Months In Arm Research Articles

Abstract A001: An open label, phase II trial of ERK inhibition alone and in combination with autophagy inhibition in patients with metastatic cancreatic cancer

Abstract Background: Approximately 92% of pancreatic ductal adenocarcinoma (PDAC) harbor activating mutations in the KRAS oncoprotein. Therapeutic targeting of key elements of the MAPK pathway, including RAF, MEK and ERK, have failed to yield clinical benefit in patients with metastatic PDAC. Autophagy is a putative mechanism of resistance to ERK MAPK inhibition. Hydroxychloroquine (HCQ) is an inhibitor of autophagy and functions by inhibiting acidification of lysosomes. LY3214996 is an inhibitor of ERK 1/2 and has shown anti-tumor activity in pre-clinical models of PDAC. In this study, we evaluate the clinical efficacy of LY3214996 alone and in combination with HCQ. Methods: Eligible patients had metastatic PDAC or poorly differentiated carcinoma of the pancreas. Patients had at least one, but no more than two prior lines of systemic therapy. Twelve patients were included in the safety lead-in. One patient experienced grade 3 acute kidney injury and another experienced grade 3 nausea, thus dose level -1 was chosen as the tolerable dose for combination therapy. Patients were randomized in a 1:1 fashion to receive either LY3214996 200mg PO daily + HCQ 600mg PO BID (Arm 1) or LY3214996 400mg PO daily (Arm 2). The primary endpoint was disease control rate (DCR), defined as the proportion of patients with complete responses (CR), partial responses (PR) or stable disease (SD) that persisted for at least 4 months. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). Point estimates and exact binomial 95% confidence interval (CI) were used for binary endpoints and the Kaplan Meier method was used for survival analysis. With 20 subjects in each treatment arm, there is 79% power using a one-sided alpha of 0.1 to differentiate between an unacceptable DCR of 5% and a desirable DCR of 20%. Results: A total of 39 patients met criteria for analysis (20 in Arm 1, 19 in Arm 2). The DCR rate in Arm 1 was 5% and 5.3% in Arm 2. One patient in each arm had SD. No patients achieved a CR or PR. The median PFS was 1.31 months in Arm 1 (95% CI 0.79-1.77) and 1.87 months in Arm 2 (95% CI 1.64-2.36). The median OS was 2.43 months in Arm 1 (95% CI 1.34-5.77) and 4.56 months in Arm 2 (95% CI 3.08-5.67). The most frequently observed toxicities in both arms included nausea, diarrhea, elevated creatine phosphokinase (CPK), anorexia and cytopenias. Exploratory analysis using patient-derived organoids did not show evidence of synergistic anti-tumor activity of LY3214996 in combination with chloroquine. Conclusion: LY3214996 alone or in combination with HCQ did not result in clinically meaningful activity in patients with metastatic pancreatic cancer. Further studies are needed to evaluate optimal strategies for autophagy inhibition, as well as combination strategies with other ERK MAPK targets (i.e., KRAS inhibitors) to fully elucidate the role of autophagy as a driver of resistance to ERK MAPK inhibition. Citation Format: Rishi Surana, Hui Zheng, Junning Wang, Micaela Morgado, Lauren K Brais, Kirsten L Bryant, Ashwin Somasundaram, Colin D Weekes, Bruno Bockorny, Mary Linton B Peters, Andrea J Bullock, Jessica A Zerillo, Ahmed A Rattani, Hanna K Sanoff, Jeffrey W Clark, Aparna R Parikh, Matthew B Yurgelun, Anuj Patel, Robert J Mayer, James M Cleary, Peter C Enzinger, Douglas A Rubinson, Nadine J McCleary, Andrea C Enzinger, Sarah E Slater, Kimmie Ng, Thomas A Abrams, Leah Biller, Srivatsan Raghavan, Joseph D Mancias, Jonathan O Nowak, Andrew J Aguirre, Channing J Der, Brian M Wolpin, Kimberley Perez. An open label, phase II trial of ERK inhibition alone and in combination with autophagy inhibition in patients with metastatic cancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A001.

Comparison between Trans-Arterial Chemoembolization Followed by Stereotactic Body Radiation Therapy and Trans-Arterial Chemoembolization Alone in BCLC Stage B Hepatocellular Carcinoma: A Pilot Study.

Both Stereotactic Body Radiation Therapy (SBRT) and Trans-arterial Chemoembolization (TACE) are now being widely used to treat advanced hepatocellular carcinoma (HCC) and can improve tumor local control rates. We aimed at evaluating the efficacy and toxicity of combining SBRT and TACE in comparison to TACE alone in unresectable HCC. 42 unresectable Barcelona Clinic Liver Cancer (BCLC) stage B HCC Child Pugh (CP) A patients were randomized to receive either: TACE alone (Arm A) or TACE followed by SBRT (Arm B). Dose prescribed was 40Gy in 5consecutive daily fractions over 1 week . We compared the local control (LC), Progression free survival (PFS), overall survival (OS) and toxicity between the two arms. 22 patients were in arm A versus 20 patients in arm B with median follow up 20 months starting recruitment from April 2021 till January 2023. Both LC, PFS were significantly better in Arm B. Complete remission (CR) rate was 54.5% and 75% in Arm A and B, respectively. Median PFS was 16 months in Arm B compared to 11 months in Arm A (p =0.003). Median OS was not reached in both arms. Both arms had comparable toxicities. Adding SBRT to TACE in advanced HCC, is safe and feasible with better efficacy in terms of LC and PFS with comparable side effects, in comparison to TACE alone.

Induction avelumab followed by chemoimmunotherapy and maintenance versus chemotherapy alone as first-line therapy in cis-ineligible metastatic urothelial carcinoma (INDUCOMAIN): a randomized phase II study

Platinum-based chemotherapy (ChT) has been the standard first-line treatment for metastatic urothelial carcinoma (mUC). The purpose of this study was to evaluate the use of induction avelumab followed by avelumab in combination with carboplatin-gemcitabine (carbo/gem) followed by avelumab maintenance. We tested the hypothesis that induction immunotherapy (IO) could enhance the response to ChT and prevent its detrimental effect on immune cells. INDUCOMAIN is a multicenter, randomized, investigator-initiated, open-label phase II study evaluating the safety and efficacy of induction avelumab before carboplatin-gemcitabine-avelumab, followed by avelumab maintenance (arm A), compared to carbo/gem (arm B). Eligibility criteria included patients with mUC, no prior systemic therapy, and ineligibility for cisplatin by Galsky criteria. Patients were stratified by the presence/absence of visceral metastasis and Eastern Cooperative Oncology Group performance status 0-1 versus 2. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Eighty-five patients were included and randomized to arm A (n= 42) and arm B (n= 43), respectively. ORR was similar between treatment arms: 59.5% in arm A and 53.5% in arm B (P= 0.57). Fourteen patients (33%) in arm A early progressed/died before or at first response assessment, compared to three patients (7%) in arm B. Median OS was 11.1 months in arm A and 13.2 months in arm B [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.57-1.46, P= 0.69]. Median PFS was 6.9 months in arm A versus 7.4 months in arm B (HR 0.99, 95% CI 0.61-1.60, P= 0.95). Treatment-related adverse events of grade 3-4 occurred in 70.7% of patients in arm A and in 72.1% in arm B. No predictive role of programmed death-ligand 1 expression was found. The hypothesis that induction avelumab could enhance the efficacy of subsequent ChT was not proven. Administering IO alone as induction before ChT is not an adequate strategy.

