Carboplatin AUC Research Articles

The Phase 3 KEYLYNK-006 Study of Pembrolizumab plus Olaparib versus Pembrolizumab plus Pemetrexed as Maintenance Therapy for Metastatic Nonsquamous Non–Small-Cell Lung Cancer

Poly (ADP-ribose) inhibitors, including olaparib, upregulate programmed cell death ligand 1 (PD-L1), which may increase efficacy of anti-PD-(L)1 therapies. In the phase 3 KEYLYNK-006 trial (NCT03976323), eligible adults with previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations who had complete response (CR), partial response (PR), or stable disease (SD) following induction therapy with 4 cycles of pembrolizumab 200 mg Q3W, pemetrexed 500 mg/m2 , and carboplatin AUC5 or cisplatin 75 mg/m2 were randomized 1:1 to olaparib 300 mg orally twice daily or pemetrexed Q3W, both given with ≤31 cycles of pembrolizumab Q3W. Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). PFS was tested at interim analysis 2 (IA2; ie, final PFS analysis), OS at final analysis (FA). Of 1003 patients who received induction therapy, 672 (67.0%) were randomized to pembrolizumab plus olaparib (n=337) or pembrolizumab plus pemetrexed (n=335) in the intention-to-treat population. Median follow-up at FA was 39.9 (range, 28.1-51.5) months. At IA2, median (95% CI) PFS was 7.1 (5.6-8.7) months versus 8.3 (6.9-11.5) months in the olaparib versus pemetrexed groups (HR, 1.12; 95% CI, 0.92-1.36; P=0.87). At FA, median (95% CI) OS was 20.7 (18.0-24.8) months versus 23.0 (19.0-26.4) months (HR, 1.04; 95% CI, 0.87-1.25; P=0.6649). Grade 3-5 maintenance treatment-related AEs occurred in 26.1% versus 30.1% patients. Pembrolizumab plus maintenance olaparib did not improve PFS or OS versus pembrolizumab plus pemetrexed in previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations.

Phase III randomized trial comparing neoadjuvant paclitaxel+platinum to 5-fluorouracil+platinum in esophageal/GEJ squamous cell carcinoma.

Standard neoadjuvant chemotherapy (NACT) for locally advanced esophageal/gastroesophageal junction squamous cancer (LAEGSC), 5-fluorouracil (5FU)+platinum, is toxic and logistically challenging; alternative regimens are needed. Phase III randomized open-label non-inferiority trial at Tata Memorial Center, India, in resectable LAEGSC. Patients were randomized 1:1 to three cycles of 3-weekly platinum (cisplatin 75 mg/m2 or carboplatin AUC 6) with paclitaxel 175 mg/m2 (day 1) or 5FU 1000 mg/m2 continuous infusion (days 1-4), followed by surgery. Between August 2014 and June 2022, we enrolled 420 patients; 210 to each arm. Significantly more patients on paclitaxel + platinum (194 (92.3%)] received all 3 chemotherapy cycles than on 5FU+platinum (170 [85.9%]), P = .009. 5FU + platinum caused more grade ≥ 3 toxicities (124 [69.7%]) than paclitaxel + platinum (97 [51.9%]), P = .001. Surgery was performed in 131 (62.4%) patients on 5FU + platinum vs 139 (66.2%) on paclitaxel + platinum, P = .415. Paclitaxel + platinum resulted in higher pathologic primary tumor clearance (33 [25.8%]) vs 17 [15%]; P = .04), and pathologic complete responses in 21.9% compared to 12.4% from 5FU + platinum, P = .053. Median OS was 27.5 months (95% CI, 18.6-43.5) from paclitaxel + platinum, which was non-inferior to 27.1 months (95% CI, 18.8-40.7) from 5FU + platinum; HR, 0.89 (95% CI, 0.72-1.09); P = .346. Neoadjuvant paclitaxel + platinum chemotherapy is safer, and results in similar R0 resections, higher pathologic tumor clearance and non-inferior survival, compared to 5FU + platinum. Paclitaxel + platinum should replace 5FU + platinum as NACT for resectable LAEGSC. CTRI/2014/04/004516.

A phase I/II study of nanoliposomal irinotecan and carboplatin in patients with advanced or metastatic, poorly differentiated gastroenteropancreatic neuroendocrine carcinoma characterized by tissue and liquid next-generation sequencing.

52 Background: For locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), standard chemotherapy typically incorporates etoposide or irinotecan plus platinum agents. Herein, we initiate a phase I/II trial to apply Nal-IRI in combination with carboplatin as the 1st line treatment in patients with GEP-NECs to define the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). Methods: In the phase I part, traditional 3+3 design was applied. Enrolled patients would receive escalating dose of 60 (level -1), 80 (starting dose, level 0) or 100 (level 1) mg/m2 salt-form nal-IRI plus carboplatin AUC=4 with maximum total dose of 600 mg on D1, every 21 days as a cycle. DLTs were evaluated during the first one cycle of treatment with tumor assessment every 6 weeks. Prophylaxis G-CSF was not allowed in the first cycle Paired testing of tissue (TBx) and liquid biopsy (LBx) was done by Illumina TSO500 platform before treatment. The second LBx would be repeated for confirmed partial responders when progression. Results: Totally 6 GEP-NEC patients with primary sites of colon in three, and each one in esophagus, ampulla of Vater and pancreas were enrolled to level 0. One patient had DLT of grade 4 neutropenia lasting for 3 days even under salvage G-CSF. Treatment-related adverse events showed grade 3/4 neutropenia (33.4%), grade 2 anemia (16.7%), grade 3 fatigue (16.7%), and grade 2 skin rash (16.7%). Four patients achieved confirmed partial response and 2 patients got stable disease, with the objective response rate of 66.7% (95% confidence interval: 22%-96%). After the data and safety monitoring board meeting, level 0 was decided as RP2D but not escalation to level 1 because of acceptable toxicity profiles and promising efficacies. Comprehensive genomic profiling showed that driver mutations were identified in three cases including two harboring BRAFV600E mutation and one with KRASG12D mutation. The other three cases lacking driver mutation showed frequent copy number alteration including 1 with MDM2 amplification (copy number 27) and a wild-type TP53. Homologous recombination deficiency (HRD), as determined by GIS score, was identified in a colon GEP-NEC who remained to be HRD-positive at progression but a higher TMB (from 4.7 to 10.2 Muts/Mb) and a higher BRAFV600E mutation allele frequency (from 24.1% to 43.6%) in tumor tissue, compared to the baseline profiling. Conclusions: Based on current data, the RP2D is 80 mg/m2 of nal-IRI (salt-form) and carboplatin of AUC=4, every 3 weeks. The extension phase II study in GEP-NEC is ongoing. Clinical trial information: NCT05385861 .

