6-month Progression-free Survival Rate Research Articles

Stereotactic Radiotherapy Plus Nivolumab in Patients with Locally Advanced Pancreatic Cancer: Results from Phase 1/2 Clinical CA209-9KH Trial.

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) highlights the urgent need for novel therapeutic strategies. Immune checkpoint inhibitors (ICIs) seem to be ineffective in most PDAC studies. Therefore, we conducted an open-label, multicenter phase 1/2 study (CA209-9KH) to evaluate the safety of stereotactic radiotherapy (SRT) and sequential ICI therapy in PDAC, as well as to validate the efficacy of this regimen as a potential activator of antitumor immunity. Patients aged ≥ 18years with unresectable non-metastatic PDAC following four FOLFIRINOX induction cycles were included. Treatment comprised SRT (4 × 8Gy) and sequential nivolumab administration until disease progression or unacceptable toxicity. The primary endpoints were safety and toxicity assessment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), biomarker evaluation, and quality of life (QoL) analysis. Twenty-two patients were screened, with 15 enrolled. Eleven (median) nivolumab cycles were administered. SRT demonstrated low and clinically nonsignificant toxicity, whereas nivolumab toxicity aligned with prior safety profiles, without grade 4-5 events observed. Three patients discontinued therapy owing to toxicity. Median PFS and OS were 8.1 and 13.0months, respectively, with 12-month PFS and OS rates of 0% and 66.7%, respectively, and a 24-month OS rate of 8.9%. Biomarker levels correlated with clinical or radiological disease control. Patient-reported QoL remained acceptable, deteriorating with disease progression. SRT and nivolumab therapy exhibited manageable toxicity profiles consistent with previous findings; however, long-term treatment responses were not achieved with this regimen in locally advanced PDAC. Another strategy to trigger antitumor immunity in PDAC needs to be sought. EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432.

DKN-01 in Combination With Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish.

The outcomes of anti-PD-1 agents plus fluoropyrimidine/platinum in frontline advanced gastroesophageal adenocarcinomas (aGEAs) remain poor. We investigated the safety, tolerability, and activity of fluoropyrimidine/oxaliplatin and tislelizumab with the DKK1-neutralizing antibody DKN-01 in aGEAs in a phase IIa open-label study. Patients had untreated human epidermal growth factor receptor 2-negative aGEAs, RECIST v1.1 measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Patients received intravenous DKN-01 300 mg once every 2 weeks, tislelizumab 200 mg once every 3 weeks, oxaliplatin 130 mg/m2 once every 3 weeks, and capecitabine 1,000 mg/m2 twice daily on days 1-15 of each 21-day cycle. The primary end point was safety and tolerability. Key secondary end points included objective response rate (ORR) by RECISTv1.1, progression-free survival (PFS), and overall survival (OS). Between September 18, 2020, and April 8, 2021, 25 patients were enrolled. All patients who received at least one dose of DKN-01 were included in the safety analysis. Most patients had gastroesophageal junction tumors, median age was 61 years, 76% were male, and 55% were ECOG of 0. All patients reported at least one treatment-emergent adverse event. The ORR was 73% (95% CI, 49.8 to 89.3), with a disease control rate of 95%. The ORR was 90% (95% CI, 55.5 to 99.7) in the DKK1-high tumor patients and 67% (95% CI, 29.9 to 92.5) in the DKK1-low tumor patients. The median PFS was 11.3 months (95% CI, 5.8 to 12.0) and the 12-month PFS rate was 33%. The median OS was 19.5 months (95% CI, 15.2 to 24.4) with a 12-month OS rate of 76% and an 18-month OS rate of 55%. DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier: NCT04363801).

Real World Outcomes In Patients With Recurrent, Advanced Or Metastatic Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab

ObjectivePatients with endometrial cancer who progress following first line therapy have improved survival outcomes with pembrolizumab and lenvatinib (pem/len) compared with standard of care chemotherapy, as demonstrated in KEYNOTE-775. This was in a group of trial patients with a good performance status and excluded those with carcinosarcoma histology. In KEYNOTE-775 pem/len was associated with significant toxicity leading to dose reductions, treatment cessation and patient morbidity. We set out to assess the tolerability, toxicity and outcomes following pem/len for patients with recurrent, advanced or metastatic endometrial cancer in a real-world setting. MethodsUK centres treating patients with pem/len for advanced endometrial cancer within the compassionate access programme were approached. Retrospective data was analysed for those treated between May 2022 and June 2023. Data on patient demographics, treatment, toxicity and outcomes was extracted from medical records. Toxicity and tolerability were compared in those over and under the age of 70. Results7 centres returned data for 70 patients. Median age of patients was 68.5 years (range 45-85) with a performance status of 0-1 in 77.1% and of 2 in 22.9%. Histological subtypes included serous (34.3%), endometrioid (32.9%), carcinosarcoma (14.3%), clear cell (7.1%), mixed (2.9%) and other (8.6%). Grade ≥3 toxicity was reported in 55.7% with any-grade toxicity observed in 85.7%. In those aged ≥70 years (n=30) the rate of grade ≥3 toxicity was 60.0%. Rates of dose reduction of lenvatinib were 64.3% and toxicity-related treatment interruption 45.7%. The 6-month progression-free and overall survival rates were 54.0% (95%CI: 39.0-66.8) and 70.1% (95%CI:56.5-80.1) respectively. ConclusionThis real-world, observational study of pem/len showed comparable tolerability, toxicity and outcomes to previously reported clinical trial data. Our cohort included patients with a poorer PS and a broader range of histological subtypes including carcinosarcoma.