Comparison between Reirradiation by Stereotactic Body Radiation Therapy and Moderately Hypofractionated Radiotherapy in Combination with Temozolomide for Treatment of Recurrent High Grade Glioma.

High grade glioma (HGG) is considered a lethal disease with a high recurrence rate. There is no standard of care in recurrent HGG. Many treatment options are present, such as resurgery, systemic therapy, and re-irradiation. Re-irradiation seems to be a promising option. In this study, we aimed at comparing the efficacy and toxicity of two re-irradiation protocols. Forty patients with recurrent HGG were randomized equally into two arms. Arm A received 30 Gy/10f/2w, and arm B received stereotactic body radiotherapy (SBRT) 30 Gy/5f/1w. Concurrent temozolamide (TMZ) was given in both arms. Median progression free survival (PFS) and overall survival (OS) were calculated, and brain MRI was done after 2 months of radiotherapy and then every 2 months, with documented toxicity using the Common Terminology of Adverse Events version 5 (CTCAE). The median follow-up time after the re-irradiation course was 11 months (range 8-15 months). The median PFS after recurrence was 6.4 months (95% CI 5.3-7.4), the median OS after recurrence was 8.6 months (95% CI 7.5-8.7), and the median total OS form date of diagnosis was 18.5 months (95% CI 17.3-19.8) among the included patients. There was a statistically significant difference in PFS favoring arm B, with a median PFS of 7.3 versus 6.2 months in arm A, with p values of 0.004. There was no statistically significant difference in in median OS (9.3 months in arm B versus 8.4 months in arm A) with p values of 0.088. All patients tolerated their treatment well, and acute and subacute G1-G2 toxicity, consisting of headache, malaise, and nausea, were recorded during and shortly after the end of the re-irradiation course. Re-irradiation in recurrent HGG by both protocols is safe and effective, with a significant improvement in PFS in SBRT arm but no significant improvement in OS.

Effect of chemotherapy/targeted therapy alone vs. chemotherapy/targeted therapy followed by radical surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction: The IKF-575/RENAISSANCE phase III trial.

LBA4001 Background: The IKF-575 trial investigates the long-standing question about the role of surgical intervention in limited-metastatic gastric / esophagogastric junction cancer after systemic induction therapy. Methods: Previously untreated patients (pts) with limited metastatic disease (retroperitoneal lymph node (RPLN) metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) received 4 cycles of FLOT, + trastuzumab if Her2+ or + nivolumab if PD-L1 positive. Pts without progression after 4 cycles were randomized to receive additional FLOT (Arm B) or radical complete surgical resection of primary and metastases followed by the same treatment (Arm A). It was planned to randomize 176 pts for which 271 pts had to enrolled. The primary endpoint was overall survival in the ITT population using Kaplan-Meier estimates. Recruitment was stopped after enrollment of 183 patients (141 patients randomized) with minimal impact on statistical power, due to a slow enrollment rate. Results: The ITT comprised 139 pts (A, 67; B, 72): 20% had RPLN metastases only, 58% organ metastases only, and 22% had both. Surgery in Arm A (ITT) was performed in 91% of pts and R0-resection rate (primary) was 82%. 30-d and 90-d mortalities in the surgery population were 3% and 8%. At least 4 additional cycles of post-op or post-randomization chemotherapy were achieved in 42% of pts in Arm A vs. 71% of pts in Arm B. The primary endpoint ovrall survival was not met due to increased early mortality in the surgery Arm leading to crossing survival curves with OS 25%- and 75%-Quantiles being 10 vs. 14 months and 65 vs. 41 months for Arms A vs. B, respectively. Pts with RPLN metastases only seemed to benefit most from the surgical approach (mOS, 30 vs. 17 months; 5y OS 38% vs. 19%; still having increased early mortality), while pts showing no response to chemo (mOS, 13 vs. 22 months) or pts with peritoneal disease (mOS, 12 vs. 19 months) derived a detrimental effect. Conclusions: The IKF-575/RENAISSANCE trial is negative but informs future research. Future protocols should focus on pts with RPLN only disease and exclude non-responding pts or those with peritoneal disease. There is a need for strategies against the early mortality caused by chemotherapy interruption. Clinical trial information: NCT02578368 .

A randomized phase II trial of 8 months of afatinib switching to osimertinib (A) versus osimertinib alone (B) as first-line treatment in advanced NSCLC patients with common EGFR mutation: YAMATO study (TORG1939/WJOG12919L).

8574 Background: NSCLC with common EGFR mutation (L858R or exon 19 deletion (Del19)) is known to originally comprise small portion of uncommon and compound EGFR variant cells including T790M-mutant ones albeit treatment-naïve. To overcome concomitant heterogeneous EGFR mutations, we planned a randomized phase II trial to assess the strategy of switching to osimertinib following 8 months of afatinib compared with osimertinib alone. Methods: YAMATO study is an open-label, multi-center, randomized phase II study. Patients with newly diagnosed stage III/IV/recurrent NSCLC harboring EGFR activating mutations (L858R or Del19) were randomized in a 1:1 ratio to receive up-front 8 months of afatinib (30 mg or 40 mg QD) followed by osimertinib (80 mg QD) (arm A) or osimertinib (80mg QD) alone (arm B) until disease progression or intolerable toxicity. The primary endpoint is 2-year progression free survival (PFS) rate with threshold rate of 22% and expected rate of 40% (one-tailed alpha of 0.1, beta of 0.2). Secondary endpoints are objective response rate (ORR), PFS, time to treatment failure, overall survival and adverse events. Results: Between May 2020 and Apr 2021, 113 patients were enrolled from 27 institutions (A/B 56/57). Patient characteristics were as follows: median ages, 73.5/71 years (range 41-85/41-92 years); proportion of males, 42.9/35.1%; EGFR mutation types, L858R/Del19 59/41% in A, 58/42% in B. The difference of two-year PFS rate was not observed statistically significant between groups (37.3% [80% CI, 29.0 to 45.5] in arm A vs 47.4% [80% CI, 38.5 to 55.7] in arm B; p=0.44; HR:1.28 [80% CI, 0.95-1.73]). The ORR was 82% in arm A and 87% in arm B. With the median follow-up of 27.5 months, median PFS was 16.8 months in arm A, and 22.2 months in arm B (HR: 1.280, p = 0.29). Severe pneumonitis occurred in 7% in arm A, most of which developed after switching to osimertinib, and 1.8% in arm B. Conclusions: YAMATO study failed to demonstrate the superiority of EGFR-TKI switching therapy of 8 months afatinib to osimertinib over osimertinib alone in terms of 2-year PFS rate in untreated advanced NSCLC patients with common EGFR mutations. Clinical trial information: 031200021 .