A phase 2, open-label, single-arm study evaluating the combination of pembrolizumab (pembro), lenvatinib, and chemotherapy in patients (pts) with metastatic non-small cell lung cancer (NSCLC) harbouring a targetable mutation who experienced disease progression on standard tyrosine kinase inhibitors (TKIs).

198 Background: Pts with metastatic NSCLC harbouring a targetable mutation who progressed on standard TKIs often receive chemotherapy as the next line of treatment. We report efficacy and safety of a novel combination of pembro, lenvatinib and chemotherapy for these pts. Methods: This was a phase 2, open-label, single-centre, single-arm study enrolling pts with metastatic NSCLC with sensitizing EGFR, ALK or ROS1 mutation who progressed on standard TKIs. Eligible pts had measurable disease, no untreated brain metastasis and ECOG PS ≤1. Pts received pembro 200 mg, pemetrexed 500 mg/m2 and carboplatin AUC 5 every 3 weeks for 4 cycles plus lenvatinib 8 mg QD. The maintenance regimen without carboplatin was continued as tolerated for up to 2 years. The primary endpoint was objective response rate (ORR) by independent radiology review (IRR) as per RECIST 1.1. The secondary endpoints were PFS, overall survival (OS) and safety. Results: At the data cutoff date (2nd February 2024), 24 pts were screened and 19 were enrolled: median age 64 years (range 29–77); 10 (53%) female. Four pts were excluded at screening due to untreated brain metastasis. All enrolled pts were evaluated for safety while 15 pts were evaluable for response. All pts had adenocarcinoma with targetable mutation: EGFR mutation in 18 (95%) pts and ALK fusion in 1 (5%) pt. The median follow-up time was 11.3 months. Treatment was ongoing in 8 pts on the date of analysis, while 6 pts permanently discontinued due to disease progression and 1 pt permanently discontinued due to a treatment-related adverse event (TRAE). The ORR was 40% (6/15, 95% CI 19.8%–64.3%). All responses were partial responses. The median PFS was 11.9 months (range 3.5–20.3). The OS was not reached. TRAEs of any grade (Gr) occurred in 74% (14/19) of the pts. Most of the TRAEs were Gr 1–2, which occurred in 63% (12/19) of the pts. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%), anorexia (21.1%), hypertension (15.8%), anaemia (10.5%), pruritus (10.5%) and rash (10.5%). G1 diarrhoea was reported in 1 pt (5.3%) and G1 adrenal insufficiency in 1 pt (5.3%). Gr 3 TRAEs were neutropenia in 2 pts, anaemia in 1 pt and thrombocytopenia in 1 pt. The only Gr 4 TRAE was thrombocytopenia. No treatment related death was observed. Conclusions: The combination of pembro, lenvatinib and chemotherapy demonstrated a favourable ORR and safety in treating metastatic NSCLC pts with a targetable mutation who progressed on standard TKIs. Clinical trial information: NCT04989322 .

Adaptive radiotherapy (up to 74 Gy) or standard radiotherapy (66 Gy) for patients with stage III non-small-cell lung cancer, according to [18F]FDG-PET tumour residual uptake at 42 Gy (RTEP7–IFCT-1402): a multicentre, randomised, controlled phase 2 trial

Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [18F]fluorodeoxyglucose ([18F]FDG)-PET results. In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [18F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m2 intravenously once every 3 weeks and vinorelbine 30 mg/m2 intravenously on day 1 and 60 mg/m2 orally [or 30 mg/m2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m2 intravenously and vinorelbine 20 mg/m2 intravenously on day 1 and 40 mg/m2 orally (or 20 mg/m2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing. From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [18F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3-48·3). The 15-month local control rate was 77·6% (95% CI 67·6-87·6%) in group A and 71·2% (95% CI 60·8-81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment). A thoracic radiotherapy boost, based on interim [18F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [18F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC. Programme Hospitalier de Recherche Clinique National 2014.

Nivolumab plus platinum-doublet chemotherapy in treatment-naive patients with advanced grade 3 Neuroendocrine Neoplasms of gastroenteropancreatic or unknown origin: The multicenter phase 2 NICE-NEC trial (GETNE-T1913)

The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m2/d iv on days 1–3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H0 50%, H1 72%, β 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile.

Pembrolizumab Plus Carboplatin and Paclitaxel as First-Line Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-B10): A Single-Arm Phase IV Trial.

