Doublet Chemotherapy Research Articles

Doublet vs. Triplet Systemic Chemotherapy for High Grade Appendiceal Adenocarcinoma with Peritoneal Metastases

Doublet vs. Triplet Systemic Chemotherapy for High Grade Appendiceal Adenocarcinoma with Peritoneal Metastases

Real-world treatment trends and outcomes in elderly patients with metastatic colorectal cancer in the United States.

3591 Background: Prospective data to guide management of elderly patients with metastatic colorectal cancer (mCRC) is limited. Whether elderly patients derive the same degree of benefit from doublet chemotherapy as younger patients is not well understood. In this study we utilized real-world data from patients in the United States (US) to evaluate treatment trends and compare overall survival (OS) in younger versus older patients with mCRC who receive first-line (1L) chemotherapy. Methods: The nationwide Flatiron Health electronic health record-derived de-identified database was used to select patients ≥50 years old (yo) with mCRC treated with 1L fluoropyrimidine-based chemotherapy with or without the addition of targeted therapy. Overall survival from the initiation of 1L therapy, stratified by receipt of a doublet or single agent cytotoxic chemotherapy regimen was assessed independently within three age cohorts (50-69; 70-74, ≥75) using both a cox proportional hazard model and a propensity score weighted analysis to control for potential confounding variables. A subgroup analysis was performed in patients receiving bevacizumab as part of 1L therapy. Results: Of 14,440 patients who received 1L chemotherapy, 5,874 (40.7%) were ≥70 yo, including 3,656 (25.4%) who were 75 or older. Doublet chemotherapy was received by 7,505 (87.6%) patients age 50-64 yo, 1892 (85.3%) patients age 70-74 yo, and 2297 (62.2%) patients age 75 and above. In all three groups, multivariate analysis of single agent chemotherapy vs doublet chemotherapy showed a benefit to doublet chemotherapy with a hazard ratio of 1.14, (95% CI 1.04-1.24, p = 0.006), 1.22 (95% CI 1.05-1.42, p = 0.011) and 1.19 (95% CI 1.10-1.29, p < 0.001), respectively. Similar results were noted when comparing doublet to single agent chemotherapy in the age 70-74 and ≥75 groups using a propensity score weighted analysis. In the subgroup of patients age ≥70 who received 1L bevacizumab, 2,604 received doublet chemotherapy and 441 received single agent chemotherapy. Median OS was 19 mos (95% CI: 18-20) vs 13 (95% CI: 11-15) vs with a propensity score weighted HR of 1.35 (95% CI 1.12-1.63, p = 0.001). Conclusions: A smaller percentage of patients over age 75 receive 1L doublet chemotherapy for mCRC in the US compared to patients age 50-69 or 70-74. Regardless of age, patients who receive doublet fluoropyrimidine-based chemotherapy appear to have improved overall survival compared to single agent chemotherapy. This retrospective US data is in contrast with recently presented data from a prospective phase III trial in Japan (JCOG1018). Elderly patients in the US should not be excluded from receiving doublet chemotherapy for mCRC without further prospective data.

Comparison of bevacizumab plus doublet chemotherapy regimens in patients with metastatic or recurrent ovarian cancer.

e17537 Background: Ovarian cancer is the most common cause of death due to gynecological malignancies. Although the primary treatment is surgery, there are different chemotherapy regimens that can be used in metastatic disease. In this study, it was aimed to compare doublet chemotherapy regimens in combination with bevacizumab in patients with metastatic ovarian cancer. Methods: Our study was designed as a retrospective observational study. The clinical, pathological, radiological, and treatment characteristics of the patients were recorded. Survival analyzes were performed using the Kaplan-Meier method, and multivariate analysis using cox regression analysis. Results: 198 patients were included in the study. Median follow-up period after bevacizumab was 18.7 months. The most common pathological subtype was serous carcinoma (%85.9). Before bevacizumab treatment, 96% of patients received perioperative chemotherapy. The most common sites of metastasis were the peritoneum (94.5%), liver (43.9%), lung (18.7%), bone (4.5%), and brain (3%). In combination with bevacizumab, 92 (46.4%) patients used gemcitabine + carboplatin, 76 (38.4%) patients used paclitaxel + carboplatin, and 30 (15.2%) patients used gemcitabine + cisplatin. In the whole patient group, the rate of complete response was 18.7%, partial response 56.1%, stable disease 6.6%, and progressive disease 18.7%. The patients received a median of 9 cycles of bevacizumab and a median of 7 cycles of doublet chemotherapy. Median progression-free survival was 11.9 (95% CI, 9.2-14.5) months, and median overall survival was 24.7 (95% CI, 19.9-29.4) months. History of surgery before bevacizumab (p=0.006) and type of doublet chemotherapy (p=0.024) were found to be statistically significant factors affecting overall survival. The presence of brain metastases (p=0.062) had borderline significance. Conclusions: Doublet chemotherapy regimens with bevacizumab have been found to be effective and safe in the treatment of metastatic ovarian cancer in terms of survival. The combination of bevacizumab with gemcitabine + carboplatin was superior to other doublet chemotherapy regimens in terms of overall survival.