A randomised phase II study of extended pleurectomy/decortication preceded or followed by chemotherapy in patients with early-stage pleural mesothelioma: EORTC 1205.

The role of surgery in pleural mesothelioma remains controversial. It may be appropriate in highly selected patients as part of a multimodality treatment including chemotherapy. Recent years have seen a shift from extrapleural pleuropneumonectomy toward extended pleurectomy/decortication. The most optimal sequence of surgery and chemotherapy remains unknown. EORTC-1205-LCG was a multicentric, noncomparative phase 2 trial, 1:1 randomising between immediate (arm A) and deferred surgery (arm B), followed or preceded by chemotherapy. Eligible patients (Eastern Cooperative Oncology Group 0-1) had treatment-naïve, borderline resectable T1-3 N0-1 M0 mesothelioma of any histology. Primary outcome was rate of success at 20 weeks, a composite end-point including 1) successfully completing both treatments within 20 weeks; 2) being alive with no signs of progressive disease; and 3) no residual grade 3-4 toxicity. Secondary end-points were toxicity, overall survival, progression-free survival and process indicators of surgical quality. 69 patients were included in this trial. 56 (81%) patients completed three cycles of chemotherapy and 58 (84%) patients underwent surgery. Of the 64 patients in the primary analysis, 21 out of 30 patients in arm A (70.0%; 80% CI 56.8-81.0%) and 17 out of 34 patients (50.0%; 80% CI 37.8-62.2%) in arm B reached the statistical end-point for rate of success. Median progression-free survival and overall survival were 10.8 (95% CI 8.5-17.2) months and 27.1 (95% CI 22.6-64.3) months in arm A, and 8.0 (95% CI 7.2-21.9) months and 33.8 (95% CI 23.8-44.6) months in arm B. Macroscopic complete resection was obtained in 82.8% of patients. 30- and 90-day mortality were both 1.7%. No new safety signals were found, but treatment-related morbidity was high. EORTC 1205 did not succeed in selecting a preferred sequence of pre- or post-operative chemotherapy. Either procedure is feasible with a low mortality, albeit consistent morbidity. A shared informed decision between surgeon and patient remains essential.

A randomized, open-label phase II/III efficacy and safety study of atezolizumab in combination with FLOT versus FLOT alone in patients with gastric cancer and adenocarcinoma of the oesophagogastric junction and high immune responsiveness: The IKF633/DANTE trial, a trial of AIO in collaboration with SAKK.

TPS4184 Background: Despite recent advances, long-term survival of patients with locally advanced, operable esophagogastric adenocarcinoma (EGA) is below 50%. Immune checkpoint inhibitors in the neoadjuvant setting of this tumor type have lately been shown to increase pathological responses in all comers (IKF633/DANTE pII, KEYNOTE-585, Matterhorn), but the effect on survival is still unknown. The IKF633/DANTE pIII trial evaluates the efficacy and clinical activity of atezolizumab (ATZ) with perioperative FLOT in patients (pts) with locally advanced, resectable EGA considered having an immune-responsive profile. Methods: IKF633/DANTE is conducted as a randomized, multinational, multicenter, prospective, investigator-initiated, open label phase II/III trial. For the phase III portion, pts with histologically confirmed EGA of a clinical stage ≥cT2 and/or cN+ without evidence of distant metastases and with at least one immune response criterium (MSI, PD-L1 CPS≥1, TMB ≥10/MB or EBV+) are eligible. Pts are stratified acc. to nodal stage (cN- vs. cN+), tumor site (GEJ type I vs. GEJ type II/III vs. gastric) and PD-L1 expression levels (CPS≥5 vs. CPS<5). Pts are randomized 1:1 to receive 4 pre- and post-operative cycles FLOT/ATZ, followed by 8 cycles ATZ maintenance (Arm A) or 2x4 perioperative cycles FLOT alone (Arm B). In total, 556 pts will be enrolled, thereof 379 pts in phase III. This estimates to a recruitment time of 30 months plus 18 months follow-up for 80% statistical power and a significance level of p<0.05 (two-sided log rank test). The primary endpoint is event-free survival (EFS) with a target hazard ratio of 0.72, reflecting a clinically relevant improvement to 41.65 months in arm A. Main secondary endpoints are pCR, overall survival (OS) also in high immune-responsive subgroups (CPS ≥5/ CPS≥ 10/ MSI), R0 resection rate and safety/tolerability. In addition, a prospective biomarker study with serial circulating tumor DNA (ctDNA) analysis accompanying therapy is performed to explore the prognostic impact of ctDNA on efficacy and survival parameters, as well as on relapse incidence. Recruitment of phase III started in Aug 2023 and is still ongoing. Clinical trial information: NCT03421288 .

A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer (GIANT): ECOG-ACRIN EA2186.

