Progression-free Survival In Arm Research Articles

Combination of encorafenib and binimetinib followed by ipilimumab and nivolumab versus ipilimumab and nivolumab in patients with advanced BRAF-V600E/K-mutated melanoma: The primary analysis of an EORTC randomized phase II study (EBIN).

LBA9503 Background: The benefit of an induction treatment with targeted therapy (TT) with BRAF+MEK inhibitors prior to a combined immunotherapy (IT) with ipilimumab (ipi) + nivolumab (nivo) in patients (pts) with advanced BRAF-V600E/K mutant melanoma is still unclear. Methods: EBIN is an international randomized controlled phase II trial comparing upfront IT (arm A: nivo [3mg/kg] + ipi [1mg/kg] q3w x4 followed by nivo 480 mg q4w) with the sequential approach (arm B: 3 months induction with TT with encorafenib 450 mg QD + binimetinib 45 mg BID orally, followed by IT using the same regimen as in arm A), total treatment [Tx] duration in both arms: 2 years. In arm B, pts were allowed to be rechallenged with TT after progression. Pts with measurable BRAF-V600E/K unresectable stage III/IV melanoma, except pts with uveal melanoma, untreated or symptomatic brain or leptomeningeal involvement were randomly assigned 1:1 to arm A or B. Prior Tx for advanced melanoma was not allowed but adjuvant Tx completed at least 6 months before randomization was permitted. The primary objective was to show superiority of arm B in progression-free survival (PFS) using the log-rank test stratified by stage and lactate dehydrogenase (LDH) with a 1-sided alpha error set at 5%. The study had a power of 80% to detect a HR of 0.65. The study planned to randomize 135 pts in each arm. Results: All 136 pts randomized to arm B and 131 out of 135 in arm A started protocol Tx. At baseline, 170 (63%) pts had stage M1c, 129 (48%) had LDH above upper limit normal (ULN), 74 (27%) had a liver metastasis, and 19 (7%) received adjuvant therapy. The median follow-up was 21 months. In arm B, 135 (99%) pts were free of progression at week 12, when the end of TT was scheduled. In the intention-to-treat population, there was no evidence of a longer PFS in arm B (HR = 0.87, 90% confidence interval [CI] 0.67-1.12, p = 0.36). In a prespecified subgroup analysis, the HR for arm B vs arm A was 2.09 (95% CI 0.96-4.53), 0.74 (95% CI 0.43-1.29), 0.86 (95% CI 0.54-1.37), and 0.46 (95% CI 0.21-1.03) in pts with stage III with LDH≤ULN or M1a, M1b/M1c with LDH≤ULN, ULN < LDH≤2ULN, and LDH > 2ULN, respectively (p-value for interaction 0.045). In a post-hoc subgroup analysis, pts with ≥3 metastatic sites or a sum of target lesions ≥10cm at baseline did not have a longer PFS in arm B but in pts with liver metastasis the Tx HR was 0.48 (95% CI 0.28-0.80, p-value for interaction 0.008). The objective response rate was 53% in arm B and 45% in arm A. Complete response rate was 12% in arm B and 10% in arm A. Grade ≥3 adverse events occurred in 58% of pts in arm B and 51% in arm A. Conclusion: The EBIN trial shows there is no difference in PFS between the two treatment arms for unselected patients but supports the hypothesis that patients with very high LDH and those with liver metastases benefit from the sequential approach. Clinical trial information: NCT03235245 .

Clinico-biological factors predicting the benefit of the LV5FU2 maintenance strategy as a first-line therapy in patients with metastatic pancreatic cancer

Abstract Introduction Predictive markers of LV5FU2 maintenance benefit after first-line induction with FOLFIRINOX in patients with metastatic pancreatic cancer are necessary to select patients who will not be harmed by this strategy. Patients and Methods We focused on patients who received 12 cycles of FOLFIRINOX (arm A, N = 88) or 8 cycles of FOLFIRINOX followed by LV5FU2 maintenance in controlled patients (arm B, N = 91) from the PRODIGE-35 trial. Prognostic factors and predictors of efficiency were identified by using Cox regression. Median progression-free survival (PFS), overall survival (OS), and time to deterioration of quality of life (TTD-QoL) were evaluated. Results Poor independent prognostic factors were primary tumor in place, age <65 years and the presence of liver metastases for PFS, a baseline neutrophil/lymphocyte ratio (NLR) ≥5 and CA19.9 ≥500 UI/L for OS, independent of the treatment arm. Patients with one metastatic site had a longer PFS in arm A, whereas patients with ≥2 metastatic sites had a longer PFS in arm B. We also identified predictors of OS and TTD-QoL in arm B but these differences were not statistically significant. Conclusion Except for patients with one metastatic site who benefited more from 12 cycles of FOLFIRINOX, a maintenance strategy with LV5FU2 should be widely offered to mPC patients whose survival and QoL are preserved after 4 months of FOLFIRINOX. (ClinicalTrials.gov: NCT02352337).

Efficacy and safety in unresectable hepatocellular carcinoma with VP4 tumor embolus using sinilimab plus bevacizumab: A retrospective analysis of real-world evidence.