Optimal molecular-targeted therapies as first-line treatment for RAS wild-type, right-sided metastatic colorectal cancer from the Analysis and Research in Cancers of the Digestive System (ARCAD) database.

3588 Background: Although anti-EGFR antibody plus doublet chemotherapy has become the standard of first-line treatment for RAS wild-type (wt), left sided metastatic colorectal cancer (mCRC), the optimal molecular-targeted therapy for RAS wt, right-sided mCRC is not clear. Methods: To evaluate the efficacy between anti-EGFR antibody vs. bevacizumab combination therapy, from 40,889 Individual patient (pt) data from 59 studies in ARCAD mCRC database, 723 pts with RAS wt, right-sided mCRC who received a first-line molecular-targeted therapy with backbone chemotherapy (FOLFOX/FOLFIRI when anti-EGFR antibody combination, and FOLFOX/FOLFIRI/CAPOX/FOLFOXIRI when bevacizumab combination) were selected from 10 randomized studies (FIRE-3, CALGB80495, CRYSTAL, PRIME, CAIRO2, OPUS, TRIBE, TRIBE2, ATOM, and CCOG1201). Primary objective was overall survival (OS), and secondary objectives were progression-free survival (PFS) and overall response rate (ORR); Hazard ratio (HR) and Odds ratio (OR) were adjusted for ECOG-PS, age, and gender. Propensity score matching (PSM) and inverse probability treatment weighting (IPTW) as sensitivity analysis were also performed. Secondary analyses were limited to BRAF wt pts. Results: Anti-EGFR antibody and bevacizumab were administrated in 329 and 394 pts, respectively, of whom 162 and 151 pts were BRAF wt, respectively. Baseline characteristics were as follows (anti-EGFR antibody/bevacizumab): median age, 63.0 years both; female, 47.1/46.4%; and ECOG-PS 0, 53.2/65.2%. The OS and PFS were significantly prolonged in pts receiving bevacizumab combination therapy compared to those receiving anti-EGFR antibody combination therapy (Table). These trends were more pronounced when limited to BRAF wt pts (Table). There were no significant differences in ORR for both overall and BRAF wt pts. These results were similar in the sensitivity analysis (Table). Conclusions: For patients with RAS wt or RAS/ BRAF wt, right-sided mCRC, bevacizumab combination therapy is preferred first-line treatment. [Table: see text]

Patterns of ovarian cancer care in an elderly population in Australia: A prospective cohort study from the National Gynaecology Oncology Registry (NGOR).

5572 Background: Elderly women with ovarian cancer are often undertreated in comparison to best practice. The National Gynae-Oncology Registry (NGOR) is Australia’s first country-wide clinical quality registry (CQR) measuring compliance with optimal care defined by a set of clinical quality indicators (CQIs). Objectives: To assess compliance with a predefined set of CQIs for elderly women with newly diagnosed ovarian cancer aged > 75 compared to non-elderly women aged <75 years of age from the NGOR sites. Methods: All women with newly diagnosed ovarian cancer from May 2017 – July 2022 were eligible for inclusion. Data were collected from medical records and relevant hospital linked databases by expert data managers. Results: A total of 1590 women were eligible for inclusion from 21 hospitals across 5 Australian states. The CQI data were subsequently aggregated and are summarised in the table. The proportion of elderly women receiving first-line chemotherapy with a platinum and taxane doublet was significantly lower compared to non-elderly (60% vs 89%, p < 0.001). The proportion of women with sub-optimally debulked or Stage IV cancer who received first-line chemotherapy with a platinum/taxane doublet and bevacizumab was significantly lower in elderly women compared to non-elderly (10% vs 30%, p < 0.001) . Enrolment in clinical trials or translational research was significantly lower in elderly women compared to non-elderly (13% vs 21%, p=0.002). The remaining CQIs showed no significant differences between the age groups. Conclusions: In this cohort, most measures of best practice were not significantly different between elderly and non-elderly women, with the exception of elderly women receiving less first line doublet chemotherapy, less doublet chemotherapy with bevacizumab in sub-optimally debulked or Stage IV cancer, and less likely to be enrolled in clinical trials or translational research. While these 3 CQIs represent a minority of the overall list of CQIs, such lack of compliance may result in significant differences in quality of life and overall survival for elderly women with ovarian cancer. Subsequent investigation is therefore warranted to confirm and explain these findings. [Table: see text]

Alliance A022104/NRG-GI010: A randomized phase II trial testing the efficacy of triplet versus doublet chemotherapy to achieve clinical complete response in patients with locally advanced rectal cancer—The Janus Rectal Cancer trial.