Standard-of-care first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is pembrolizumab plus platinum and fluorouracil (FU). However, FU is associated with potential challenges (continuous 4-day infusion, high administration costs, and cardiovascular and gastrointestinal toxicities), creating a clinical need for alternative chemotherapy combinations. We evaluated the efficacy and safety of first-line pembrolizumab plus carboplatin and paclitaxel for R/M HNSCC in the open-label, single-arm, phase IV KEYNOTE-B10 study (ClinicalTrials.gov identifier: NCT04489888). Eligible adults had previously untreated, histologically or cytologically confirmed R/M HNSCC regardless of PD-L1 status, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received pembrolizumab 200 mg intravenously once every 3 weeks for ≤35 cycles and carboplatin AUC 5 mg/mL/min intravenously once every 3 weeks for ≤6 cycles and investigator's choice of paclitaxel 100 mg/m2 on days 1 and 8 or 175 mg/m2 on day 1, intravenously once every 3 weeks. The primary end point was objective response rate per RECIST v1.1 by BICR. Between October 27, 2020, and April 29, 2022, 149 patients were screened and 101 received treatment. As of February 20, 2023, the median follow-up was 18.9 months (range, 9.1-27.0). At this final analysis, 49 (49%) of 101 patients had an objective response (95% CI, 38.4 to 58.7), including seven patients (7%) with a confirmed complete response. Of the 101 treated patients, grade 3-5 and serious treatment-related adverse events occurred in 76 (75%) and 27 (27%), respectively. There were no new safety signals. Pembrolizumab plus carboplatin and paclitaxel showed promising antitumor activity and a manageable safety profile in first-line R/M HNSCC, suggesting this combination may be an alternative option for this patient population.

Radiotherapy for patients with locally advanced esophageal squamous cell carcinoma receiving neoadjuvant immunotherapy combined with chemotherapy

With the success of immunotherapy in advanced esophageal cancer, neoadjuvant chemo-immunotherapy (CIT) is being increasingly used for local staged esophageal cancer, especially in the context of clinical trials, which brings similar pCR with neoadjuvant chemoradiotherapy and shows promising results. However, there is still a part of potentially operable patients can't undergo surgery after neoadjuvant chemo-immunotherapy. The follow-up treatment and prognosis of this population remain unclear. Patients pathologically diagnosed with ESCC, clinical stage T1-3N+M0 or T3-4aNanyM0 (AJCC 8th), PS 0–1 were retrospectively enrolled from 1/2020 to 6/2021 in Zhejiang Cancer Hospital. All patients firstly received PD-1 inhibitors plus chemotherapy (albumin paclitaxel, 260 mg/m2 on day 1 plus carboplatin AUC = 5 on day 1) every 3 weeks for 2–4 cycles. For those patients who did not receive surgery, definitive radiotherapy with 50.4 Gy/28F or 50 Gy/25F was adopted using VMAT, concurrent with chemotherapy or alone. The concurrent chemotherapy regimens included weekly TC (paclitaxel 50 mg/m2, d1, carboplatin AUC = 2, d1) or S1 (60 mg bid d1–14, 29–42). The survival outcomes and treatment toxicity were recorded and analyzed. A total of 56 eligible patients were finally identified from 558 patients who were treated in department of thoracic surgery, among all the patients, 25 (44.6%) received radiotherapy alone, and 31 (55.4%) received chemoradiotherapy after neoadjuvant CIT. The median follow-up was 20.4 months (interquartile range [IQR] 8.7–27 months). The median PFS and OS were 17.9 months (95% confidence interval [CI] 11.0–21.9 months) and 20.5 months (95% CI 11.8–27.9 months), respectively. In the subgroup analysis, the median OS was 26.3 months (95% CI 15.33–NA) for patients exhibiting partial response (PR) to CIT, compared to 17 months (95% CI 8.77–26.4) for those with stable disease (SD) or progressive disease (PD), yielding a hazard ratio (HR) of 0.54 (95% CI 0.27–1.06, P = 0.07). No significant difference was observed for patients received radiotherapy alone or chemoradiotherapy with HR = 0.73 (95% CI 0.72–2.6, P = 0.33). The most common Adverse events (AEs) observed during this study were anemia (98.2%), leukopenia (83.9%), thrombocytopenia (53.6%). AEs of grade ≥ 3 radiation-induced pneumonitis and esophagitis were 12.5% and 32.1%, especially, 6 patients (10.7%) died from esophageal fistula and 2 patients (3.6%) died from grade 5 pneumonitis. For local advanced ESCC patients after neoadjuvant CIT who did not receive surgery, definitive radiotherapy was an optional treatment strategy. However, those patients with no response to CIT also showed poor response to radiotherapy, and particular attention should be paid to treatment related toxicity, especially esophageal fistula.

BEAT-meso: A randomized phase III study of bevacizumab (B) and standard chemotherapy (C) with or without atezolizumab (A), as first-line treatment (TX) for advanced pleural mesothelioma (PM)—Results from the ETOP 13-18 trial.

LBA8002 Background: The currently approved frontline TXs for PM are the combination of ipilimumab/nivolumab or platinum plus pemetrexed. The addition of B to C has been shown to improve overall survival in a randomized clinical trial. While combined immunotherapy or single agent immunotherapy with C is superior to C alone, there is potential for a synergistic triple combination of C, B, and immunotherapy. Methods: BEAT-meso (NCT03762018) is an international open-label, 1:1 randomized phase III trial, stratified by histology and stage. The objective is to determine the efficacy and safety of adding A (1200 mg, Q3W until progression) to B (15mg/kg, Q3W until progression) and standard C (4-6 cycles of carboplatin AUC5 with pemetrexed 500 mg/m2, Q3W), as first-line TX for advanced PM. The trial is designed to detect an increase in the median overall survival (OS, primary endpoint) with the addition of A, aiming for a hazard ratio (HR) of 0.708, at 2.5% 1-sided alpha and 82% power (284 deaths, sample size 400 patients (pts)). In the pre-specified interim efficacy analysis (80% of the events, 01/2023), boundary was not crossed, and the trial continued to completion. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), disease control rate, duration of response (DoR), adverse events (AEs) assessed by CTCAE v5.0 and symptom-specific and global quality of life (QoL). Results: Between 04/2019 and 03/2022, a total of 400 pts was randomized, 200 per arm. The median age was 70 years, 79% were male, 50% were former smokers, 65% had ECOG performance status 1 and 78% had epithelioid histology. At a median follow-up of 35 months (m) (as of 1/09/2023), median OS was 20.5m [95% CI: 17.5-23.3] in the ABC and 18.1m [15.7-20.9] in the BC arm (deaths: 145 & 150; HRABC vs BC=0.84; [0.66 - 1.06], 2-sided stratified p=0.14, ITT final analysis). PFS was significantly longer in ABC with median 9.2m [8.1-10.9] vs 7.6m [6.9-8.3] in BC (HR=0.72; [0.59 - 0.89], 2-sided stratified p=0.0021). Histology shows a significant TX interaction for both PFS and OS. The OS HR is 0.51 [0.32-0.80] for non-epithelioid and 1.01 [0.77-1.32] for epithelioid (interaction p=0.012). In an exploratory analysis, post-progression OS was significantly different between the two arms, adjusted for post-progression TX (HR=0.76; [0.58 - 0.99]). The ORR was 55% in ABC and 49% in BC (p=0.27), while median DoR was 8.2m [6.8-9.7] in ABC and 5.6m [4.8-7.0] in BC (p=0.0041). Global QoL change was not significantly different between the two arms. Grade≥3 TX-related AEs occurred in 55% of pts in ABC and 47% of pts in BC (grade 5: 7 and 1 pt, respectively). Conclusions: The significant increase in median PFS with the addition of A did not translate into a significant increase in median OS. ABC demonstrated superiority over BC in non-epithelioid cases. Clinical trial information: NCT03762018 .