e16156 Background: Recently, sinilimab plus bevacizumab has shown promising effects on unresectable hepatocellular carcinoma (uHCC) in ORIENT-32. However, its efficacy and safety in uHCC patients with VP4 cancer embolus remained unclear. Methods: In this retrospective study, uHCC patients with VP4 tumor embolus who received first-line sinilimab plus bevacizumab were consecutively enrolled. We also included similar patients who were treated with first-line sorafenib as comparison. Main efficacy endpoint was overall survival (OS), following progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR) to be secondary endpoints, evaluated in accordance with RECIST v1.1. Adverse events (AEs) were recorded according to CTCAE v5.0. Results: Total 43 eligible patients were enrolled, with 15 in sinilimab plus bevacizumab arm (arm 1) and the other 28 in sorafenib arm (arm 2). No statistical differences were found in etiology, liver function and performance status. At data cut-off at February 2023, median PFS in arm 1 and arm 2 were 3.7 (95%CI: 1.2-6.2) and 3.8 (95%CI:3.1-4.5) months, following ORR and DCR were 6.7% & 46.7% and 7.1% & 35.7%. OS in arm 1 was not matured and in arm 2 was 16.1 (11.1-21.1). Not any difference was detected among all efficacy endpoints. AEs happened among almost all patients. But nobody died of AEs. Conclusions: Efficacy and safety of sinilimab plus bevacizumab in uHCC patients with VP4 tumor embolus was similar with sorafenib, which needs to be further confirmed. [Table: see text]

TEDOVA/GINECO-OV244b/ENGOT-ov58 trial: Neo-epitope based vaccine OSE2101 alone or in combination with pembrolizumab vs best supportive care (BSC) as maintenance in platinum-sensitive recurrent ovarian cancer with disease control after platinum.

TPS5618 Background: Besides PARP inhibitors and bevacizumab, there are no approved maintenance therapies after platinum based chemotherapy for patients with a platinum sensitive relapsed epithelial ovarian cancer (OC). Immune checkpoint inhibitors (ICI) as single agents have limited activity in OC. One attractive strategy is to turn OC from immunogenic “cold” to “hot” tumors via vaccination with tumor-associated antigens (TAAs). OSE2101 is a multiple-neoepitope vaccine restricted to HLA-A*02-positive patients (45% of OC patients) targeting 5 TAAs: TP53, MAGE2, MAGE3, CEA and HER2. These neo-epitopes are modified to increase both major histocompatibility complex and the T cell receptor binding affinity. The proof of concept for this approach was recently demonstrated with OSE2101 improving overall survival in a phase III trial in lung cancer progressing after ICI (Besse et al. 20211). The combination of OSE2101 with an ICI may most effectively harness anti-tumor immunity. Methods: TEDOVA is an international randomized open-label, phase II trial evaluating the benefit of maintenance by OSE2101 alone or in combination with PD1 inhibition (pembrolizumab) after platinum based chemotherapy in relapsed OC, previously treated with bevacizumab (if eligible) and a PARP inhibitor (if eligible). Patients (N=180) with CR/PR/SD at the end of chemotherapy are randomized (1:1:2) to: Observation/BSC (Arm A), OSE2101 alone (Arm B), or OSE2101 in combination with pembrolizumab (Arm C). Experimental treatments are continued until progression, or intolerance, for up to 2 years. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall response rate, safety, time to subsequent first or second treatment (TTST-1, TTST-2) and overall survival. 180 HLA-A*02 positive patients will be randomized. HLA-A*02 negative patients will be followed in a separate observational cohort. The sample size is calculated to provide 90% power to detect an improvement in PFS for Arm C vs Arm A with a HR of 0.57. Three one-sided Log-rank tests will be considered in a pre-defined sequence: H1: C (OSE2101+pembrolizumab) vs A (BSC); H2: C (OSE2101+pembrolizumab) vs B (OSE2101) and H3: B vs A. The type I error will be α=5%. The type II error will be β=10%. Tests will be one-sided. Status: The TEDOVA/GINECO-OV244b/ENGOT-ov58 trial is currently recruiting. Clinical trial information NCT04713514. 1. Besse B, Garcia MR, Cobo MA, Quoix E, Madroszyk A, Felip E, et al. LBA47 - Activity of OSE-2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (IO): Final results of phase III Atalante-1 randomised trial. Annals of Oncology 2021;32(suppl_5) : S1283-S1346. Clinical trial information: NCT04713514 .

Abstract PD13-05: PD13-05 Updated results of a Phase 1b study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: Subgroup analysis by PIK3CA mutation status

Abstract Background: Addition of PI3K/mTOR inhibitor after progression on CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) can potentially restore sensitivity to CDK4/6i and prevent adaptive activation of the PI3K/mTOR pathway. To evaluate this hypothesis, we conducted a Phase Ib study of gedatolisib (G), a dual inhibitor of PI3K/mTOR, palbociclib (P) a CDK4/6i, and ET (with letrozole [LET] or fulvestrant [FUL]) in women with hormone receptor positive (HR+)/HER2- advanced breast cancer (ABC). Manageable toxicity and preliminary antitumor activity were observed in 35 patients(pts) enrolled in the dose escalation portion of the study (Forero-Torres, ASCO 2018) and 103 pts enrolled in the expansion portion of the study (Layman, SABCS 2021). Here, we report updated efficacy and safety data and sub-group analysis by PIK3CA mutation status in the four expansion study arms with a March 3, 2022, data cut-off. Methods: Pts with HR+/HER2- ABC were treated in four expansion arms: A) G+P+LET as first-line treatment, B) G+P+FUL as 2nd line treatment in pts without prior CDK4/6i; C & D) G+P+FUL as 2nd or 3rd line therapy in pts with prior CDK4/6i. P, LET, and FUL were administered at standard doses. G 180 mg was intravenously administered weekly in Arms A, B, and C and three weeks on/one week off in Arm D. The primary endpoint was investigator assessed objective response rate (ORR). Secondary endpoints included safety, duration of response and progression free survival (PFS). Results: Of the 103 pts treated with G+P+ ET in the expansion arms (A-D), 100% had measurable disease at baseline, 71% (73/103) lacked PIK3CA mutations (wild type; WT), 27% (28/103) had PIK3CA-mutations (MT), 70% (72/103) had evidence of bone metastases, and 59% (61/103) had liver metastases. The most frequent grade 3 and 4 treatment related AEs (TRAE) with G+P+ET included neutropenia (63%), stomatitis (27%), rash (20%), fatigue (11%) and hyperglycemia (7%). Treatment discontinuation due to TRAEs was 6.5% in Arm A, 15.4% in Arm B, 9.4% in Arm C and 3.7% in Arm D. Efficacy data for each arm is presented in Table 1. Promising ORR and PFS were seen in all arms regardless of PIK3CA mutation status. In Arm D, ORR was 63% overall, 73% in PIK3CA-MT pts, and 60% in PIK3CA-WT pts. Median PFS in Arm D was 12.9 months with a median follow up of 29 months. 60% and 48% of pts in the PIK3CA-MT and PIK3CA-WT Arm D sub-groups, respectively, were progression free at 12 months. Conclusions: These preliminary data demonstrate promising activity of G+P+ET combination in pts who were CDK4/6i-naïve and in those whose disease progressed on or after CDK4/6i therapy regardless of PIK3CA mutation status. Encouraging results in CDK4/6i treatment naïve patients warrant further evaluation of gedatolisib in combination with CDK4/6i treatment in the front-line setting. Arm D results provide a strong basis for the initiated Phase 3 study (VIKTORIA-1) in pts whose disease progressed on or after CDK4/6i therapy. Table 1. Efficacy Data by Expansion Arms Citation Format: Robert Wesolowski, Hope Rugo, Erica Stringer-Reasor, Hyo S. Han, Jennifer M. Specht, E. Claire Dees, Peter Kabos, Ulka Vaishampayan, Seth A. Wander, Janice Lu, Keerthi Gogineni, Alexander I. Spira, Anne F. Schott, Maysa Abu-Khalaf, Pratima Nayak, Brian F. Sullivan, Igor Gorbatchevsky, AND Rachel M. Layman. PD13-05 Updated results of a Phase 1b study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: Subgroup analysis by PIK3CA mutation status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-05.

Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small-cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial

The APPLE trial aimed to evaluate the feasibility of longitudinal plasma epidermal growth factor receptor (EGFR) T790M monitoring for the best sequencing strategy of gefitinib and osimertinib. APPLE is a randomized, non-comparative, phase II study in patients with common EGFR-mutant, treatment-naive non-small-cell lung cancer including three arms: arm A (osimertinib upfront until RECIST progression, PD), arm B [gefitinib until emergence of circulating tumor DNA (ctDNA) EGFR T790M mutation by cobas EGFR test v2 or RECIST PD], and arm C (gefitinib until RECIST PD), and then switch to osimertinib in both arms. The primary endpoint is the progression-free survival (PFS) rate 'on osimertinib' at 18 months (PFSR-OSI-18) after randomization in arm B (H0: PFSR-OSI-18 of ≤40%). Secondary endpoints include response rate, overall survival (OS), and brain PFS. We report the results of arms B and C. From November 2017 to February 2020, 52 and 51 patients were randomized into arms B and C, respectively. Most patients were females (70%) and had EGFR Del19 (65%); one-third had baseline brain metastases. In arm B, 17% of patients (8/47) switched to osimertinib based on the emergence of ctDNA T790M mutation before RECIST PD, with a median time to molecular PD of 266 days. The study met its primary endpoint of PFSR-OSI-18 of 67.2% (84% confidence interval 56.4% to 75.9%) in arm B versus 53.5% (84% confidence interval 42.3% to 63.5%) in arm C, with a median PFS of 22.0 months versus 20.2 months, respectively. The median OS was not reached in arm B versus 42.8 months in arm C. Median brain PFS in arms B and C was 24.4 and 21.4 months, respectively. The serial monitoring of ctDNA T790M status in advanced EGFR-mutant non-small-cell lung cancer during treatment with first-generation EGFR inhibitors was feasible, and a molecular progression before RECIST PD led to an earlier switch to osimertinib in 17% of patients with satisfactory PFS and OS outcomes.

Preoperative chemotherapy prior to primary tumor resection for asymptomatic synchronous unresectable colorectal liver-limited metastases: A multicenter randomized controlled trial.

132 Background: Most recently, there were 3 reports of prospective randomized clinical trials comparing the effects of primary tumor resection (PTR) for multiorgan metastatic colorectal cancer followed by chemotherapy with chemotherapy alone, but the results differed and unconvincing due to the prematurely study termination and research protocol changes. PTR was preferably performed for patients with asymptomatic synchronous unresectable colorectal liver-limited metastases (CRLMs) with conversion therapy purpose, including the CELIM, OLIVIA and our study (J Clin Oncol 2013;31:1931-8). This randomized phase III study investigated the superiority of preoperative chemotherapy prior to PTR for patients with asymptomatic synchronous unresectable CRLMs. Methods: Patients with asymptomatic synchronous unresectable CRLMs were randomly assigned to receive pre-PTR chemotherapy (arm A) or upfront PTR (arm B). Chemotherapy regimens of mFOLFOX6 plus cetuximab, mFOLFOX6 plus bevacizumab or mFOLFOX6 alone were decided according to the RAS genotype. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), tumor response, disease control rate (DCR), liver metastases resection rate, surgical complications and chemotherapy toxicity. Results: Between June 2012 and June 2018, a total of 320 patients were randomly assigned to arm A (160 patients) or arm B (160 patients). The cutoff date for survival data was June 2021, the median follow-up time was 36.2 months. Patients were well balanced. For the intention-to-treat population, the median PFS, median OS, and 3-year OS rates were 9.9 months, 28.0 months, and 37.0%, respectively. The median PFS in arm A was significantly improved compared with arm B (10.5 v 9.1 months; hazard ratio [95% CI, 0.60 to 0.95], 0.76; P = 0.013). Patients in arm A also had a significantly better DCR (84.4% v 75.0%; P = 0.037). The median OS was not significantly different (29.4 v 27.2 months; hazard ratio [95% CI, 0.58 to 1.01], 0.77, P = 0.058), and the objective response rates were also not significantly different (53.1% v 45.0%; P = 0.146). The actual resection rate of liver metastases was not significantly different (21.9% v 18.1%; P = 0.402). There were mild morbidities and no 30-day postoperative mortalities in both arms. The rate of complications was not significantly different (37.7% v 30.8%, P = 0.201). The incidence of Clavien–Dindo 3-4 complications also did not reach statistical significance (4.5% v 3.8%, P = 0.759). Overall the observed toxicity was mostly mild. There was no significant difference in the overall incidence of predefined grade 3/4 events (42.2% v 40.4%, P = 0.744). There were no grade 5 events in either arm. Conclusions: For asymptomatic synchronous unresectable CRLMs, Pre-PTR chemotherapy improved the PFS compared with upfront PTR. Clinical trial information: NCT01307878 .