TPS3640 Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients (pts) with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated it as a primary endpoint. Collaborating with a multidisciplinary oncology team and pt groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation and improve quality of life for pts. Methods: In this Alliance for Clinical Trials in Oncology randomized phase II trial (1:1), up to 312 pts with microsatellite stable LARC, clinical stage T4N0, any T, N+ or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Pts will be randomized to receive neoadjuvant long course CRT (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks (w) + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Pts will undergo assessment 8-12 w post-TNT completion for the primary endpoint of cCR per previously validated criteria and recommended WW and surveillance if cCR is achieved or TME if an incomplete response is noted. Secondary objectives include time-to event outcomes (disease-free and overall survival, organ preservation time and time to distant metastasis) and adverse effects. Statistical power, based on cCR, incorporates a one-sided alpha = 0.048 and power = 90% yielding 312 patients (156 per arm). Biospecimens including archival tumor tissue, matched / normal blood samples and serial rectal MRI will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and is actively recruiting. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . U10CA180868 (NRG); U10CA180888 (SWOG); Clinicaltrials.gov ID: NCT05610163 Clinical trial information: NCT05610163 .

P-269 Efficacy and safety of doublet adjuvant chemotherapy for elderly patients with stage III colorectal cancer

P-269 Efficacy and safety of doublet adjuvant chemotherapy for elderly patients with stage III colorectal cancer

Trends in presentation, treatment, and survival in young multiple myeloma patients age 50 and under from 2000-2021.

e20028 Background: Multiple myeloma (MM) is a disease predominantly of older adults with an average age of 69 at diagnosis. Limited data is available on the diagnostic details and outcomes of MM patients ≤50 years old, and particularly how these trends have changed over the past two decades. We present data from one of the largest retrospective cohorts of younger MM patients. Methods: This retrospective review identified 213 MM patients by pooling two datasets: 88 MM patients aged ≤50 years at first stem cell transplant (SCT) between 1/1/2000-6/1/2021 at University of California (UC), San Diego; and 125 MM patients age ≤50 years old at diagnosis between 1/1/2014-7/1/2021 at UC Davis. Demographics, diagnostic details, treatment, response, and overall survival (OS) data were collected. Results: The pooled dataset included 209 patients with MM and 4 with plasma cell leukemia. The median age was 45, with 58 (27%) Hispanic and 37 (17%) Black patients. In 89 patients with available data, 23% were R-ISS-1, 58% were R-ISS-2, and 19% were R-ISS 3. Overall, 14% of patients had high-risk cytogenetics [ t(4;14), del17p, or t(14;16]] . Patients diagnosed and treated in 2000-2010 were more likely to have received doublet or cytotoxic chemotherapy for induction therapy, while 80% of patients in 2010-2021 received triplet-based therapies. Responses to induction improved across decades, with 23% of patients in the earlier cohort vs 49% patients in the later cohort achieving a very good partial response (VGPR) or better. Eighty-five percent of patients received a SCT, the majority being autologous with only 13 upfront or salvage allogeneic SCTs in the earlier and 1 in the later cohort. The median OS for the entire cohort is 168 months, 171 months in the early cohort, and not reached in 2011-2021 cohort. Conclusions: We present retrospective data of a large and diverse cohort of California MM patients ≤50 years old, with nearly 50% of patients from underrepresented populations spanning over 2 decades. We found similar diagnostic features and risk group to those reported in the general MM population. Noticeable improvements in treatment responses were seen in the later decade with the introduction of modern therapies. A median OS of 14 years for the entire cohort over 20 years offers a glimpse into the hopeful promise for extended survival of younger patients as more effective therapies lead to deeper and more durable responses. [Table: see text]

Influence of levothyroxine concomitant treatment on treatment responses and outcomes in patients with metastatic colorectal adenocarcinoma.

e15593 Background: Hypothyroidism is the most common thyroid disorder and levothyroxine is the mainstay treatment. Levothyroxine is mainly used to restore the euthyroid clinical and biochemical status in the gland. Recent literature has correlated chronic hormonal treatment with adverse effects on bone and heart function, as well as correlated with an increased risk of tumor onset. Data available in the literature are controversial, therefore the aim of our study was to evaluate the correlation between chronic levothyroxine intake and outcomes and response to first line treatments in patients affected by metastatic colorectal cancer. Methods: We retrospectively collected the data from 139 patients with metastatic colorectal adenocarcinoma, belonging to the Medical Oncology Department of the University Hospital of Cagliari from 2016 to 2019. All patients enrolled in the study had received metastatic first-line treatment with doublet or triplet chemotherapy associated with anti-VEGF or anti-EGR monoclonal antibody. Patients with ECOG PS ≤1 with no more than two relevant comorbidities were included in the study. The primary objective of the study was median overall survival (mOS) and secondary objectives were: median progression free progression (PFS), median overall survival (mOS) differences between RAS wild type and mutant tumour. BRAF mutant tumors were excluded from the evaluation. Results: Median age was 65 years (±10), 51% were male and 49% were female. 63% patients had an ECOG-PS 0, while 37% had an ECOG-PS 1. 67% developed from the left colon; 33% from the right colon and the transverse colon. All patients had synchronous metastases. 18% patients took levothyroxine and 82% patients did not take it. Among the patients receiving levothyroxine therapy, 64% had a RAS wild type and 36% a RAS mutated. Levothyroxine treated patients showed a significantly lower median OS than not treated patients (15 months versus not reached, p = 0,0001). Levothyroxine treated patients also showed a significantly lower median PFS than non treated patients (6 versus 8 months, p = 0,035). Within levothyroxine treated pts, no statistically significant differences were found in mOS and mPFS between RAS wt and RAS mut (mOS 15 versus 14 months, respectively, p = 0.9; mPFS 8 versus 7 months, respectively, p = 0,7). Conclusions: The results show a possible correlation between levothyroxine therapy and outcomes in mCRC. This would deserve further study to understand further biological-molecular aspects, to date partially explained by preclinical studies, in order to clarify some of the possible underlying mechanisms.