A retrospective, single-center study comparing two neoadjuvant protocols for patients with HER2-positive breast cancer.

e12623 Background: Neoadjuvant treatment is common in Stage 2+3 HER2 positive tumors. Cytotoxic and anti-HER2 drug combinations are used. Pathological complete response (pCR) correlates with improved survival and decreased risk of relapse. Trastuzumab may cause temporarily congestive heart failure (CHF) while anthracyclines may cause irreversible CHF. Current guidelines advise non-anthracycline based regimens. Here, we compare the efficacy and toxicity of these two regimens. Methods: Retrospective data were collected on 179 patients with clinical stage II-III, who received neoadjuvant treatment with either 6 cycles of DCHP (Docetaxel, Carboplatin AUC6 [53.2% received AUC5], Trastuzumab, Pertuzumab) or ACTHP (doxorubicin, cyclophosphamide followed by weekly Paclitaxel combined with HP). According to pCR response post surgery, adjuvant HP or TDM-1 were given to go complete one year of treatment. Efficacy Indices of pCR were evaluated in both cohorts and according to HER2 IHC staining (3+ or 2+ FISH positive), hormone receptor (HR) and nodal status. Toxicity indices were reductions in left ventricular ejection fraction (LVEF), dose reductions, hospitalizations and febrile neutropenia. Results: Between 9.2017 and 6.2022, 106 patients received ACTHP and 73 received DCHP. Median age at diagnosis, HR status, HER2 IHC (2+FISHpos or 3+) and nodal status were balanced. PCR occurred in 63.1% of all patients, numerically higher in the ACTHP group at 67.0% vs. 57.5% in the DCPH group (p=0.129). Symptomatic LVEF decrease (>10% or LVEF≤50%) was observed in 6.6% of the ACTHP group vs. 0% in the DCHP group (p<0.001). Hospitalization rates were similar (14%). Dose reductions occurred more often in the DCHP regimen vs ACTHP (54.8% vs 24.5% respectively) (p<0.00001) mostly due to asthenia and diarrhea. Febrile neutropenia was slightly higher in the ACTHP group but not statistically significant. Conclusions: In this study, pCR rates were numerically better in the ACTHP regimen vs. DCHP, though not statistically significant. Dose reductions were more common in the DCHP but had less cardiotoxicity. pCR rates were relatively low in both regimens where Her-2 +2, FISH pos. This study shows that the DCHP is a safe and effective alternative to anthracycline based chemotherapy though total dosage may be an important factor in the level of pCR.[Table: see text]

De-escalation treatment of patients with HPV-positive oropharyngeal squamous cell carcinoma.

e18052 Background: According to Globocan in 2020 were identified 98 412 new cases of oropharyngeal squamous cell carcinoma in the world. It was proved that the human papillomavirus (HPV) is a favorable prognostic factor. Patients with HPV-positive oropharynx cancer have higher indicators of progression-free survival (PFS) and overall survival (OS). As induction chemotherapy, the only TPF regimen (cisplatin/ docetaxel/ 5-fluorouracil) has been approved which has high toxic profile. Published results of randomized trials demonstrate the possibility of de-escalation CRT without reduction OS and PFS, but there is no data about safety of de-escalated IC regimen. Given the high toxicity of the standard regimen, as well as the presence of a favorable prognostic factor (HPV infection), since 2021 has started a prospective trial, investigating the possibility of use the dual-component IC regimen according to the TP scheme (cisplatin/ docetaxel). Objective: Improve the results of treatment of patients with locally advanced HPV- positive squamous cell carcinoma of the oropharynx by optimizing the scheme IC. Methods: In the prospective trial included 68 patients with p16-positive oropharyngeal squamous cell carcinoma (T3-4N0-1M0, or T1-4N2-3M0), who were divided into 2 equal groups. The research group received 3 cycles of IC to the de-escalated TP regimen and the control group according to the standard three-component TPF regimen. After completion IC patients of both groups had a standard CRT 70 Gy with carboplatin AUC 2.0 weekly. The primary endpoints were the assessment of objective response rate after the IC and toxicity. The Secondary endpoints: 1-year OS and PFS. Results: Complete response (CR) was achieved in 3 patients (8,8%), a partial response (PR) in 22 (64,7%), stable disease (SD) in 8 (23,5%) patients in the research arm. In the control arm: CR 4 patients (11,8%), PR 24 (70,6%), SD 6 (17,6%) patients. Both IC regimens demonstrated high efficacy rates, and there was no statistically significant ORR in the group (p=0,2133).Toxic manifestations were often observed in the arm of standard IC. The higher incidence of mucositis in the control group was statistically significant (p=0,025). The effect of IC regimen on subsequent CRT was also assessed. In the research arm, the time before the start of CRT was statistically significantly less than in the control arm (30 days vs 63 days, p=0,0035.). And the period of development mucositis of CRT in the TP group was longer than in the TPF group (34G vs 32G, p=0,0298). 1 year - PFS 94%, 1 year - OS 100% in the research group and 92% and 100% in the control arm. There was no statistically significant 1 year – PFS and 1 year - OS in the group (р=0,6547). Conclusions: The research scheme of IC demonstrated high results of an objective response, 1-year OS and 1 year - PFS, comparable to the standard TPF scheme, against the background of better tolerance.