Comparative outcome of cisplatin-capecitabine regimen with oxaliplatincapecitabine regimen in advanced gastric carcinoma: a quasi-experimental study

Chemotherapy is the primary therapeutic choice for advanced gastric cancer. The goal of this study was to assess the effectiveness and toxicity of the cisplatin-capecitabine regimen versus the oxaliplatin-capecitabine regimen in treating advanced gastric cancer. Between February 2021 and March 2022, this quasi-experimental study was conducted on 64 advanced gastric cancer patients. Purposive sampling was used to include those who met the inclusion criteria and distributed them evenly between the two arms. Arm A got an injection of cisplatin (80 mg/m2 on day 1) with oral capecitabine (1000 mg/m2 b.i.d. on days 1–14), whereas arm B received an injection of oxaliplatin (130 mg/m2 on day 1) plus oral capecitabine (1000 mg/m2 b.i.d. on days 1–14), every 3 weeks for 6 cycles. A final check-up was done at 12 weeks after the treatment. In arm A, 18 (56.2%) patients exhibited partial response compared to 15 (46.9%) in arm B. Stable diseases were also reported in both arms (18.8% in arm A and 21.9% in arm B). There were 8 (25.0%) cases of progressive disease in arm A and 10 (31.2%) cases in Arm B. The median progression-free survival in arms A (5.6 months) was almost similar to arm B (5.9 months). The most prevalent toxicities in both arms were vomiting, diarrhea, anemia, neutropenia, oral mucositis, paresthesia, handfoot syndrome, and renal toxicity. There were no statistically significant variations in outcomes between the two arms. In conclusion, the cisplatincapecitabine regimen is as effective as the oxaliplatin-capecitabine regimen in advanced gastric cancer. BSMMU J 2022; 15(3): 180-185

LBA21 FOLFOX/FOLFIRI plus either bevacizumab or panitumumab in patients with initially unresectable colorectal liver metastases (CRLM) and left-sided and RAS/BRAFV600E wild-type tumour: Phase III CAIRO5 study of the Dutch Colorectal Cancer Group

Patients (pts) with initially unresectable CRLM may qualify for curative-intent local therapy after downsizing by induction systemic therapy. CAIRO5 was designed to find the optimal induction regimen. We present results of pts with left-sided and RAS/BRAFV600E wild-type tumour. Pts were randomised between FOLFOX/FOLFIRI (patient preference) plus either bevacizumab (arm A) or panitumumab (arm B) up to 12 cycles. Prior systemic or local therapy for metastases was not allowed. (Un)resectability of CRLM was assessed by a liver expert panel of surgeons and radiologists, at baseline by predefined criteria and every 2 months thereafter by individual opinion. Primary endpoint was progression-free survival (PFS). Pts were stratified by potentially resectable vs permanently unresectable CRLM, serum LDH (normal/abnormal) and choice of irinotecan vs oxaliplatin. 256 events were required to detect a hazard ratio (HR) of 0.70 for PFS with 80% power and 2-sided log-rank test at 5% assuming a median PFS of 11.6 months in arm A. 236 pts (118 in each arm) were included in 43 Dutch sites from November 2014 until closure due to futility in March 2022. 6 ineligible pts were excluded. Median follow up was 44 months. Main characteristics were (arm A/B): median age 59/60, male 61/63%, synchronous CRLM 88/92%, prior adjuvant chemotherapy 4/3%, median number of CRLM 12/12. With 197 events, median PFS in arm A vs B was 10.6 vs 10.3 months (stratified HR 1.12, 95% CI 0.84-1.50, p=0.44). Response rate (RR) was 52% vs 76% (p<0.01). Median depth of response (DOR) was 33% vs 49% (p<0.01). R0/1 resection ± ablation rate was 58% vs 56% (p=0.79). Grade ≥3 toxicity occurred in 52% vs 69% (p=0.01), Clavien Dindo grade ≥3 surgical complications in 21% vs 14% (p=0.30). In first-line treatment of pts with initially unresectable CRLM and left-sided and RAS/BRAFV600E wild-type tumour there is no difference in median PFS between the addition of either bevacizumab or panitumumab to FOLFOX/FOLFIRI. The addition of panitumumab significantly increases RR and DOR but this does not translate in an increased local therapy rate of CRLM.

A Randomized Study of Short Course (One Week) Radiation Therapy with or without Temozolomide in Elderly and/or Frail Patients with Newly Diagnosed Glioblastoma (GBM).