VIC regimen (vemurafenib/irinotecan/cetuximab) versus bevacizumab plus chemotherapy as first-line treatment for BRAF V600E-mutated advanced colorectal cancer.

3596 Background: The need for safe and effective therapies for untreated, BRAF V600E-mutated, unresectable locally advanced or metastatic colorectal cancer remains unmet. The purpose of this study was to compare the efficacy and safety of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen versus bevacizumab plus chemotherapy as first-line setting in Asian patients. Methods: In the single-center prospective cohort study, 78 untreated, BRAF V600E-mutant, locally advanced or metastatic CRC patients were enrolled. Every two weeks, the VIC regimen and bevacizumab plus doublet or triplet chemotherapy are administered. We evaluated the objective response rate (ORR), the disease control rate (DCR), and the conversion resection rate. In progression-free survival (PFS) and overall survival, the Kaplan-Meier method was utilized (OS). Results: In the evaluable population, 32 patients received VIC regimen and 35 patients received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 68.8% versus 40.0%, P = 0.018; DCR: 100.0% versus 80.0%, P = 0.023). The VIC regimen was significantly superior to bevacizumab plus chemotherapy for PFS (median, 11.9 vs 7.9 months; hazard ratio [HR] = 0.48, 95% CI, 0.27-0.87; P = 0.012) and OS (median, 24.5 vs 14.4 months; HR = 0.36, 95% CI, 0.16-0.78; P = 0.007). In the VIC group, the conversion resection rate for liver metastases was 42.1% (8 of 19 patients), and for local CRC it was 66.7% (6 of 9 patients with initially unresectable local CRC). Rates of treatment-related adverse events of Grade 3 to 4 were 32.4% and 31.1% for the VIC regimen and bevacizumab plus chemotherapy, respectively. Conclusions: Among Asian patients with BRAF V600E-mutated advanced CRC, the VIC regimen was superior to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting. Clinical trial information: NCT05540951 .

PD-27 The use of pre-operative systemic oxaliplatin or irinotecan doublet chemotherapy in colorectal cancer peritoneal metastases (CRPM): Results from a single UK peritoneal tumour centre

PD-27 The use of pre-operative systemic oxaliplatin or irinotecan doublet chemotherapy in colorectal cancer peritoneal metastases (CRPM): Results from a single UK peritoneal tumour centre

MSH3 and MSH6 gene polymorphisms: Association with lung cancer susceptibility and prognostic value in patients with NSCLC undergoing platinum-based chemotherapy.

9031 Background: DNA mismatch repair (MMR) pathway is responsible for recognizing and repairing errors (insertion, deletion and misincorporation of bases) occurring during DNA replication and recombination. Single nucleotide polymorphisms (SNPs) in MSH3 and MSH6 genes are related to development of various cancers. SNPs of particular interest include rs26279 G > A polymorphism for MSH3 and rs3136228 557G > T polymorphism for MSH6. In this cohort study, we evaluated the association of MSH3 (rs26279) and MSH6 (rs3136228) SNPs with occurrence of lung cancer (LC), baseline demographic and clinical characteristics and with overall survival (OS) amongst LC patients undergoing platinum-based doublet chemotherapy. Methods: 500 LC patients and 500 healthy controls were enrolled. Genomic DNA was isolated from 4ml of peripheral blood using a phenol-chloroform extraction procedure and genotyping of patients and controls was performed using PCR-RFLP. All enrolled patients had pathologically confirmed LC. Written informed consent was obtained from all enrolled subjects and the study was approved by institutional ethics committee. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using logistic regression analysis. Kaplan-Meier method was used for OS analysis and (multivariate) Cox regression models to obtain (adjusted) hazards ratios (HRs). Results: Mean age (61 years) was similar for cases and controls. Compared to controls, LC cohort had higher prevalence of non-smokers (20% vs. 10%), female sex (20% vs. 9%) and smoking pack-years (mean 20.8 vs. 13.8). Majority of LC patients had metastatic disease (54%) and ECOG performance status of 0-1 (45%) or 2 (40%). Adenocarcinoma and squamous were equi-prevalent (41% each). Mutant genotype (TT) for MSH6 polymorphism was more frequent in LC patients (OR = 1.43; 95% CI = 1.01 – 2.03; p = 0.03) with the association more marked in adenocarcinoma histology (OR = 1.74; 95% CI = 1.05 – 2.93; p = 0.03). For non-smokers, mutant genotype (TT) for MSH6 polymorphism was associated with a 3-fold increased risk of LC (OR = 3.22; 95% CI = 1.26 – 8.18; p = 0.01). Amongst females, heterozygous genotype (GA) for MSH3 polymorphism was more frequent amongst LC cases (24%) than controls (16%) (OR = 2.35, 95% CI = 0.85 – 6.52, p = 0.04). Patients treated with docetaxel-platinum chemotherapy and carrying heterozygous (GT) genotype for MSH6 polymorphism had worse OS (median 4.9 vs 9.1 months; adjusted HR = 2.3; p = 0.03). No association was observed between MSH3 (rs26279) and MSH6 (rs3136228) polymorphisms and other baseline clinical/demographic characteristics. Conclusions: The results of this cohort study suggest that MSH3 and MSH6 polymorphisms are involved in modulating the risk towards LC occurence. MSH6 polymorphism is also associated with higher mortality amongst patients treated with docetaxel-platinum chemotherapy.