De-escalation neoadjuvant chemotherapy in triple negative breast cancer.

e12520 Background: Neoadjuvant chemotherapy (NAT) represents the predominant therapeutic approach in the early triple negative breast cancer. NAT has demonstrated high overall survival rates in patients that achieve a pathological complete response (pCR). In patients with a tumor size less than 5 cm and no involvement of axillary lymph nodes, it may be advisable to consider a shorter chemotherapy regimen to evaluate the achievement of pCR percentages compared to longer regimens. Methods: We conducted an analysis of a cohort comprising 62 patients with triple-negative breast cancer in stages I and II that received 4 cycles of NAT with paclitaxel 80 mg/m2 weekly for 12 weeks plus carboplatin in AUC 5 doses every three weeks. Results: The median age within the cohort was 61 years (32-83) with an initial tumor size of 22 mm (10-82) and Ki67 expression of 54% (13-90). Ten patients (16%) presented histologically confirmed initial axillary involvement. The group attained a pCR rate of 56% while only 21% exhibited a minor response with a residual tumor exceeding 10 mm. Over a median follow-up period of 34 months, the recurrence rate was only 5%. The distribution of pathological response across the different clinical variables is delineated in the Table. Conclusions: The NAT regimen with carboplatin AUC 5 + weekly paclitaxel (80 mg/m2) for four cycles is safe for patients diagnosed with stage I and II, demonstrating a high pCR (56%) and a lower recurrence rate (5%). The pathological response observed across all clinical variable subgroups suggests that this regimen could be considered a potential standard for NAT in patients with stage I and II triple-negative breast cancer. [Table: see text]

The efficacy of PARP inhibitors in the treatment of patients with synchronous breast cancer.

e13041 Background: Currently, the role of BRCA1/2 in the development of primary and multiple malignant breast tumors is under discussion, along with the effectiveness of targeted therapy for this oncopathology. At the same time, there is a lack of sufficient research dedicated to the treatment of patients with synchronous breast cancer (BC) concurrent with ovarian cancer (OC) and the outcomes of using PARP inhibitors in this patient population. Methods: A retrospective analysis of treatment outcomes based on long-term survival indicators was conducted for 23 patients with synchronous BC, where the second tumor was OC. These patients underwent evaluation and treatment between 2017 and 2022. The average age of the patients was 45.3±5.6 years, with a prevalence of patients in stages IIb-IIIa of BC and IIb-IIIc of OC. Germline mutations in the BRCA1/2 genes were detected in 8 patients, among whom 5 exhibited the triple-negative phenotype of BC. The 1st group included 11 (47.8%) patients without BRCA1/2 mutations, who received neoadjuvant chemotherapy with paclitaxel 175 mg/m2 + carboplatin AUC 6 once every 3 weeks. In the 2nd group, consisting of 12 (52.2%) patients, olaparib 800 mg was added to this chemotherapy regimen. This group also included 8 patients with BRCA1/2 mutations. Results: In the majority of patients in both groups, a significant elevation in CA125 levels in serum was observed, averaging 563 U/mL, with practically normal CA153 levels at 32 U/mL. Identified mutations included 5382insC and 4154delA mutations in the BRCA1 gene, as well as the 6174delT mutation in the BRCA2 gene. Patients underwent three courses of treatment, and four weeks after completing the last course, surgical intervention was performed in the form of radical mastectomy, hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Following surgical treatment, patients received adjuvant chemotherapy following the same regimens. In the 2nd group, patients continued to receive olaparib for one year, and no signs of unacceptable toxicity were reported. The median overall survival in the first group of patients was 34.2 months (95% CI: 28.6-37.5), while in the second group, it was 36.8 months (95% CI: 31.4-41.1). The addition of bevacizumab significantly increased the median time to progression from 13.8 months (95% CI: 11.8-14.5) to 15.2 months (95% CI: 12.4-15.8), p=0.042. Lethal outcomes primarily occurred due to the progression of ovarian cancer. Conclusions: Thus, the addition of the PARP inhibitor olaparib to a platinum-based chemotherapy regimen in patients with synchronous breast cancer, associated with germline mutations in BRCA1/2 genes and the presence of ovarian cancer as a second tumor, has a positive impact on treatment outcomes. This contributes to the resectability of patients and significantly increases the median time to progression.

De-escalation of breast cancer surgery using vacuum-assisted biopsy (VAB): Interim results.