Short-course radiotherapy (25 Gy in 5 fractions) has been shown to be non-inferior to standard course radiotherapy in elderly and frail patients (60 Gy in 30 fractions). The purpose of this study was to determine the effects of temozolomide combined with short-course radiotherapy on the outcome of elderly and frail patients. Between January 2017 and November 2018, 90 patients (65 years old and KPS score of 50-70; 65 years old and KPS score of 80-100; and 65 years old and KPS score of 50-70) were assessed for eligibility. Nine patients were excluded because they did not meet the inclusion criteria, six patients declined to participate, and four patients were unable to complete the quality-of-life questionnaire. The remaining 71 patients were divided into two arms at random in a 1:1 ratio. Short-course radiotherapy with concurrent temozolomide and adjuvant temozolomide was given to Arm 1, while short-course radiotherapy alone was given to Arm 2. In terms of overall survival and progression-free survival, radiotherapy with concurrent temozolomide and adjuvant temozolomide outperformed short-course radiotherapy alone. The median overall survival in arm 1 was 146 days and 121 days in arm 2 (P=0.146). The median progression-free survival in arm 1 was 109.50 days, while it was 77 days in arm 2 (P=0.028). With a median follow-up time of 6 months, the quality of life at 4 weeks and 12 weeks after treatment was not different between the two arms. We concluded that adding temozolomide to short-course radiotherapy significantly improved progression-free survival and showed an increasing trend in overall survival without compromising the quality of life.

Abstract 1279: Early radiologic signal of nivolumab responsiveness after short-course oxaliplatin-based chemotherapy in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC)

Abstract Purpose: Immune checkpoint inhibition (ICI) may result in tumor response patterns that differ from efficacy measures of directly cytotoxic chemotherapies. Hence, the selection of patients for experimental ICI schedules, for instance in MSS-mCRC, calls for applicable and reliable signals of activity or early failure that enable treatment adaptation and maintain patient safety. Experimental procedures: In the ongoing METIMMOX phase 2 study, we hypothesize that patients with previously untreated unresectable MSS-mCRC can obtain durable disease control to ICI when given short-course oxaliplatin-based chemotherapy (2 cycles of FLOX Q2W) before 2 cycles of nivolumab (240 mg Q2W) in a repeat sequential schedule to a total of 8 cycles. Patients have been randomly assigned to either this experimental study arm or a control arm of 8 FLOX cycles Q2W (standard-of-care; SoC), in both cases before treatment break until disease progression and reintroduction of a new treatment sequence. Radiologic response assessment is performed every 8 weeks with progression-free survival (PFS) as the primary end point. Results: At analysis 10 November 2021, median PFS was 9.3 months (95% CI, 8.3-10.3) for SoC (n = 34) and 11.4 months (95% CI, 7.4-15.5) for the experimental therapy (n = 39) (p = 0.335; log-rank test). In the latter group, 37 patients had available response evaluation at minimum 8 weeks of study treatment, as 2 patients (compared to 4 in the control group) had discontinued treatment due to intolerable toxicity before the first post-baseline assessment. The control arm patients had deeper responses with mean 23% (SD, 19%) target lesion reduction compared to mean 8%(SD, 33%) reduction for the experimental schedule (p = 0.028; Student’s t-test). We categorized the experimental arm patients into those with ≥10% (n = 20) or &amp;lt;10% (n = 17) target lesion reduction at 8 weeks. Median PFS for the ≥10% group was 15.2 months (95% CI, 11.4-19.0) and for the &amp;lt;10% group 4.5 months (95% CI, 3.2-5.7), which was clearly superior and inferior to the control arm PFS (p = 0.007 for the ≥10% group and p = 0.019 for the &amp;lt;10% group; log-rank test). Categorisation of experimental arm patients set at higher than 10% target lesion change at the first radiologic response assessment did not identify patients with longer PFS. Conclusions: While the SoC first-line chemotherapy resulted in deeper early responses, target lesion reduction of ≥10% at 8 weeks identified MSS-mCRC patients who held ICI responsiveness evoked by short-course oxaliplatin-based chemotherapy, with significantly improved PFS compared to the SoC. An early radiologic signal of clinical activity may guide the selection of patients to the safe continuation of investigational ICI schedules; however, we do not know if adopting it may compromise prognosis for patients with early ICI failure who can proceed with SoC. Citation Format: Sebastian Meltzer, Anne Negård, Hanne Mari Hamre, Christian Kersten, Eva Hofsli, Marianne Grønlie Guren, Halfdan Sørbye, Kjersti Flatmark, Anne Hansen Ree. Early radiologic signal of nivolumab responsiveness after short-course oxaliplatin-based chemotherapy in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1279.

FOLFOXIRI + bevacizumab versus FOLFOX/FOLFIRI + bevacizumab in patients with initially unresectable colorectal liver metastases (CRLM) and right-sided and/or RAS/BRAFV600E-mutated primary tumor: Phase III CAIRO5 study of the Dutch Colorectal Cancer Group.