Long-term outcome for patients with advanced non‒small-cell lung cancer treated by autologous cytokine-induced killer (CIK) cell immunotherapy in combination with sintilimab plus chemotherapy: NSCLC-CCICC-002.

9096 Background: Autologous cytokine-induced killer (CIK) cell immunotherapy in combination with Sintilimab demonstrated robust antitumor activity and safety in the phase Ib CCICC-002 study (NCT03987867) of Non‒Small-Cell Lung Cancer. Long-term outcomes in patients are reported herein. Methods: Systemic therapy naïve patients received platinum-based doublet chemotherapy, Sintilimab (PD1 inhibiter), and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or two years. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were based on immune-related response criteria by investigator assessment (data cut-off, January 31, 2023). Results: From May 2019 to Jan 2021, CCICC-002 enrolled 33 patients（19 squamous, 14 non-squamous NCSLC; 1 patient was excluded because the second biopsy revealed EGFR mutation) aged 46-73 years with median follow-up was 31.4 months (range, 7.6-44.4 months). Estimated 3-year OS was 51.8% in all patients; median OS was not reached (95% CI, 26.6 months-not reached) in all patients. In subgroups, median OS was 27.6 months (95% CI, 13.4 months-not reached) in squamous NCSLC and not reached (95% CI, 29.9 months-not reached) in non-squamous NCSLC, respectively. Median OS was not reached (95% CI, 27.6 months-not reached) in PD-L1 positive patients and 28.3 months (95% CI, 15.6 months-not reached) in PD-L1 negative patients, respectively. Estimated 3-year PFS rate was 27.5% and median PFS was 17.9 months (95% CI, 8.2-26.5 months) in all patients. Median PFS was 17.3 months (95% CI, 5.0-24.0 months) in squamous NCSLC and 22.4 months (95% CI, 5.7 months-not reached) in non-squamous NCSLC, respectively. Median response duration was 18.7 months (95% CI, 10.1-27.6 months). 30.3% of patients were ongoing at data cut-off, and the longest response was ongoing at 41.3 months. 1 of the 5 CMR (complete metabolic response by PET-CT) patients experienced disease progression during observation. Treatment-related AEs (TRAEs) occurred in 94.0% of patients and resulted in study discontinuation in 7.8%, and 15.2% experienced grade 3/4 TRAE. Conclusions: This long-term analysis of CCICC-002 represents the longest follow-up for CIK to date and confirms the durable antitumor activity and tolerability of CIK cells therapy in combination with Sintilimab plus chemotherapy in advanced NCSLC. Further studies are warranted to confirm these preliminary results. Clinical trial information: NCT03987867 .

Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations.

The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Reconsidering the cutoff between sensitive and refractory relapses in extensive-stage small cell lung cancer in the era of immunotherapy.

8576 Background: The use of platinum-based doublet chemotherapy combined with immune checkpoint inhibitors (ICIs) has demonstrated promising outcomes in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Relapsed SCLC has been classified into "sensitive" or "refractory" relapse types according to cutoff values (60 or 90 days) of duration from the last chemotherapy administration to disease progression. However, it is unclear whether these cutoff values can be applied to ICI combination therapy. Methods: We retrospectively analyzed a multicenter database of ES-SCLC patients who received second-line therapy after the platinum-etoposide plus ICI (atezolizumab or durvalumab). An optimal cutoff value for the platinum-free interval (PFI) was selected, which minimized the two-sided p-value and maximized hazard ratio (HR) regarding relapse type (sensitive or refractory according to a cutoff value) calculated from a multivariable Cox regression model for overall survival (OS) including performance status (PS) and sex as covariates. The internal validity of the selected cutoff value was assessed via two-fold cross-validation (CV) manner. Results: A total of 101 patients (61 deaths) from 10 hospitals were included in the study. The median follow-up period was 21.1 months. The optimal cutoff value was 75 days (p=0.0002), and when applying this cutoff value, median OS was 15.9 and 5.0 months of sensitive- (n=51) and refractory- (n=50) relapsed patients, and the HR calculated from a two-fold CV was 3.13 (95% confidence interval [CI], 1.66 to 5.90). Additionally, traditional cutoff values of 60 and 90 days also predicted prognosis better, but cutoff values of 110 days or longer did not (Table). Conclusions: Even in the era of combined immunotherapy in ES-SCLC patients, the threshold days for classifying as sensitive- or refractory- relapse did not exhibit a significant change compared to the pre-immunotherapy era. Although further validation studies with a larger sample size would be needed, relapse type classification using the selected cutoff value of 75 days is worth considering as a new prognostic factor for relapsed ES-SCLC patients. [Table: see text]