e12590 Background: Currently, there is a point of view according to which, in patients diagnosed with breast cancer (BC), surgical intervention when achieving a complete pathological response (pCR) after neoadjuvant systemic therapy (NST) is diagnostic, not therapeutic, and does not affect long-term treatment outcomes. Vacuum-assisted biopsy (VAB) of the tumor bed in breast cancer has shown promising results as a minimally invasive method for diagnosing pCR. This work presents a prospective analysis of treatment of patients with triple-negative and HER2-positive breast cancer who achieved pCR after NST and who underwent VAB alone without subsequent breast surgery. Methods: Women aged 18 years old and older with unicentric (cT1-2N0-1M0) triple-negative or HER2-positive breast cancer were included. Primary lesions were marked with a single clip before NST. In cases with nodal involvement (cN1) the affected lymph nodes were also clipped. Patients with TNBC received 4 cycles of AC q21d followed by 12 cycles of weekly paclitaxel and carboplatin AUC 2.0. HER2+ patients received dual anti-HER2 blockade with chemotherapy (TCHP or AC-DHP regimen). Breast US, mammography and mammolymphoscintigraphy were used at baseline and at response evaluation. Patients with complete clinical response after NST underwent VAB with 7G needle and US-guidance simultaneously with the sentinel lymph node biopsy and/or targeted axillary dissection. In case if no invasive or in situ residual tumor cells were detected (ypT0N0), no further breast surgery was performed and patients underwent subsequent radiation therapy. Primary endpoint was 2-year ipsilateral breast tumour recurrence-free survival [IBTR-FS]. Secondary endpoints included 2-year disease-free survival (DFS) and complication rates. The study is registered on сlinicaltrials.gov, NCT04293796. Results: 35 patients with a mean age of 48.3 (31–67) years were included in the trial. Examination of VAB samples showed that 11 (31.4%) patients had a residual tumor, and in 24 (68.6%) patients no tumor cells were detected (ypT0N0). This 24 patients were included in the analysis. Median follow-up was 26 months. Median survival was not reached for any endpoint. 2-year IBTR-FS was 91.7% in the VAB group. 2-year DFS was 83.3% in the VAB group. We registered 4 events: in 2 patients biopsy-proven de novo breast cancer occurred in contralateral breast, in 1 patient recurrence occurred in the postoperative zone and in 1 patient recurrence occurred in another quadrant of the ipsilateral breast. Conclusions: Additional observation and large randomized prospective studies are needed to determine the safety of VAB use. Clinical trial information: NCT04293796 .

A phase II/III study of peri-operative nivolumab (nivo) and ipilimumab (ipi) in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: Results of the neoadjuvant pathologic complete response (pCR) rate (ECOG-ACRIN EA2174).

4000 Background: E/GEJ adenocarcinoma has a high mortality rate despite curative intent therapy. Although the use of immune checkpoint inhibition (ICI) in combination with chemotherapy in the metastatic setting and as adjuvant monotherapy both confer survival benefits, its role in combination with neoadjuvant chemoradiation or with other ICIs in the adjuvant setting remains unclear. Here we report the impact of nivo on pCR rate in pts with E/GEJ adenocarcinoma receiving neoadjuvant chemoradiation as part of the EA2174 clinical trial. Methods: Pts with a localized T1N1-3M0 or T2-3N0-2M0 E/GEJ adenocarcinoma with an ECOG PS of 0-1 and deemed surgical candidates for an esophagectomy were eligible. In step 1, pts were randomized to neoadjuvant therapy with carboplatin AUC 2 and paclitaxel 50 mg/m2 intravenously (IV) weekly x 5 along with 41.4-50.4 Gy radiation without (Arm A) or with (Arm B) nivo 240 mg IV during weeks 1 and 3 of treatment, followed by esophagectomy. Pts underwent a second randomization (step 2) to 6-12 months of adjuvant nivo with or without 6 months of ipi. Planned accrual for step 1 was 278 pts. The primary neoadjuvant endpoint was pCR rate with H0= 23% vs HA= 38%, 90% power, one-sided α = 0.10. The primary adjuvant endpoint comparing nivo to nivo/ipi is disease free survival and will be reported separately once data are mature. Results: Between May 2019 and Dec 2022, 275 pts were enrolled to step 1 of the study (Arm A, n = 138; Arm B, n = 137). Male = 89.5%; White = 92%, Asian = 2.2%, Black 1.5%; median age 65.5 years; E = 60.4%, GEJ = 39.3%. Only 78.5% of pts proceeded to surgery (Arm A = 76.1%, Arm B 81.0%). The pCR rate in Arm A was 21.0% (95% CI, 14.5-28.8) and in Arm B was 24.8% (95% CI, 17.8-32.9), showing no statistically significant difference (p = 0.27). Surgical complication rates between the two arms were similar (Arm A = 28.7%, Arm B = 25.4%). Grade (G) 3/4 events occurring in at least 5% of pts on Arm A—anemia (n = 7), dysphagia (n = 9), esophagitis (n = 7), decreased lymphocytes (n = 80), decreased neutrophils (n = 7); decreased white blood cells (n = 20). G3/4 events occurring in at least 5% of pts on Arm B—anemia (n = 10), dysphagia (n = 8), nausea (n = 8), decreased lymphocytes (n = 84), decreased neutrophils (n = 20), decreased white blood cells (n = 31). Three treatment related deaths occurred on Arm A and two on Arm B. There were no notable differences in chemotherapy or radiation exposure between the two arms. Conclusions: The addition of nivo to neoadjuvant carboplatin, paclitaxel and radiation does not improve the pCR rate in pts with resected E/GEJ adenocarcinoma. Given the known benefit of the addition of ICI to chemotherapy, a further understanding of the impact of radiation on ICI activity is needed. Clinical trial information: NCT03604991 .

Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC): Subgroup analysis from TROPION-Lung02.

8617 Background: Dato-DXd is an antibody-drug conjugate (ADC) composed of an anti-TROP2 monoclonal antibody linked to a potent topoisomerase I inhibitor payload. We report updated findings from TROPION-Lung02 (NCT04526691) evaluating Dato-DXd plus pembro with or without Pt-CT as 1L therapy for aNSCLC. Methods: Patients (Pts) received Dato-DXd (4 or 6 mg/kg) plus pembro 200 mg alone (doublet) or with Pt-CT (triplet; cisplatin 75 mg/m2 or carboplatin AUC 5) Q3W across 6 cohorts. Pts in the expansion stage were primarily treatment (tx)-naïve. PD-L1 expression was evaluated by tumor proportion score (TPS < 50% or ≥50%) using immunohistochemistry (22C3 assay). The primary objectives were safety and tolerability, with efficacy a secondary objective. Results: 96 pts were treated with doublet (n = 42) or triplet (n = 54) therapy in the 1L setting. At data cutoff (Oct 31, 2023), 45% and 20% of pts receiving doublet or triplet tx were ongoing. Median age was 66 years in both subgroups. Median treatment durations were 6.6 and 5.8 months. Across doublet and triplet tx, the most common any-grade (Gr) treatment-emergent adverse events (TEAEs) were stomatitis (57%, 33%) and nausea (40%, 46%), mainly Gr 1–2. Gr ≥3 TEAEs were seen in 57% and 76% of pts; serious TEAEs in 38% and 44%. TEAEs associated with Dato-DXd discontinuation occurred in 29% and 39% of pts receiving doublet or triplet tx. TEAEs associated with death were seen in 2% and 9%, none considered related to study drug. Efficacy outcomes, including ORR and preliminary PFS, in the 1L setting overall and by PD-L1 status are summarized in the Table. Conclusions: As 1L therapy for aNSCLC, Dato-DXd plus pembro with or without Pt-CT continues to demonstrate durable antitumor activity. Efficacy was observed regardless of PD-L1 expression. Tolerability of the combinations was as expected based on known profiles of the individual agents, with no new safety signals observed. To date, this is the largest dataset reported for any ADC combined with an anti-PD-1/L1 agent in the 1L setting for aNSCLC. Clinical trial information: NCT04526691 . [Table: see text]

Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III NSCLC (TRAILBLAZER): Efficacy, safety and feasibility of surgical conversion outcomes from a proof-of-concept, phase 2 trial.

8082 Background: Consolidation immunotherapy after chemoradiation is the standard of care for unresectable stage III NSCLC. Addition of immunotherapy-based induction treatment may further improve outcome, partly by enabling surgery. We conducted a proof-of-concept, phase 2 trial to assess neoadjuvant SHR-1701 (an anti-PD-L1/TGF-β bifunctional fusion protein) with or without chemotherapy, followed by surgery or radiotherapy in unresectable stage III NSCLC and without EGFR/ ALK alterations. Methods: Patients with MDT-assessed surgically unresectable disease were given 3 cycles of neoadjuvant SHR-1701 (30 mg/kg Q3W) with or without chemotherapy (paclitaxel 175 mg/m2 Q3W + carboplatin AUC = 5 Q3W).Patients with PD-L1 TPS < 50% received combination therapy (arm A) and those with PD-L1 TPS ≥50% were randomized (1:1) to receive combination therapy (arm B) or SHR-1701 alone (arm C). After reassessment by MDT, patients received either surgery or definitive radiotherapy (60 Gy/30 fractions) plus concurrent cisplatin (30 mg/m2 QW), all followed by consolidation SHR-1701 for 16 cycles. The primary endpoints were post-induction objective response rate (ORR) and 18-month event-free survival (EFS) rate. Arm A+B (patients receiving neoadjuvant chemoimmunotherapy) was the primary analysis cohort. Results: Between Nov. 20, 2020 and Jan. 27, 2022, 107 patients were enrolled (arm A/B/C, n = 88/9/10). Median follow-up was 22.2 months. In arm A+B, both primary endpoints were met, with a post-induction ORR of 58% (95% CI 47-68) and an 18-month EFS rate of 56.6% (95% CI 45.2-66.5). In arm C, the post-induction ORR was 40% (95% CI 12-74) and 18-month EFS rate was 77.1% (95% CI 34.5-93.9). 24-month overall survival rate was 78.3% (95% CI 68.0-85.7) in arm A+B and 100% in arm C. Overall, 27 (25% of 107; arm A+B/C, n = 24/3) patients underwent surgery; all achieved R0 resection. Among them, 12 (44%) MPR and seven (26%) pCR were recorded. The 18-month EFS rate was 74.1% (95% CI 53.2-86.7) in resected patients and 57.3% (43.0-69.3) in those receiving radiotherapy. Across arms, all grade ≥3 TRAEs with frequency ≥10% were hematological toxicities. No new safety signals were identified. Conclusions: NeoadjuvantSHR-1701 with chemotherapy, followed by surgery or radiotherapy, showed promising anti-tumor activity with a tolerable safety profile in unresectable stage III NSCLC. We provided first evidence that surgical conversion was feasible in a notable proportion of patients, and was associated with better survival outcomes. Clinical trial information: NCT04580498 .

Neoadjuvant sintilimab and platinum-doublet chemotherapy followed by transoral robotic surgery for HPV-associated resectable oropharyngeal cancer: Single-arm, phase II trial.

6011 Background: De-escalation treatments for HPV-associated (HPV+) oropharyngeal cancer (OPC) have been well discussed. Meanwhile, the combination of anti-PD-1 therapy and chemotherapy (immunochemotherapy, ICT) and transoral robotic surgery (TORS) shows promising results in OPC, especially in HPV+ ones. This study aims to investigate the efficacy and safety of neoadjuvant ICT and sequential TORS to reduce functional impairments and omit adjuvant radiotherapy for resectable HPV+ OPC. Methods: In the single-arm, phase II trial, patients with resectable HPV+OPC (cT2-4N0-3M0, AJCC 8.0) were recruited and received neoadjuvant sintilimab (200mg), platinum (cisplatin 60mg/m2, or carboplatin AUC=5), and paclitaxel (nab-paclitaxel 260mg/m2, or docetaxel 75mg/m2) every 3 weeks for 2 cycles, followed by radical surgery (with TORS as an option). The primary endpoint was major pathological response (MPR; defined as residual viable tumor of less than or equal to 10%) in the primary lesion. The secondary endpoints include pathologically complete response (pCR) of all resected lesions, objective response rate (ORR) according to RECIST 1.1, disease-free survival (DFS) rate and overall survival (OS) rate at 1 and 3 years, quality of life (QoL) by EORTC QLQ-H&N35 questionnaire. Results: From February 1, 2022 to November 30, 2023, 27 patients were enrolled and received 2 cycles of neoadjuvant ICT. After neoadjuvant therapy, all 27 cases achieved partial response (PR), the ORR was 100%. Among them, 25 patients received radical surgery (per-protocol population), including 21 with TORSs. The pathological evaluation showed 24 patients (96.0%) achieved MPR, and 13 (52.0%) achieved pCR of all samples including primary lesions and resected lymph nodes. Grade 1-2 treatment-related adverse events (TRAE) occurred in 24/27 patients (88.9%). The most common TRAEs included rash (12, 44.4%), alopecia (10, 37.0%), nausea (8, 29.6%) and weakness (8, 29.6%), while only one patient (3.7%) experienced grade 3 TRAEs, including febrile leukopenia, pneumonia and diarrhea. These adverse reactions were manageable and no surgical delay occurred. After the surgery, the majority of patients had active follow-up without any adjuvant treatment (19/25, 76%), while 4 patients received adjuvant anti-PD-1 therapy and only 2 had adjuvant radiotherapy. At an average follow-up time of 8.2 months, the 6-month DFS and OS were both 100%. Furthermore, compared to the baseline, 22 patients (88%) reported similar or improved QoL scores at 3 months after surgeries. Conclusions: Neoadjuvant sintilimab plus platinum-doublet chemotherapy and sequential TORS achieved satisfactory pathological response, favorable functional preservation and tolerable toxicity in patients with resectable HPV+OPC. Further follow-up is warrant to confirm long-term survival benefits. Clinical trial information: ChiCTR2200058650.