LBA3506 Background: Patients (pts) with initially unresectable CRLM may qualify for curative-intent local therapy after downsizing by induction systemic therapy. The CAIRO5 study aims to find the optimal induction regimen. We present the results of pts with right-sided and/or RAS/ BRAFV600E mutated primary tumors. Accrual in pts with left-sided and RAS/ BRAFV600E wildtype tumors is ongoing. Methods: Pts were randomized between FOLFOX or FOLFIRI + bevacizumab (B) (arm A) and FOLFOXIRI-B (arm B), in both arms up to 12 cycles and followed by 5FU/LV/B maintenance. Prior systemic or local therapy for metastases was not allowed. Unresectability of CRLM at baseline was assessed by an online liver expert panel of surgeons and radiologists based on predefined criteria, and resectability every 2 months thereafter based on panel majority vote. The primary endpoint was progression-free survival (PFS). Secondary endpoints were R0/1 resection, overall survival, overall response rate (ORR), toxicity, pathologic response, postoperative morbidity and correlation of panel evaluations with outcome. Pts were stratified by potentially resectable vs permanently unresectable CRLM, serum LDH (normal/abnormal), BRAFV600E mutation, sidedness, choice of irinotecan vs oxaliplatin and institute. To detect a hazard ratio (HR) of 0.70 for PFS with 80% power and a 2-sided log-rank test at 5%, 257 events were required, assuming a median PFS of 8.7 months for arm A. Results: From December 2014 until March 2021, 294 pts were randomized, 148 in arm A and 146 in arm B in 43 Dutch and 1 Belgian sites. 3 ineligible pts were excluded. Median follow up was 40 months. Pts received a median of 10 vs 9 induction cycles in arm A vs B. Main characteristics were (arm A/B): median age 61/65 years, male 63.9/60.4%, right-sided primary tumor 39.5/41.7%, RAS mutant 85.7/86.1%, BRAFV600E mutant 6.8/8.3%, synchronous disease 86.4/89.6%, prior adjuvant chemotherapy 4.8/4.9%, median number of CRLM 12/12. With 259 events, median PFS in arm A vs B was 9.0 vs 10.6 months (stratified HR 0.74, 95% CI 0.57-0.96, p=0.02). ORR was 32.0% vs 52.1% (p&lt;0.001), any grade ≥3 adverse events occurred in 58.5% vs 75.0% (p=0.003), the most frequent were neutropenia (12.9/38.2%, p&lt;0.001), hypertension (14.3/13.9%, p=1) and diarrhea (3.4/19.4%, p&lt;0.001) in arm A vs B, respectively. R0/1 resection ± ablation rates were 37.4% vs 51.4% (p=0.02) with 2-stage procedures in 16.4% vs 32.4% (p=0.04), postoperative complications occurred in 38.2% vs 51.2% (p=0.14), Clavien Dindo grade ≥3 in 14.7% vs 26.8% (p=0.08). Conclusions: FOLFOXIRI-B vs FOLFOX/FOLFIRI-B significantly increases PFS, ORR and R0/1 resections at the cost of increased toxicity in pts with initially unresectable CRLM and right-sided and/or RAS/ BRAFV600E mutated primary tumor. Clinical trial information: NCT02162563.

A phase I/II study of ruxolitinib with frontline neoadjuvant and post-surgical therapy in patients with advanced epithelial ovarian, Fallopian tube, or primary peritoneal cancer.

5501 Background: The Interleukin-6/JAK/STAT3 axis, via an increase in cancer stem-like cell (CSC) survival, is a reported driver of chemotherapy resistance. We hypothesized that addition of the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and, by targeting therapy-resistant cells, improve the progression-free survival (PFS) of ovarian/fallopian tube/primary peritoneal carcinoma (OV/FT/PPC) patients treated in the up-front setting. Methods: Patients with OV/FT/PPC dispositioned to neoadjuvant chemotherapy were eligible for NRG-GY007 (NCT #02713386). In phase I, treatment was with dose-dense paclitaxel (P) 70 or 80 mg/m2 days 1, 8, and 15; carboplatin (C) AUC 5 or 6 day 1; and ruxolitinib (R) 15mg PO BID, every 21 days. In the absence of tumor progression or an inability to tolerate surgery, interval tumor reductive surgery (TRS) was required after cycle 3. After TRS, 3 additional cycles were administered, followed by maintenance ruxolitinib until progression, unacceptable toxicity, or voluntary withdrawal. In phase II, patients were randomized to dose-dense PC (arm 1) or dose-dense PC plus ruxolitinib (arm 2) at the phase I-defined dose of 15mg PO BID. After 3 cycles, TRS was performed, followed by another 3 cycles of the randomized regimen, without maintenance ruxolitinib. The primary phase II endpoint was progression-free survival (PFS). Results: 17 patients were enrolled in phase I. The MTD was P at 70, C at 5, and R at 15, which was chosen as the phase II dose. 130 patients were enrolled in phase II with a median follow-up of 24 months. There were five Grade 5 events in phase II, 2 in arm 1 and 3 in arm 2, with all except one being unrelated to therapy; a G5 febrile neutropenia in arm 2 was considered possibly related. In arm 2 there was potential trend towards higher grade 3-4 anemia (64% v 27% control), grade 3-4 neutropenia (53% v 37%), thromboembolic events (12.6% v 2.4%), and febrile neutropenia (6% v 0%). The HR for PFS was 0.702 (90% 1-sided CI = 0-0.89, log-rank p = 0.059). The median PFS in arm 1 was 11.6 versus 14.6 in arm 2. The overall survival HR = 0.785 (90% CI = 0.44 to 1.39, p = 0.70). There were no differences between rates of total gross resection. Conclusions: Ruxolitinib 15mg PO BID was well-tolerated with acceptable toxicity in combination with dose-dense PC. The primary endpoint of prolongation of PFS was achieved in the experimental arm. Further study of this combination can be considered. This trial also demonstrates the feasibility of early-phase randomized studies with novel agents and biospecimen collection in front line neoadjuvant treatment of ovarian cancer. Clinical trial information: 02713386.

TEDOVA/GINECO-OV244b/ENGOT-ov58 trial: Neo-epitope based vaccine OSE2101 alone or in combination with pembrolizumab versus best supportive care (BSC) as maintenance in platinum-sensitive recurrent ovarian cancer with disease control after platinum.

