.7% to 70.2%). Fourteen (33.3%) patients had SD and the DCR was 88.1% (95% CI 74.4% to 96.0%). In the efficacy-evaluable patients (n = 39), the ORR was 59% (95% CI 42.1% to 74.4%) and the DCR was 94.9% (95% CI 82.7% to 99.4%). The median PFS was 9.46 months (95% CI 8.2 to 11.9) and the 6-month PFS rate was 73.4% (95% CI 60.6% to 89.0%). OS events occurred in 18 patients (42.9%). The median OS was 17.4 months (95% CI 12.4 to not reached). The 12-month OS rate and 24-month OS were 71.8% (95% CI 59.0% to 87.4%) and 49.1% (95% CI 34.5% to 69.9%), respectively. Conclusions: Anlotinib plus sintilimab showed a long-term survival benefit for patients with recurrent advanced cervical cancer. Additional investigations in larger randomized controlled trials are warranted in the future. Clinical trial information: ChiCTR1900023015.

4082 Background: Triplet chemotherapy with CF plus docetaxel (DCF) improved survival compared to CF as a neoadjuvant treatment for locally advanced esophageal squamous cell cancer (ESCC) based on the result from JCOG1109 (jRCTs031180202). Here we report results with 5 years minimum follow-up. Methods: Eligible patients (pts) with ESCC of clinical stage IB, II, III (excluding T4) (UICC 7th) from 44 institutions were randomized 1:1:1 to neoadjuvant CF (cisplatin 80 mg/m2 on day1 plus 5-FU 800 mg/m2 on days 1-5 Q3W/2 course), DCF (docetaxel 70 mg/m2 on day 1, cisplatin 70 mg/m2 on day1, plus 5-FU 750 mg/m2 on days 1-5 Q3W/3 course), or CF-RT (cisplatin 75 mg/m2 on day 1 plus 5-FU 1000 mg/m2 on days 1-4 Q4W/2 course, radiation 41.4 Gy/23 fr). Primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), and safety. Differences in OS was assessed in the ITT using the stratified log-rank test. The data cutoff date for the analysis was July 20, 2023. Results: Of 601 pts 199 CF, 202 DCF, and 200 CF-RT were enrolled from December 5, 2012 to July 20, 2018. Among 601 pts, 88.2% were male, median (range) age was 65 (30-75), clinical stage III (nonT4) pts were 62.6%. Median follow-up time (range) was 5.5 years (y) (0-10.6). Median OS in CF, DCF, and CF-RT arm were 5.8 y, 10.2 y, and 8.2 y, and 5-year OS was 51.9%, 65.1%, and 60.2%, respectively (stratified log-rank test: one-sided p = 0.004 for CF vs. DCF and one-sided p = 0.15 for CF vs. CF-RT). By the stratified Cox regression analysis for OS, hazard ratios (HR) [95% CI] with DCF vs. CF was 0.68 [0.51–0.91] and that with CF-RT vs. CF was 0.86 [0.66–1.13]. The HR for OS in exploratory comparison between DCF vs. CF-RT was 0.78 [0.59-1.05]. Median PFS in CF, DCF, and CF-RT arm were 2.7 y, 9.5 y, and 5.8 y, and 5-year PFS was 42.6%, 55.7%, and 53.5%, respectively. In the CF arm, there were initially 4 treatment-related and 15 other deaths, with 1 additional treatment-related and 2 other deaths over two more years. The DCF arm reported 4 and 10 deaths respectively, with 3 additional deaths from other causes. In the CF-RT arm, there were 4 treatment-related and 27 other deaths, followed by 2 more treatment-related and 4 other deaths in the extended period. Conclusions: After 5 years follow-up, neoadjuvant DCF continued to demonstrate clinically meaningful improvements in OS and PFS compared to CF in patients with locally advanced ESCC. Clinical trial information: jRCTs031180202 .