4003 Background: Evidence-based data is lacking to guide the care of vulnerable older adults with newly diagnosed metastatic pancreatic ductal adenocarcinoma (mPDAC) resulting in extrapolation of the treatment approach utilizing data from younger patients. EA2186 is a phase II randomized controlled trial, and the first prospective study aiming to define the optimal treatment approach for vulnerable older adults with newly diagnosed mPDAC. Methods: EA2186 enrolled vulnerable patients ≥70 years of age with histologically confirmed mPDAC, ECOG PS 0-2 and adequate organ function. Vulnerability was defined by a screening geriatric assessment (GA) demonstrating mild abnormalities in functional status, comorbidities, cognition, or age ≥80 years. Patients were randomized to Arm A: Gemcitabine (1000mg/m2) and Nab-Paclitaxel (125mg/m2) every 14 days or Arm B: 5-Fluorouracil (2400mg/m2 over 46hr) Leucovorin (400mg/m2) and Liposomal Irinotecan (50mg/m2) every 14 days. A comprehensive GA and quality of life (QOL) evaluation were completed at baseline and 3 time points. Primary endpoint was overall survival (OS); secondary endpoints included progression free survival (PFS), response rate (RR), safety, and QOL. The study had 90% power to detect a difference in median OS of 7.7 vs. 10.7 months (HR of 0.72) using a one-sided log-rank test at the 0.10 significance level. Stratification factors included age 70-74 vs ≥75, and ECOG PS 0-1 vs 2. The study met the planned futility boundary for OS at its single interim analysis (60.6% information) and was closed early by the DSMC. Results: 176 patients were enrolled at 92 US sites between 6/2020 – 10/2023, 88 patients per arm. Median age of enrolled patients was 77 (range 70-90), 49% females, 24% ECOG-0, 64% ECOG-1 and 12% ECOG-2. Majority of patients were deemed vulnerable by cognition (46%), age (36%) or co-morbidities (31.4%), with some patients meeting vulnerability criteria in multiple domains. No significant difference was seen in median OS between the arms (4.7 vs. 4.4 months in Arms A and B respectively; p = 0.72). PFS, RR, and factors contributing to early treatment discontinuation and affecting the lower-than-expected survival will be presented at the meeting. At the time of data cut off rates of ≥grade 3 toxicity was 45.6% in Arm A and 58.7% in Arm B (p = 0.10); rates of ≥grade 4 toxicity were 7.6% in Arm A vs 14.7% in Arm B (p = 0.16). Most common ≥grade 3 toxicities included anemia, neutropenia, fatigue in both Arms, and diarrhea in Arm B. Conclusions: EA2186 did not demonstrate a significant difference in efficacy or overall toxicity between two attenuated regimens tested in vulnerable older adults with mPDAC. These results provide important data to guide treatment decisions and goals of care discussions in this vulnerable patient population. Clinical trial information: NCT04233866 .

A pilot study of tazemetostat and pembrolizumab in advanced urothelial carcinoma (ETCTN 10183).

4574 Background: Mutations of COMPASS-related proteins KMT2D, KMT2C, and KDM6A are observed in 66% of advanced urothelial carcinomas (UC). In vivo, the administration of tazemetostat, an enzymatic EZH2 inhibitor (EZH2i), reduced tumor burden and enhanced the immune response in animal models of UC. We hypothesized that tazemetostat might improve response to immunotherapy in advanced UC. Methods: ETCTN 10183 (NCT03854474) is a multicenter pilot study evaluating the safety and efficacy of tazemetostat 800 mg BID+ pembrolizumab 200 mg given every three weeks for up to two years in patients (pts) with platinum-refractory (Arm A) or cisplatin/chemo-ineligible advanced UC (Arm B). The primary objective was to identify the recommended phase two dose (RP2D) of tazemetostat in combination with pembrolizumab. Secondary objectives included safety, response rate, and progression-free survival. Translational objectives included determining tumor mutational burden in COMPASS-related genes, tumor subtyping, TCR clonality, T cell infiltration, and PDL-1 expression. Results: There were no dose-limiting toxicities in the safety lead-in phase (n=6 pts), and the RP2D for tazemetostat was established at 800 mg BID. Baseline characteristics for Arm A N=12, Arm B N=13: 72% males; 96% white, 4% Black; 88% ECOG PS 0-1; 88% had bladder primary, 20% Stage III, 72% stage IV; 80% had visceral or bone metastases. The median number of cycles was 5 in Arm A (range 1-35) and 4 in Arm B (range 2-12). Treatment related G3/4 adverse events (AEs) were observed in 8 patients, most common were anemia and lymphopenia (n=2 each). Treatment related G1/2 AEs included nausea (n=6); skin and subcutaneous tissue disorders (n=3); anemia, lymphopenia, and thrombocytopenia (n=2 each). Among evaluable patients (n=10 in each arm), partial response rate was: Arm A 30%, Arm B 20%; stable disease: Arm A 30%, Arm B 30%; and progressive disease: Arm A 30%, Arm B 20%. 8 pts were on study treatment for ≥ 9 cycles (5 in Arm A, 3 in Arm B). All pts are off protocol treatment. Median progression-free survival was 3.06 (95% CI: 1.38-7.75) months for Arm A and 3.02 (95%CI: 2.4-5.65) for Arm B. Conclusions: Tazemetostat 800 mg BID and pembrolizumab combination is feasible and well-tolerated in patients with advanced UC. In this pilot study, improvement in efficacy relative to historical controls of pembrolizumab alone appears to be modest. Response in tumors with COMPASS-related mutations and EZH2 activity will be evaluated. Clinical trial information: NCT03854474 .

Abstract PO3-14-06: Immunologic features and association with prognosis in hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) treated with chemotherapy (CT) or CDK4/6-inhibitors (CDK4/6i) + endocrine therapy (ET)