Alliance A022102: Randomized phase III trial of mFOLFIRINOX +/- nivolumab vs. FOLFOX +/- nivolumab for first-line treatment of metastatic HER2-negative gastroesophageal adenocarcinoma (GEA).

TPS4175 Background: Platinum/fluoropyrimidine (FP) with PD-1 inhibitor is now established as the standard first-line therapy for most patients with advanced HER2 negative gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinoma. The FP doublet chemotherapy backbone, most commonly FOLFOX, is recommended based on marginal survival benefits of taxane-containing triplet therapy at the cost of increased toxicity. Although several agents are approved as standard treatment options in later lines, only about 10% of patients in the US receive a third line of therapy, and very few have the opportunity to benefit from all approved agents in this disease. This challenge will only increase as more agents and targeted therapies are approved. FOLFIRINOX is a triplet regimen commonly used in gastrointestinal malignancies with established safety and often with superior efficacy. Two single arm phase II trials of FOLFIRINOX have reported promising activity in GEA with manageable toxicities. Reported median overall survival (OS) from these trials is around 15 months, which is superior to what is expected from FP doublet first-line chemotherapy (about 11 months). We hypothesize that using upfront triplet therapy with a more effective and less toxic triplet combination will result in improved patient outcomes by optimization of available therapies in GEA. Methods: This study is a randomized phase III, open-label, multicenter clinical trial with the primary objective to determine whether modified FOLFIRINOX (FU 2400 mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 every 2 weeks) as first-line treatment improves OS compared to mFOLFOX in patients with advanced HER2 negative GEA. Eligible patients will have unresectable or metastatic adenocarcinoma of esophagus, GEJ, or stomach with no prior systemic treatment. Patients must have adequate organ function, and measurable or evaluable disease as defined by RECIST 1.1. Prior neoadjuvant or adjuvant therapy is allowed if completed at least 1 year prior to registration. Patients who will receive nivolumab (mandatory for PD-L1 combined positive score > 5) in addition to chemotherapy must not have any contraindications to immune checkpoint inhibitors. Patients with treated, asymptomatic and stable brain metastases are eligible. The total sample size is 382 evaluable patients for this study (191 patients per arm). The study accrual began January 2023. Clinical trial information: NCT05677490 .

Real-world comparison of triplet- versus doublet-chemotherapy with bevacizumab in patients with newly diagnosed metastatic colorectal cancer (mCRC).

3574 Background: Meta-analysis of five randomized intensification trials in mCRC demonstrated an overall survival (OS) benefit of triplet chemotherapy (5FU/leucovorin, oxaliplatin, irinotecan) plus bevacizumab (Triplet/Bev) compared to doublet chemotherapy plus bevacizumab (Doublet/Bev) (HR 0.81). Guidelines recommend first-line Triplet/Bev for patients with excellent performance status and normal organ function who can withstand increased toxicity, but such patients are less represented in the real world. In this retrospective cohort study, we examine the real-world effectiveness of Triplet/Bev compared to Doublet/Bev in the U.S. Methods: We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data curated via technology-enabled abstraction from ~ 280 cancer clinics. Included were mCRC patients treated with first-line Triplet/Bev or Doublet/Bev between 10/23/14 and 10/31/22. OS by treatment was assessed using the Kaplan Meier method and adjustment for confounding variables was performed using Cox proportional hazards modeling with stabilized inverse probability of treatment weighting (IPTW). Pre-specified confounding variables included age, gender, race/ethnicity, year of metastatic diagnosis, health insurance, practice setting, KRAS/NRAS/BRAF mutation status, MMR/MSI status, synchronous/metachronous metastases, primary tumor sidedness, CEA, renal dysfunction, hepatic dysfunction, and ECOG performance status. Missing data were imputed using multiple imputation with chained equations. Results: Among 10,016 patients, 391 (3.9%) received Triplet/Bev and 9,625 (96.1%) received Doublet/Bev. Patients who received Triplet/Bev were younger (median age 52 vs 63 years) and were more likely to be treated at academic practices (27% vs 8%), to have synchronous metastatic disease (83% vs 65%), and to have KRAS/NRAS/BRAF wild-type disease (30% vs 17%). In the univariate analysis, median OS was 30.0 months (95% CI 24.7 – 34.7) in the Triplet/Bev cohort versus 23.4 months (95% CI 22.8 – 24.1) in the Doublet/Bev cohort (HR 0.73; 95% CI 0.62 – 0.85; p < 0.001). In Cox proportional hazards modeling with IPTW, there was no significant difference in hazard of death between Triplet/Bev and Doublet/Bev (HR 0.92; 95% CI 0.75 – 1.12; p = 0.4). Conclusions: In this large, national, real-world population of patients with mCRC, first-line treatment with Triplet/Bev was not associated with improved survival compared to Doublet/Bev after accounting for differences in baseline patient characteristics. The benefit to Triplet/Bev observed in randomized trials does not translate well to a more heterogeneous, real-world population. Sub-group analyses including by age, tumor sidedness, KRAS/NRAS/BRAF status, and baseline CEA level will be performed.