Neoadjuvant toripalimab plus chemotherapy for resectable stage II-IIIB non-squamous non-small cell lung cancer with EGFR mutations: A multi-center, multi-cohort, exploratory study.

TPS8120 Background: Neoadjuvant immunotherapy has been widely applied in the treatment of resectable stage II-IIIB NSCLC patients without driver gene mutation. However, as for the EGFR-positive patients, the therapeutic effect of neoadjuvant treatment, either TKI or chemotherapy, is far from satisfied and the outcome of neoadjuvant immunotherapy plus chemotherapy in these patients remains an unanswered but crucial question. Herein, we conducted a phase 2 prospective trial (NCT05962021). Methods: This is a multicenter, multi-cohort prospective phase 2 study in the treatment-naïve patients with resectable stage II-IIIB (N2) (AJCC 8th edition) non-squamous NSCLC harboring EGFR mutations (19DEL or L858R). Enrolled patients will be divided into two cohorts according to EGFR status and receive neoadjuvant toripalimab (240mg, q3w) plus platinum-based doublet chemotherapy (pemetrexed 500mg/m2 plus carboplatin AUC 5, q3w) for 3 cycles. Surgery will be performed after completion of neoadjuvant therapy based on the multidisciplinary discussion, while local radiotherapy will be considered if the patient cannot undergo surgery due to disease progression. Key inclusion criteria: non-squamous NSCLC, resectable stage II-IIIB (N2), EGFR mutations (19DEL or L858R), age≥18 years, ECOG PS 0-1 and adequate cardiopulmonary function. Exclusion criteria: prior systemic anticancer treatment, contraindication to immunotherapy, active autoimmune disease. Adequate pre-treatment tissue samples are required for RT-PCR or next-generation sequencing to determine the EGFR mutation status and PD-L1 expression immunohistochemical detection. The primary study endpoint is complete pathological response (pCR) rate, per blinded independent pathologist review. Simon's optimal two-stage design will be used to test the null hypothesis of pCR rate ≤5% and alternative hypothesis of pCR rate ≥15%, and 5 or more pCRs among 56 patients per arm are needed for the primary endpoint to be met. Secondary endpoints include major pathological response (MPR) rate, pCR/MPR rate in different EGFR mutation subgroups (19DEL or L858R) and different PD-L1 expression subgroups (TPS < 1% and ≥ 1%), event-free survival and safety and tolerability. Peripheral blood, stool and tissue samples will be obtained longitudinally at baseline, during perioperation and at follow-ups for exploratory analysis. Clinical trial information: NCT05962021 .

Prognostic analysis of PD-1/CTLA-4 bispecific antibody combined with chemotherapy first-line treatment for recurrent or metastatic cervical cancer: A multicenter real-world study.

e17520 Background: PD-1/CTLA-4 bispecific antibody, cadonilimab, has shown excellent efficacy in advanced cervical cancer patients who have previously received platinum containing chemotherapy. However, its effectiveness in first-line treatment remains unclear yet. This study aims to evaluate the efficacy, safety, and prognostic biomarker of cadonilimab combined with chemotherapy for the first line treatment of recurrent or metastatic cervical cancer. Methods: Information on patients with recurrent or metastatic cervical cancer who received chemotherapy combined with cadonilimab as first-line treatment at three cancer centers from July 2022 to September 2023 were collected. Patients have not received systemic chemotherapy previously and are not suitable for curative local treatment, received cadonilimab 10mg/kg Q3W for up to 17 cycles + chemotherapy for up to 6 cycles (paclitaxel 135-175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5), ± bevacizumab 10-15 mg/kg. Clinical outcomes were analyzed using the Kaplan–Meier method with log-rank test. RNA-seq was used to analyze differential expressed genes (DEGs) between PR+CR group and PD+SD group. Results: There are 52 patients enrolled, median age 56.5 years (39–87 years). The median follow-up time was 12 months (5–23 months). There were 29 cases of lung metastasis, 7 cases of liver metastasis, 11 cases of bone metastasis, 12 cases of pelvic metastasis, and 11 cases of lymph node metastasis. The median number of cycles of cadonilimab and chemotherapy were 8 and 5, respectively. The 1-year overall survival (OS) and progression-free survival (PFS) rates were 91% and 72.5%, respectively. The objective response rate (ORR) was 75%.The expression of PD-L1 and bevacizumab had no effect on prognosis. The most common treatment-related adverse events (TRAEs) were neutropenia (78.2%), anemia (82.7%), thrombocytopenia (51.9%), thyroid dysfunction (50%), nausea and vomiting (88.5%), fatigue (71.2%). Grade 3 or 4 adverse events (AE) were reported in 36.5% patients, mainly hematological toxicity. The most significant differential pathways between PR+CR group and PD+SD group were adhesion, Hippo signaling pathway, NOD like receptor signaling pathway, programmed cell death, and secretory granules. Conclusions: Cadonilimab combined with chemotherapy ± bevacizumab as first-line treatment for recurrent or metastatic cervical cancer was effective and well-tolerant.