Abstract Purpose: Little is known regarding the prognostic and predictive role of tumor immunological features in HR+/HER2- MBC treated with CT or CDK4/6i+ET. Methods: The Italian KENDO phase 2 trial randomized CT-naïve patients with HR+/HER2-neg. MBC with aggressive characteristics to receive CDK4/6i+ET (arm A) or CT+/-ET (arm B). Primary endpoint was progression-free survival (PFS). A tumor sample from the primary or metastatic tumor (archived or newly-obtained) was mandatory for inclusion. In this correlative biomarker analysis, tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLS) were detected on baseline tumor samples by hematoxylin&eosin staining, while immune genomic signatures were assessed with the nCounter BC360 panel. Immune pattern at immunohistochemistry was defined as inflamed (IF), excluded (IE) or desert (ID). TILs and signatures were dichotomized (high vs. low) with the maximally-selected rank statistics (MSRS) method. Survival analyses were conducted with the Kaplan-Meier (KM) method and differences were tested with log-rank test. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated with Cox regression. Significance was set at p≤0.05. Since the trial was stopped earlier due to slow accrual all analyses were exploratory. Results: Forty-nine patients were randomized, 17 (34.7%) in arm A and 32 (65.3%) in arm B. No significant clinicopathological differences were observed at baseline between the two arms, except for tumors in arm B showing more TLS (50.0% vs. 12.5%, p=0.013). Median PFS (mPFS) with CT+/-ET was numerically shorter than mPFS with CDK4/6i+ET (11.2 vs. 19.9 months, HR: 1.41, 95%CI: 0.75-2.64, p=0.289). The median OS (mOS) for arm A was not estimable (NE) vs. 30.6 months in arm B (p=0.283). In arm A, median TILs levels were 3% (interquartile range [IQR]: 1-5%) and TLS, with/without germinal centers, were present in 2 cases (12.5%). These were also the only IF tumors in the arm, whereas the rest (87.5%) were ID. In arm B, 7 (25.0%) tumors were IF, 19 (87.5%) ID and 2 (7.1%) IE. Median TILs were 4.5% (IQR: 2-12.8%) and TLS were present in 50% cases. In arm A, ID tumors showed lower mPFS than IF (15.8 vs. 27.5 months), with concordant trend at the OS KM curve. In arm B there was no clear difference in PFS, but IF tumors did not reach mOS, differently from ID (28.7 months) and IE (28.1 months). High vs. low TILs levels were significantly associated with better PFS (p=0.003) and OS (p=0.005) in arm A. High levels of a TGFβ gene expression signature were significantly associated with better PFS (p=0.020) and OS (p=0.005) in arm A and PFS (p=0.03) in arm B; higher levels of a cytokine/chemokine signature were associatedwith better PFS (p=0.02) in arm A, and higher levels of a mastcells signature was associated with worse OS in both arms (p=0.02 and p=0.03). In arm B, higher levels of a macrophage (p < 0.001) and antigen presentation signatures (p=0.04) were associated with worse and better OS, respectively, whereas higher levels of an immune infiltration and a cytotoxic cells signature were associated with better PFS (p=0.03 both). TLS presence was numerically associated to longer mPFS (23.5 vs. 15.8 months) in arm A, with consistent OS KM curve’s trend, and longer mOS (44.5 vs. 28.1 months) in arm B. Conclusions: The KENDO trial further supports CDK4/6i+ET use in aggressive CT-naïve HR+/HER2- MBC. Biomarkers of immune activation such as IF tumors, higher TILs and presence of TLS pointed towards better survival outcomes. Genomic immunological features also showed prognostic effect, with differences according to treatment arm and/or the immune process or cell line tracked. Further research on larger cohorts is needed to confirm these preliminary findings. Citation Format: Francesco Schettini, Michela Palleschi, Francesca Mannozzi, Fara Brasó-Maristany, Lorenzo Cecconetto, Patricia Galván, Marita Mariotti, Alessia Ferrari, Emanuela Scarpi, Anna Miserocchi, Oriana Nanni, Esther Sanfeliu, Aleix Prat, Andrea Rocca, Ugo De Giorgi. Immunologic features and association with prognosis in hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) treated with chemotherapy (CT) or CDK4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-14-06.

Abstract CT255: AdvanTIG-204: A phase 2, multicenter, randomized, 3-arm, open-label study investigating the preliminary efficacy and safety of ociperlimab (anti-TIGIT) + tislelizumab (anti-PD-1) + concurrent chemoradiotherapy (cCRT) in patients with untreated limited-stage small cell lung cancer (SCLC)

Abstract Background: Despite a high response rate to cCRT, patients with limited-stage SCLC generally experience recurrence of disease after a few months and survival remains poor. Immunotherapy has shown benefit in many tumor types, including SCLC. In preclinical and clinical studies of solid tumors, co-inhibition of T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains (TIGIT) and PD-1 enhanced antitumor activity of anti-PD-1. AdvanTIG-204 (NCT04952597) investigated the efficacy and safety of ociperlimab + tislelizumab + cCRT in patients with untreated limited-stage SCLC. Methods: Patients with limited-stage SCLC and no prior systemic therapy were randomized 1:1:1 to Arm A (ociperlimab [900 mg IV Q3W] + tislelizumab [200 mg IV Q3W] + cCRT for 4 cycles, then ociperlimab + tislelizumab), Arm B (tislelizumab + cCRT for 4 cycles, then tislelizumab), or Arm C (cCRT for 4 cycles). Study drugs (Arms A and B) were continued for up to 12 months or until progression, unacceptable toxicity, or withdrawal. Primary endpoint: investigator-assessed PFS per RECIST v1.1. Secondary analyses included additional efficacy and safety endpoints in the ITT population, and efficacy in patient subgroups by PD-L1 and TIGIT expression (both <1% vs ≥1%), using tumor area positivity (PD-L1) and immune cell scoring (TIGIT). No hypothesis testing was predefined (p-value for descriptive purposes only). Descriptive comparisons were conducted for Arm A vs C, B vs C, and A vs B. Results: As of July 26, 2023, 126 patients (median age, 61.5 years) were randomized to Arm A (n=41), Arm B (n=42), or Arm C (n=43). Median follow-up: ~18 months (all arms). There was a trend of improvement in median PFS in Arm A (12.6 months) and Arm B (13.2 months) vs Arm C (9.5 months); HR (95% CI): Arm A vs C, 0.84 (0.46-1.52; p=0.2793); Arm B vs C, 0.80 (0.45-1.44; p=0.2414). ORR was 85.4% (3 CR) in Arm A, 88.1% (4 CR) in Arm B, and 76.7% (1 CR) in Arm C. Median DoR was 10.1 months in Arm A, 11.5 months in Arm B, and 8.2 months in Arm C. Median OS was not reached in any arm. Analyses showed that PD-L1 or TIGIT expression did not correlate with efficacy, however, small subgroup size limits interpretability. All patients experienced ≥1 treatment-related adverse event (TRAE); rates of grade ≥3 TRAEs were 73.2%, 78.6% and, 65.1% in Arms A, B, and C, respectively. The most common TRAEs included anemia (80.5% in Arm A vs 83.3% in Arm B vs 81.4% in Arm C), nausea (80.5% vs 76.2% vs 65.1%), and WBC count decreased (78.0% vs 76.2% vs 62.8%). Rates of TRAEs leading to any treatment discontinuation were 26.8%, 21.4%, and 4.7% in Arms A, B, and C, respectively. One patient in each arm experienced a TRAE leading to death. Conclusion: In patients with untreated limited-stage SCLC, tislelizumab + cCRT yielded a trend of improvement in PFS and ORR vs cCRT; addition of ociperlimab did not show detectable improvement. The overall safety profile of the treatments was tolerable, manageable, and generally consistent with the known risks of ociperlimab, tislelizumab, and cCRT. Citation Format: Youling Gong, Qingsong Pang, Rong Yu, Zhengfei Zhu, Jiangqiong Huang, Yufeng Cheng, Diansheng Zhong, Hongbo Wu, Seung Soo Yoo, Tracy Dobbs, Zinan Bao, Yunxia Zuo, Boxian Wei, Pu Sun, You Lu. AdvanTIG-204: A phase 2, multicenter, randomized, 3-arm, open-label study investigating the preliminary efficacy and safety of ociperlimab (anti-TIGIT) + tislelizumab (anti-PD-1) + concurrent chemoradiotherapy (cCRT) in patients with untreated limited-stage small cell lung cancer (SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT255.