Stereotactic body radiation therapy with sequential immunochemotherapy as neoadjuvant therapy in resectable non-small cell lung cancer (SACTION-01 study).

8540 Background: Neoadjuvant PD-1 inhibitor plus chemotherapy increases pathological response for resectable non-small cell lung cancer (NSCLC) compared with chemotherapy alone. Previous phase II trial indicated that stereotactic body radiation therapy (SBRT) served as an immunomodulator and enhanced the effect of preoperative immuno-monotherapy. However, whether SBRT would further increase the efficacy of immunochemotherapy for NSCLC remains unknown. Methods: In this phase II trial, patients with resectable EGFR wild-type stage IIA to IIIB NSCLC were recruited to receive SBRT (24 Gy in 3 daily fractions) to the primary tumor followed by two cycles of PD-1 inhibitor tislelizumab (200 mg) plus platinum-based doublet chemotherapy (Q3W) before surgical resection. The primary endpoint was major pathological response (MPR) defined as no more than 10% of viable tumor cells in the specimen. Simon’s optimal two-stage design was used for conducting the trial. The null hypothesis was that the MPR rate is 0.30, and the alternative hypothesis was that the true MPR rate was 0.50. More than 4 MPRs were needed in stage 1 (n=15) to continue, and if there were 19 or more MPRs in 46 patients by the end of stage 2, the null hypothesis can be rejected. The design controls the type I error rate at 0.05 and yields the power of 0.80. (NCT05319574). Results: Between May 2022 and Jan 2023, 32 patients were enrolled with 31 (96.9%) male and 19 (59.4%) having squamous cell lung cancer. Twenty-six (81.3%) patients had stage IIIA/B disease. All patients received at least one cycle of immunochemotherapy; 23 of the 25 patients (92.0%) who completed treatment had undergone R0 resections, except for one patient who had disease progression and the other one that unable to tolerate surgery because of grade 4 neutropenia. Twenty-two patients underwent minimally invasive approaches and 3 of them (13.6%) converted to thoracotomy. The median percentage of the viable tumor was 0 (interquartile range: 0-4.0%). Twenty patients achieved MPR, which surpassed the prespecified required number to reject the null hypothesis, resulting in the MPR rate of 80.0% (20/25) in the intention-to-treat population, and 87.0% (20/23) in the per-protocol population. Pathological complete response (pCR) was found in 14 patients (56.0% in the intention-to-treat population and 60.9% in the per-protocol population). Nodal clearance status (pN0) was found in 20 of 23 cN1/2 cases (87.0%). Grade 3-4 adverse events related to neoadjuvant treatment included neutropenia (13.0%), anemia (4.3%), and pneumonia (4.3%). No 30-day or 90-day mortality was observed. Conclusions: Neoadjuvant SBRT followed by immunochemotherapy yields unprecedently high MPR and pCR rates in NSCLC without EGFR mutation. The trial will continue to recruit 14 more patients to reach a final sample size of 46 participants. Clinical trial information: NCT05319574 .

Phase II results of ivonescimab (AK112/ SMT112), a novel PD-1/VEGF bispecific, in combination with chemotherapy for first line treatment of advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGA) in EGFR/ALK.