TPS5614 Background: Besides PARP inhibitors and bevacizumab, there are no approved maintenance therapies after platinum based chemotherapy for patients with a platinum sensitive relapsed epithelial ovarian cancer (OC). Immune checkpoint inhibitors (ICI) as single agents have limited activity in OC. One attractive strategy is to turn OC from immunogenic “cold” to “hot” tumors via vaccination with tumor-associated antigens (TAAs). OSE2101 is a multiple-neoepitope vaccine restricted to HLA-A2-positive patients (45% of OC patients) targeting 5 TAAs: TP53, MAGE2, MAGE3, CEA and HER2. These neo-epitopes are modified to increase both major histocompatibility complex and the T cell receptor binding affinity. The proof of concept for this approach was recently demonstrated with OSE2101 improving overall survival in a phase III trial in lung cancer progressing after ICI (Besse et al. 2021). The combination of OSE2101 with an ICI may most effectively harness anti-tumor immunity. Methods: TEDOVA is an international randomized open-label, phase II trial evaluating the benefit of maintenance by OSE2101 alone or in combination with PD1 inhibition (pembrolizumab) after platinum based chemotherapy in relapsed OC, previously treated with bevacizumab (if eligible) and a PARP inhibitor (if eligible). Patients (N=180) with CR/PR/SD at the end of chemotherapy are randomized (1:1:2) to: Observation/BSC (Arm A), OSE2101 alone (Arm B), or OSE2101 in combination with pembrolizumab (Arm C). Experimental treatments are continued until progression, or intolerance, for up to 2 years. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall response rate, safety, time to subsequent first or second treatment (TTST-1, TTST-2) and overall survival. 180 HLA-A*02 positive patients will be randomized. HLA-A*02 negative patients will be followed in a separate observational cohort. The sample size is calculated to provide 90% power to detect an improvement in PFS for Arm C vs Arm A with a HR of 0.57. Three one-sided Log-rank tests will be considered in a pre-defined sequence: H1: C (OSE2101+pembrolizumab) vs A (BSC); H2: C (OSE2101+pembrolizumab) vs B (OSE2101) and H3: B vs A. The type I error will be α=5%. The type II error will be β=10%. Tests will be one-sided. Status: The TEDOVA/GINECO-OV244b/ENGOT-ov58 trial is currently recruiting. Clinical trial information: NCT04713514.

Alliance Foundation Trial 09: A Randomized, Multicenter, Phase 2 Trial Evaluating Two Sequences of Pembrolizumab and Standard Platinum-Based Chemotherapy in Patients With Metastatic NSCLC

IntroductionThe sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy. MethodsThis multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a “pick a winner” design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years. ResultsFrom March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%–54.1 %) and 40.4 % (95 % CI: 26.4%–54.5 %), respectively (p = 0.93). The progression-free survival in arms A and B was as follows: hazard ratio of B versus A equals to 1.06, 95 % CI: 0.68–1.66, p value equals to 0.84, and median progression-free survival of 5.8 months and 4 months, respectively. The overall survival was as follows: hazard ratio of B versus A equals to 1.04, 95 % CI: 0.63–1.74, p value equals to 0.85, and median overall survival of 15.5 months and 14 months, respectively. ConclusionsAdditional evaluation of either sequence in a phase 3 trial is not warranted.

Randomized Phase II Study of R-CHOP-14 Versus R-CHOP-14 Followed By Chaser As Induction Therapy for High-Dose Chemotherapy (HDT), LEED, and Autologous Stem-Cell Transplantation (ASCT) in Poor-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Japan Clinical Oncology Group (JCOG) Study (JCOG0908)

Randomized Phase II Study of R-CHOP-14 Versus R-CHOP-14 Followed By Chaser As Induction Therapy for High-Dose Chemotherapy (HDT), LEED, and Autologous Stem-Cell Transplantation (ASCT) in Poor-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Japan Clinical Oncology Group (JCOG) Study (JCOG0908)

Randomized Phase II Study with Cetuximab in Combination with 5-FU and Cisplatin or Carboplatin vs. Cetuximab in Combination with Paclitaxel and Carboplatin for Treatment of Patients with Relapsed or Metastatic Squamous Cell Carcinoma of the Head and Neck (CETMET Trial).

Simple SummaryThe purpose of the CET-MET trial was to find a new platinum- based chemotherapy regimen in combination with cetuximab for relapsed or metastatic squamous cell carcinoma of the head and neck (RM- SCCHN), that would achieve an equivalent PFS with standard cetuximab and 5-FU/platinum-based chemotherapy (EXTREME regimen), albeit with less toxicity. RM-SCCHN is a disease which affects patients with severe comorbidity and unhealthy life styles, rendering it difficult to treat with toxic regimens such as the EXTREME trial regimen. Immune checkpoint inhibition (ICI) with/or without the addition of chemotherapy has recently been introduced as a first- line treatment option for RM-SCCHN. However, these new treatment options will not be suitable for all patients. The experimental arm of this trial with Cetuximab and paclitaxel/carboplatin is easier to administer and perhaps more beneficial to combine with ICIs due to its favorable toxicity profile and the potential immunomodulatory effects of taxanes.Background: Platinum-based chemotherapy with cetuximab is the standard of care for relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). The aim of this trial was to investigate whether cetuximab and paclitaxel/carboplatin can achieve similar progression-free survival (PFS) with standard cetuximab and 5-FU/platinum-based chemotherapy. Standard chemotherapy treatment for SCCHN is related to severe toxicity and new, less toxic regimens are needed. Methods: In this multicentre, randomized, controlled, phase 2 trial, 85 patients with relapsed or metastatic SCCHN were randomized in a 1:1 ratio to cetuximab and 5-FU/cisplatin or carboplatin (arm A) vs. cetuximab and paclitaxel/carboplatin (arm B). Eligibility criteria included age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, and adequate organ functions. The primary endpoint was to investigate whether PFS in arm B is significantly worse than PFS in arm A. Results: Median PFS in arm A was 4.37 months (95% CI: 2.9–5.9 m) and 6.5 months (95% CI: 4.8–8.2 m) in arm B, (p = 0.064). Median overall survival (OS) was 8.4 months (95% CI: 5.3–11.5 m) in arm A and 10.2 months (95% CI: 5.4–15 m) in arm B, (HR = 0.71; 95% CI: 0.43–1.16). PFS HR for arm B was not significantly worse than arm A (HR = 0.65; 95% CI: 0.41–1.03). Adverse events ≥ grade 3 were more frequent in arm A than arm B (60% vs. 40%; p = 0.034). Conclusion: Cetuximab and paclitaxel/carboplatin was found to have similar efficacy and less toxicity compared to cetuximab and 5-FU/cisplatin or carboplatin. The experimental arm is easier to administer rendering it a favorable alternative to standard therapy.