Phase II randomized trial comparing metronomic anthracycline-containing chemotherapy versus standard schedule in untreated HER2 negative advanced breast cancer: activity and quality of life results of the GOIM 21003 trial

BackgroundOptimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC. MethodsPatients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity. ResultsFrom August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A). ConclusionsFirst line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.

Abstract CT125: A phase 0/2 ‘trigger’ trial of pamiparib or olaparib plus radiotherapy in patients with newly-diagnosed or recurrent glioblastoma

Abstract Background: This Phase 0/2 clinical trial evaluates the pharmacokinetic (PK), pharmacodynamic (PD), and clinical response of newly-diagnosed and recurrent glioblastoma (GBM) patients to the PARP1/2 selective inhibitors, pamiparib and olaparib, in combination with radiotherapy. Materials/Methods: In this study, newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID) prior to resection. In the Phase 0 component of the study total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug > 5-fold biochemical IC50 in Gd-nonenhancing tumor, determined eligibility for Phase 2. PARP inhibition was assessed via ex vivo tumor tissue radiation and quantification of PAR levels compared to non-irradiated control. When demonstrating a PK response, newly-diagnosed, MGMT-unmethylated GBM or recurrent GBM patients were eligible for Phase 2 dosing of pamiparib (Arms A and B) or olaparib (Arm C) with concurrent RT followed by maintenance pamiparib or olaparib. Results: A total of 41 patients (Arm A, n=16; Arm B, n=19; Arm C, n=6) were enrolled in the Phase 0 component of the study. In Arms A and B, mean unbound concentrations of pamiparib in Gd-nonenhancing tumor were 167.3 nM and 104.3 nM respectively, and in Arm C the mean unbound concentration of olaparib was 5.2 nM. All patients in the pamiparib arms (n=35) but only 1 of 6 patients in the olaparib Arm C exceeded the PK threshold. Radiation-induced PAR expression was 2.44-fold in untreated control vs 1.16 in Arm A (p<0.05), 0.82 in Arm B (p<0.01) and 1.11 in Arm C patients. In Arm A, 7 of 11 MGMT-unmethylated GBM patients advanced to Phase 2. Two patients were ineligible due to clinical status, 1 patient was ineligible per physician decision, and 1 patient declined to participate. In Arm B, 11 of 19 patients advanced to Phase 2. Eight patients were ineligible due to clinical status. At a mean follow-up of 5.8 months, median progression-free survival (PFS) was 5.8, 6.0, and 3.8 months for Arms A (n=7), B (n=11), and C (n=1), respectively. Grade 3+ toxicities related to pamiparib occurred in 4 patients, with 2 adverse events resulted in treatment discontinuation. No grade 3+ toxicities were documented in the olaparib arm. Conclusions: Pamiparib achieved pharmacologically-relevant concentrations in Gd-nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation. The majority of newly-diagnosed patients with MGMT-unmethylated GBM and recurrent GBM patients advanced to therapeutic dosing in this trial, and pamiparib was generally well-tolerated in these patients. Citation Format: Nader Sanai, Yu-Wei Chang, Jun Jiang, Jennifer Molloy, Chelsea Pennington-Krygier, Jocelyn Harmon, Amy Hong, John Wanebo, William Kennedy, Michael Garcia, Igor Barani, Wonsuk Yoo, Artak Tovmasyan, An-Chi Tien, Jing Li, Shwetal Mehta. A phase 0/2 ‘trigger’ trial of pamiparib or olaparib plus radiotherapy in patients with newly-diagnosed or recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT125.

Single-Agent Trabectedin Versus Physician's Choice Chemotherapy in Patients With Recurrent Ovarian Cancer With BRCA-Mutated and/or BRCAness Phenotype: A Randomized Phase III Trial.

Literature evidence suggests that trabectedin monotherapy is effective in patients with recurrent ovarian cancer (OC) presenting BRCA mutation and/or BRCAness phenotype. A prospective, open-label, randomized phase III MITO-23 trial evaluated the activity and safety of trabectedin 1.3 mg/m2 given once every 3 weeks (arm A) in BRCA 1/2 mutation carriers or patients with BRCAness phenotype (ie, patients who responded to ≥two previous platinum-based treatments) with recurrent OC, primary peritoneal carcinoma, or fallopian tube cancer in comparison with physician's choice chemotherapy in the control arm (arm B; pegylated liposomal doxorubicin, topotecan, gemcitabine, once-weekly paclitaxel, or carboplatin). The primary end point was overall survival (OS) evaluated in the intention-to-treat population. Overall, 244 patients from 21 MITO centers were randomly assigned (arm A = 122/arm B = 122). More than 70% of patients received ≥three previous chemotherapy lines and 35.7% had received a poly (ADP-ribose) polymerase inhibitor (PARPi) before enrollment. Median OS was not significantly different between the arms: arm A: 15.8 versus arm B: 17.9 months (P = .304). Median progression-free survival was 4.9 months in arm A versus 4.4 months in arm B (P = .897). Among 208 patients evaluable for efficacy, the objective response rate was 17.1% in arm A and 21.4% in arm B, with comparable median duration of response (5.62 v 5.66 months, respectively). No superior effect was observed for trabectedin in the prespecified subgroup analyses according to BRCA mutational status, chemotherapy type, and pretreatment with a PARPi and/or platinum-free interval. Trabectedin showed a higher frequency of grade ≥3 adverse events (AEs), serious AEs, and serious adverse drug reactions compared with control chemotherapy. Trabectedin did not improve median OS and showed a worse safety profile in comparison with physician's choice control chemotherapy.

Thoracic radiation in combination with erlotinib-results from a phase 2 randomized trial.