9087 Background: Since the initial approval of bevacizumab (bev) with chemo in NSCLC, the subsequent focus of bev use in combination with PD1 therapy for first line metastatic disease has largely focused on non-squamous (non-SCC) histology. Ivonescimab is a novel anti-PD-1/VEGF bispecific antibody. The bispecific approach to these targets has the potential to recalibrate the malignant immuno-architecture in favor of a more immune-responsive and anti-tumor microenvironment. Cooperative VEGF binding with the bispecific has been shown to elevate affinity of ivonescimab to PD-1 by more than 10-fold. Ivonescimab has a mean T1/2 of 6-7 days while bev T1/2 is 20 days. Therefore, we aimed to assess the efficacy and safety of ivonescimab combined with chemotherapy for first line advanced or metastatic NSCLC in patients (pts) with squamous (SCC) or non-SCC NSCLC. Methods: An open-label, multi-center phase II study evaluating the efficacy and safety of ivonescimab combined with chemotherapy in pts with advanced or metastatic NSCLC. Pts were enrolled into 3 cohorts based on prior therapy and presence of AGA. Data from pts with prior therapy for advanced or metastatic disease were presented in ASCO 2022 and here we report additional pts and longer-term data from pts with NSCLC without AGA receiving first line therapy for advanced/metastatic disease. Pts were treated with 10 or 20 mg/kg ivonescimab once every 3wks combined with carboplatin and pemetrexed (non-SCC) or carboplatin and paclitaxel (SCC). The primary endpoint was ORR per RECIST by investigator. Results: 135 pts with advanced or metastatic NSCLC received ivonescimab plus chemotherapy including 63 with SCC and 72 with non-SCC. Median age was 61 yrs (. 78% male, 3% and 97% pts had ECOG PS 0 and 1, respectively, and 20% pts had baseline brain metastasis. Median follow-up was 11.5 mo. Pts with SCC experienced a 75% ORR with median DOR 15.4 mo, 95% DCR, the 9-mo PFS and OS rate was 67% and 93%, respectively. Pts with non-SCC experienced a 55% ORR, DOR was not reached, 100% DCR, the 9-mo PFS rate and OS rate was 61% and 81%, respectively. The most common treatment related adverse events (TRAEs)≥ 10% were epistaxis, proteinuria, rash, amylase increased, anemia, ALT increased, infusion related reaction, AST increased, pruritus, decreased appetite, and WBC decreased. Grade ≥3 TRAEs occurred in 28.1% TRAE leading to discontinuation occurred in 6.7% of pts. Conclusions: Ivonescimab, plus chemotherapy has shown promising anti-tumor activity in pts with advanced/metastatic NSCLC without AGA and can be administered safely in combination with platinum doublet chemotherapy to patients with SCC and non-SCC histology. Clinical trial information: NCT04736823 .

Phase II trial of safety and efficacy of tislelizumab plus chemotherapy in stage II-IV non small cell lung cancer (LungMark).

8564 Background: The current study aimed to investigate the safety and efficacy of chemotherapy with PD-1 inhibitor, tislelizumab, for stage II-IV NSCLC. Meanwhile to explore the potential biomarkers for safety and efficacy of tislelizumab plus chemotherapy in NSCLC. Methods: This was an open-label, multicenter, phase 2 trial conducted at 3 hospitals in China. Patients with treatment-naïve, stage II-IV NSCLC without EGFR/ALK driver mutations were enrolled. This study consisted of two cohorts, one cohort is potentially resectable disease (PRD) and the other is unresectable disease (URD). The PRD patients received 3-4 cycles of tislelizumab (200 mg Q3w) plus carboplatin-based chemotherapy. Candidates eligible for surgery underwent surgery, followed by adjuvant tislelizumab monotherapy for 1 year. The URD patients received platinum-based doublet chemotherapy plus tislelizumab for 4-6 cycles, followed by tislelizumab for squamous and tislelizumab in combination with pemetrexed for non-squamous, until disease progression or intolerable toxicity. Primary endpoint was safety. Secondary endpoints were efficacy, such as MPR/pCR(PRD cohort), ORR, PFS and OS, etc. Multi-omics analysis of baseline and post-treatment samples were conducted to explore the safety and efficacy for chemoimmunotherapy. (NCT05244837). Results: Between December 2020 and November 2022, a total of 100 eligible patients were enrolled and received at least one cycle of immunochemotherapy. 58 patients were with PRD, of whom 40 (68.9%) were squamous cell lung cancer. 50 (86.2%) patients were stage III disease. During neoadjuvant treatment period, 52 patients (91.2%) experienced neoadjuvant TRAEs. Most of the TRAEs were grade 1or 2. No grade 4 or 5 TRAEs was observed. The most common grade 1 or 2 TRAEs were alopecia (n = 29;50.9%), anemia (n = 25;43.9%), rash (n = 29; 50.9%). Four patients (7.0%) experienced severe TRAE of grade 3 increased ALT/AST.39 patients received surgical resection, R0 resection was performed for 38 (97.4%) patients. 29 (74.4%) achieved MPR (major pathological response), including 19 (48.7%) with a complete pathological response (pCR). 42 patients with URD were enrolled, 26 (61.9%) patients were stage IV disease. 37 patients (88.1%) experienced TRAEs. The most common grade 1 or 2 TRAEs TRAEs were anemia (n = 27; 64.3%), rash (n = 12; 57.0%). Severe TRAEs occurred in 8 (2.0%) cases, including increased ALT/AST, decreased white blood cell count etc. 29 genes were identified as differentially expressed in pre-treatment tumors from patients with pCR compared to non-pCR. Conclusions: Neoadjuvant tislelizumab plus chemotherapy was safe and effective with high MPR and manageable TRAEs in patients with PRD. For patients with URD, tislelizumab plus chemotherapy was generally well tolerated. We have identified a differential immune landscape between pCR and non-pCR tumors. Clinical trial information: NCT05244837 .