1447P S-1 maintenance therapy in non-Asian patients with advanced, Her-2 negative esophagogastric adenocarcinoma – First results of the international MATEO trial initiated by the AIO

Platinum-fluoropyrimidine-based polychemotherapy is standard for advanced Her-2 negative esophagogastric adenocarcinoma. The optimal duration of treatment is unknown; prolonged application of platinum compounds leads to side effects with questionable overall survival (OS) benefit. MATEO is an international, multicenter, randomized phase II trial exploring the role of fluoropyrimidine maintenance therapy with S-1 (tegafur/gimeracil/oteracil) compared with prolonged polychemotherapy. Patients without progression after 12 weeks of platinum-based induction therapy were randomized in a 2:1 allocation to receive S-1 (Arm A) or to continue with the same polychemotherapy regimen (Arm B) until tumor progression or limiting toxicity. The primary endpoint was OS, secondary endpoints included progression-free survival (PFS), response rate (ORR), safety/toxicity and quality of life. Between November 2014 and April 2019, 217 patients were registered and 165 patients were randomized following 12 weeks of induction therapy. Recruitment was stopped prematurely due to delayed accrual and emerging new therapeutical options. Oxaliplatin-fluoropyrimidine doublet and triplet regimens were the preferred induction regimens (FLO/FOLFOX 47.0%; FLOT 44.7%). Median OS from randomization for patients in Arm A was 13.3 months (95% CI 10.6-15.5) versus 11.4 months (95% CI 9.0-16.5) in Arm B (Hazard Ratio (HR) 1.02 [95% CI 0.70-1.49], p=0.91). Median PFS in Arm A and B was 4.8 months (95% CI 4.0-6.6) and 5.9 months (95% CI 3.8-9.0) respectively (HR 0.93 [95% CI 0.65-1.34], p=0.70). During maintenance phase treatment-related grade 3-5 toxicity was observed in 24.5% (Arm A) versus 27.3% (Arm B), treatment-related peripheral sensory neuropathy (grade 1,2,3) was observed in 11.8%/7.3%/2.7% (Arm A) vs. 7.3%/30.9%/9.1% (Arm B). S-1 as maintenance therapy showed comparable activity in comparison to a prolonged platinum-based therapy with a favorable toxicity pattern. Updated results will be presented at the meeting.

Late toxicities and recurrences in patients with clinical stage I nonseminomatous germ cell tumor after one cycle of adjuvant BEP versus primary retroperitoneal lymph node dissection: A 13-years follow-up analysis of a phase III trial cohort.

5512 Background: One cycle of adjuvant BEP has shown superiority in recurrence free survival over RPLND in patients (pts) with clinical stage (CS) I nonseminomatous germ cell tumor of the testis (NSGCT) (JCO 2008). We report recurrences and late toxicities of this randomized trial after 13 yrs of follow-up (FU). Methods: Questionnaires of 382 unselected pts with CS I NSGCT treated within a phase III trial comparing recurrence rate after 1 cycle of adjuvant BEP (arm A) vs. RPLND (arm B) were evaluated regarding recurrences and late toxicity. Overall (OS) and progression free survival (PFS) was calculated by Kaplan-Meier and arms were compared using logrank test. Categorial data were analyzed by chi-square test (PRISM v8). Results: In each arm 191 pts were analyzed as intention-to-treat with a median FU of 13.75 yrs (0-22.9 yrs); 3/191 pts (1.6 %) in arm A and 16/191 pts (8.4 %) in arm B had a recurrence. 20-yrs PFS in arm A / B was 97 % (CI 96-99 %) / 92 % (CI 90-95 %), ( p = .0049). 20-yrs OS in arm A / B was 90 % (CI 86-94 %) / 88 % (CI 86-94 %), ( p = .83). 23/382 (6 %) pts have died, 22/23 not related to testis cancer, 1/23 died of a recurrence in arm B. 8/191 pts (4.2 %) in arm A and 4/191 pts (2.1 %) in arm B showed metachronous secondary testis cancer ( p = .26). 5/191 pts (2.6 %) in arm A and 4/191 pts (2.1 %) in arm B developed other malignancies. 170/382 questionnaires were evaluable (arm A: 95; arm B: 75). 45 pts were lost to FU. There were no significant differences comparing both treatment arms regarding potentially treatment-related late toxicities. However, excluding pre-existing complaints, ototoxicity (9/95 (9 %) vs. 4/75 (5 %) pts, p = .31) was reported more frequently in arm A. Excluding pre-existing neurological conditions, peripheral neuropathy of all grades was more frequently reported in arm A (15/95 pts; 16 % vs. 9/75 pts; 12 % pts; p = .48). Retrograde ejaculation occurred more frequently after RPLND (9/95 pts; 9% vs. 18/75 pts; 24 %, p = .01). Conclusions: After more than 13 yrs of FU, recurrences in non-risk factor selected pts with CS I NSGCT remain to be significantly more frequent with RPLND. No excess mortality due to secondary malignancies was observed. Late toxicities did not differ between 1 cycle of BEP and RPLND. Only retrograde ejaculation was observed significantly more frequent after RPLND. With long-term observation, 1 cycle of BEP has not only a high efficacy to prevent recurrence but also seems to be tolerated without clinically relevant long-term toxicity.

A Phase 3 Trial Comparing the Efficacy and Safety of Acalabrutinib in Combination with Venetoclax with or without Obinutuzumab, Compared with Investigator's Choice of Chemoimmunotherapy in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL) without Del(17p) or TP53 Mutation

A Phase 3 Trial Comparing the Efficacy and Safety of Acalabrutinib in Combination with Venetoclax with or without Obinutuzumab, Compared with Investigator's Choice of Chemoimmunotherapy in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL) without Del(17p) or TP53 Mutation