Radiotherapy (RT) can be used to reduce symptoms and maintain open airways for patients with non-small cell lung cancer when systemic treatment is not sufficient. For some patients, tumor control is not achieved due to radioresistance. Concurrent inhibition of epidermal growth factor receptors has been proposed as a strategy to overcome radioresistance but may increase toxicity. We performed a randomized trial to assess the efficacy, tolerance, and quality of life of concurrent erlotinib and palliative thoracic RT for patients with advanced non-small cell lung cancer. Patients were randomized 1:1 to RT alone (arm A) or in combination with erlotinib (arm B). A computed tomography (CT) scan at baseline and one at 4-12 weeks after inclusion was used to evaluate treatment response. Adverse events were registered during treatment and the subsequent 30 days. Health-related quality-of-life questionnaires were completed by the patients at baseline, weeks 2, 6, and 20. A total of 114 patients were included. Of the 74 patients with CT scans available for evaluation of treatment effect, there were no significant differences in tumor size reduction between the two groups: median 14.5% reduction in the control arm A and 17.0% in the erlotinib arm B (p = 0.68). Overall survival was not significantly different between the two treatment arms: 7.0 and 7.8 months in arm A and arm B, respectively (log-rank p = 0.32). There was no significant increase in adverse events in the experimental arm, other than what is expected from erlotinib treatment alone. Overall, patients reported similar quality of life in both treatment arms. Concurrent erlotinib and palliative thoracic RT for patients with advanced non-small cell lung cancer was well tolerated but did not improve the efficacy of the RT. ClinicalTrials.gov, identifier NCT02714530.

Timing of High-Dose-Rate Brachytherapy With External Beam Radiation Therapy in Patients With Intermediate- and High-Risk Localized Prostate Cancer and Its Effects on Toxicity and Quality of Life: A Randomized Controlled Trial (THEPCA)

BackgroundHDR brachytherapy(HDR-BT) and external beam radiotherapy(EBRT) are effective treatments for prostate cancer(PC) but cause genitourinary(GU) and gastrointestinal(GI) toxicities. There is no consensus on the timing of HDR-BT in relation to EBRT and the effect of sequencing on patients. ObjectiveThe primary objective was to assess differences, if any, in the incidence of Grade 3 or higher GU toxicities from treatment. We also aimed to explore the incidence of G1-4 GI toxicities, quality of life and patient satisfaction. Suppression of PSA and signals for survival differences were also analysed. MethodologyA single-centre randomised trial in intermediate and high-risk localised PC patients to receive HDR-BT before (Arm A) or after (Arm B) EBRT. Toxicities were graded using CTCAE. IIEF and FACT-P were used to assess erectile dysfunction and QOL at 0, 3, 9 and 12 months. Results50 patients were recruited to each arm, with 48 and 46 patients completing treatment and follow up in each arm. 81.5% had high-risk disease. There were no G3 or G4 GU or GI toxicities. G1 urinary frequency was the most common adverse event experienced in both arms, peaking in incidence 3 months after commencing treatment (45.7 and 42.2% in Arm A and B, respectively). Up to 11 % of patients reported G1 urinary frequency at 12 months. Other G1 GU toxicities experienced by >10% of patients were urinary tract obstruction, tract pain and urgency. These symptoms also peaked in incidence at 3 months. G2 GU toxicities were uncommon and experienced in a maximum of 2 patients within each arm at any time point.Over 30% of patients had G1 flatulence at baseline and this remained the most frequently occurring G1 GI toxicity throughout the study, peaking at 12months (21.4% and 25.6% in Arm A and Arm B, respectively). Other GI toxicities experienced by more than 10% of patients were GI pain, proctitis and rectal mucositis, most of which demonstrated a peak incidence at 3 or 9 months. G2 GI toxicities were uncommon, except G2 flatulence.No significant difference was found in CTCAE, IPSS, IIEF, FACT-P and QOL scores between the arms.Median PSA follow-up was 5 years. 7 patients had treatment failure in each arm. DFRS was 93.3% and 90.7% at 5 years in Arm A and B respectively, with median failure time of 60 and 48 months in Arm A and B respectively. There were no statistically significant difference between arms. ConclusionsThe sequencing of HDR-BT and EBRT did not impact the incidence of G3 or G4 toxicities and no significant differences were seen in other patient reported outcomes. Treatment was well tolerated with maintained QOL scores. Treatment failure was low in both arms in a high-risk cohort, however a larger study with longer follow up is underway to establish whether the difference in median time to failure between the two arms is a signal of superiority.

Abstract LB_A10: Efficacy of ATR inhibitor berzosertib plus topotecan or topotecan alone in patients with relapsed small cell lung cancer: A randomized clinical trial

Abstract Background: Patients with relapsed small cell lung cancer (SCLC) have a poor prognosis and few therapeutic options, especially after standard treatment of platinum doublet chemotherapy +/- immunotherapy. SCLC is characterized with high replication stress. A previous single-arm phase 2 study showed anti-tumor activity with the addition of ataxia-telangiectasia–mutated and rad3-related (ATR) kinase inhibitor berzosertib to topotecan. This study aimed to investigate whether the addition of berzosertib to topotecan improves clinical outcomes in patients with relapsed SCLC. Patients and methods: The randomized, open-labeled phase 2 study recruited patients with SCLC and relapse after one or more prior therapies from 16 US cancer centers as members of the National Cancer Institute Cancer Therapy Evaluation Program. Patients previously treated with topotecan were not eligible. Eligible patients were randomly assigned to receive topotecan (arm 1: 1.25 mg/m2 intravenously on days 1 through 5) alone or with berzosertib (arm 2: 210 mg/m2 intravenously on days 2 and 5), in 21-day cycles. Randomization was stratified by sensitivity to first-line platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints included overall survival (OS), objective response rate (ORR), and duration of response (DOR) in the overall population and in platinum-sensitive or -resistant patients. Results: Between December 2019 and December 2022, sixty patients were randomly assigned to receive topotecan alone (n=20) or in combination of with berzosertib (n=40). After a median potential follow-up of 21.3 months, there was no difference in PFS between the two arms [median: 3.0 months in arm 1 versus 3.9 months in arm 2, hazard ratio (HR) (95% CI): 0.80 (0.46 to 1.41), P = 0.44]. OS was significantly longer with the combination [5.4 months in arm 1 versus 8.9 months in arm 2, HR (95% CI): 0.53 (0.29 to 0.96), P = 0.033]. Of 57 evaluable patients, a numerically higher ORR was observed in patients receiving the combination: 5.6% (1/18, 95% CI: 0.1% to 27.3%) in arm 1 versus 25.6% (10/39, 13.0% to 42.1%) in arm 2. In an unplanned post hoc analysis, the depth of target lesion responses was significantly associated with better OS in patients on the combination arm (adjusted P = 0.022 by landmark analysis), suggesting that the deeper tumor regressions by the combination of berzosertib and topotecan may have eventually contributed to OS improvement. Adverse event profiles were similar between the two arms. Conclusions: In this randomized clinical trial, berzosertib plus topotecan did not improve PFS compared with topotecan alone in patients with relapsed SCLC. However, the combination significantly improved OS, suggesting potential efficacy of replication-stress targeted therapies in SCLC. Citation Format: Nobuyuki Takahashi, Zhonglin Hao, Liza C Villaruz, Jun Zhang, Jimmy Ruiz, W. Jeffrey Petty, Hirva Mamdani, Jonathan W Riess, Jorge Nieva, Jose M Pachecho, Alexander D Fuld, Elaine Shum, Aman Chauhan, Samantha Nichols, Hirity Shimellis, Jessie McGlone, Linda Sciuto, Danielle Pinkiert, Chante Graham, Meenakshi Shelat, Robbie Kattappuram, Melissa Abel, Brett Schroeder, Deep Upadhyay, Manan Krishnamurthy, Ajit Kumar Sharma, Rajesh Kumar, Justin Malin, Christopher W Schultz, Shubhank Goyal, Christophe E Redon, Yves Pommier, Mirit I Aladjem, Steven D Gore, Seth M Steinberg, Rasa Vilimas, Parth Desai, Anish Thomas. Efficacy of ATR inhibitor berzosertib plus topotecan or topotecan alone in patients with relapsed small cell lung cancer: A randomized clinical trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A10.

Multicenter randomized controlled trial of neoadjuvant chemoradiotherapy alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a challenging target for immunotherapy because it has an immunosuppressive tumor microenvironment. Neoadjuvant chemoradiotherapy can increase tumor-infiltrating lymphocyte (TIL) density, which may predict overall survival...

Salvage Autologous Transplant and Lenalidomide Maintenance Versus Continuous Lenalidomide/Dexamethasone for Relapsed Multiple Myeloma: Long Term Follow up Results of the Randomized GMMG Phase III Multicenter Trial Relapse

Introduction The randomized, controlled, multicenter, phase III GMMG ReLApsE trial compared lenalidomide/dexamethasone (Rd) re-induction, salvage high dose chemotherapy, autologous stem cell transplantation (HDCT/ASCT) and lenalidomide (R) maintenance with standard continuous Rd. We have previously reported the absence of a significant survival benefit in the primary analysis. However, landmark analyses from salvage HDCT performed due to the fact that ~30% of patients in the HDCT arm did not receive salvage HDCT/ASCT suggested a survival benefit in patients undergoing salvage HDCT/ASCT. Here we report long term follow up results from the GMMG ReLApsE trial. Methods Between 2010 and 2016, 282 patients were randomized of whom 277 constituted the intention-to-treat (ITT) population (arm B/A n=139/138). Arm B received 3 cycles of Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, 22; 4 week cycles) re-induction, HDCT (melphalan 200 mg/m 2), ASCT and R maintenance (10 mg daily) until progression (PD). Arm A was treated with Rd until PD. Key inclusion criteria were 1-3 prior treatment lines, age ≤ 75 years, time to PD ≥ 12 months in case of front-line HDCT/ASCT and WHO PS ≤ 2. R-refractory disease was not permitted and only 30/277 patients (11%) were previously exposed to R. The primary endpoint was progression free survival (PFS). Protocol-specified long term follow up collection included overall survival (OS), further lines of treatment and further salvage HDCT/ASCT after trial participation. ISRCTN16345835, Eudra CT-No: 2009-013856-61. Results Within the extended follow up period of 99 months, 238 PFS events (86%) and 174 deaths (63%) occurred. Median PFS in the ITT population was 20.5 months in arm B and 19.3 months in arm A without a statistically significant difference (HR 0.98; 95% CI 0.76-1.27; p=0.9). Median OS was 67.1 months in arm B vs. 62.7 months in arm A (HR 0.89; 95% CI 0.66-1.20; p=0.44). The absence of a significant PFS and OS benefit was consistent among key disease subgroups according to age, R-ISS, renal function, frontline single vs. tandem HDCT/ASCT, prior lines of treatment and prior maintenance treatment post HDCT/ASCT. Time to progression after frontline HDCT/ASCT was significantly associated with PFS in the total ITT population (p=0.001) as well as in both trial arms independently, but was not associated with a survival benefit from arm B vs. A (interaction test PFS p=1.0, OS p=0.7). Multivariate analyses revealed significant associations of survival with age (PFS: HR 0.8, p=0.045), high risk cytogenetic aberrations (PFS: HR 2.1, p<0.001; OS: HR 2.5, p<0.001), ISS stage III vs. I (OS: HR 2.0, p=0.02), elevated LDH (PFS: HR 1.5, p=0.04; OS: HR 2.1, p<0.001), >1 prior lines of treatment (PFS: HR 2.3, p=0.003), and no prior HDCT/ASCT (PFS: HR 1.8, p=0.04; OS: HR 2.2, p=0.009), but not with treatment arm B vs. A (PFS: HR 0.9, p=0.4; OS: HR 0.9, p=0.37). In landmark analyses from HDCT and the contemporaneous Rd cycle 5 in arm A (median interval from randomization to HDCT/Rd cycle 5: 117/122 days; n=103[B]/114[A]) no significant differences in PFS (23.0 vs. 20.3 months; HR 0.91; 95% CI 0.68-1.22; p=0.52) or OS (76.3 vs. 66.0 months; HR 0.8; 95% CI 0.56-1.13; p=0.2) in arm B vs. A were observed. Further lines of treatment after trial participation were reported in 88/139 (63%) and 96/138 (70%) patients in arm B and A (p=0.31). Significantly more salvage HDCT/ASCT were administered after trial participation in arm A vs. B (48/138 [35%] vs. 19/139 [14%], p<0.001). Immunomodulatory drug (lenalidomide, pomalidomide) based regimens were used comparably after both trial arms. The rate of second primary malignancies was comparable in arm B and A (26/139 [19%] vs. 19/138 [14%], p=0.3). Conclusions The GMMG ReLApsE trial is the only randomized, controlled trial comparing salvage HDCT/ASCT with continuous novel agent treatment. With extended follow up, no significant PFS or OS difference is observed in the overall trial population and the previously reported survival benefit in patients who actually received salvage HDCT/ASCT is not confirmed. Time to progression after frontline HDCT/ASCT which is frequently used to stratify for salvage HDCT/ASCT in clinical practice is a general prognostic parameter for PFS, but does not predict benefit from salvage HDCT/ASCT vs. continuous Rd treatment. The GMMG ReLApsE trial does not support salvage HDCT/ASCT for relapsed or refractory multiple myeloma.