Southwest Oncology Group S0826: A phase 2 trial of SCH 727965 (NSC 727135, dinaciclib) in patients with stage IV melanoma.

Cell cycle inhibition is an established therapeutic approach for some cancers. A multicenter, single-arm, phase 2 trial (ClinicalTrials.gov identifier NCT00937937) of the cyclin-dependent kinase inhibitor SCH 727965 (NSC 747135; dinaciclib) was conducted in patients with metastatic melanoma to determine its clinical activity. Patients with metastatic melanoma of cutaneous or mucosal origin were eligible if they had zero to one previous treatments, a Zubrod performance status of 0-1, and adequate organ function. SCH 727965 50 mg/m2 was given intravenously every 3 weeks until progression. Co-primary end points were 1-year overall survival (OS) and 6-month progression-free survival (PFS). Seventy-two patients were enrolled from July 1, 2009, to November 1, 2010, at 24 institutions. Sixty-eight percent of patients had M1c disease, and 43% had elevated lactate dehydrogenase levels. Twenty-eight patients (39%) experienced grade 4 adverse events, including 20 cases of neutropenia. Sixty-seven patients were evaluable for response. There was a response in zero of 67 patients (95% confidence interval [CI], 0%-5%), and stable disease was observed in 21%. The estimated median PFS was 1.4 months (95% CI, 1.4-1.5 months), and the 6-month PFS rate was 6% (2%-13%). The median OS was 8.2 months (95% CI, 5.5-10.5 months), and the 1-year OS rate was 38% (95% CI, 26%-49%). This multicenter, US National Cancer Institute Cancer Therapy Evaluation Program-sponsored trial of SCH 727965 was conducted at a time when the current generation of effective therapies for melanoma were not available. Although the null hypothesis of 1-year OS was rejected, the minimal PFS impact and substantive toxicity indicated that this regimen lacks justification for further investigation as a single agent.

Lenvatinib and pembrolizumab versus platinum doublet chemotherapy as second-line therapy for advanced or recurrent endometrial cancer.

There is no consensus on whether platinum doublet chemotherapy or lenvatinib and pembrolizumab (LEN/PEM) is superior for advanced or recurrent endometrial cancer. Thus, this study aimed to compare the prognosis and adverse events in patients with advanced or recurrent endometrial cancer treated with platinum doublet chemotherapy or LEN/PEM. We retrospectively reviewed the medical records of patients who received platinum doublet chemotherapy or LEN/PEM at our institution for advanced or recurrent endometrial cancer and had a history of platinum-based chemotherapy between January 2013 and August 2023. During the study period, 11 regimens were identified in the platinum doublet chemotherapy group, and 11 regimens were identified in the LEN/PEM group. The objective response rates of the platinum doublet chemotherapy and LEN/PEM groups were 36.4% and 54.5% (P=0.67), respectively. The 6-month progression-free survival (PFS) rates of the platinum doublet chemotherapy and LEN/PEM groups were 27.3% (95% confidence interval [CI], 13.8-40.7%) and 70.0% (95% CI, 55.5-84.5%), respectively. The differences were significant between the two groups. Multivariate analyses of histology, prior lines of chemotherapy, platinum-free intervals, and regimens revealed that the LEN/PEM group had significantly better PFS rates. Treatment with LEN/PEM resulted in significantly longer PFS than that of treatment with platinum doublet chemotherapy in patients with advanced and recurrent endometrial cancer. However, further large-scale studies are required to validate these findings.

Abstract PR-04: Phase 2 Trial Testing The PARP Inhibitor Niraparib In Patients With Advanced Pancreatic Cancer with Pathogenic Variants In BRCA 1, BRCA2, PALB2, ATM and CHEK2

Abstract Background: Poly-(adenosine diphosphate ribose) polymerase (PARP) inhibitors have demonstrated efficacy in patients with platinum-sensitive pancreatic cancer who harbor germline BRCA 1/2 pathogenic variants (PVs). Whether PARP inhibitors are effective in a broader population of pancreatic cancer patients is still under investigation. Methods: This was a multicenter, single arm, open-label phase II trial (NCT03601923) investigating the use of the PARP inhibitor niraparib in patients with advanced pancreatic cancer. Eligible patients were required to have germline or somatic mutations in BRCA1, BRCA2, PALB2, ATM and/or CHEK2. Prior treatment with PARP inhibitors and prior progression on a platinum chemotherapy were not allowed, though patients could be included if they had progression on non-platinum based therapy. Patients were treated with weight-adjusted niraparib (200 mg or 300 mg) once daily on a 28-day cycle. The primary endpoint was 6-month progression free survival (PFS) rate (binary). Secondary endpoints were PFS, overall survival (OS), objective response rate (ORR) by RECIST v1.1, and safety. Serial plasma samples were collected for circulating tumor DNA analyses. Results: Thirty-two patients (10 females [31%]; median age 67) were evaluable for the primary endpoint. Patients had a germline or somatic alteration in one or more of the following genes: ATM (n=14), BRCA2 (n=10), PALB2 (n=3), CHEK2 (n=4), or BRCA1 (n=2). There were 10 patients who received niraparib as maintenance therapy and 12 patients whose tumors previously progressed on a non-platinum-based chemotherapy. The 6-month PFS rate was 25% (90% CI: 13-41), rejecting the null hypothesis of a 17% 6-month PFS rate. The median PFS for the entire population was 2.0 months (90% CI: 1.7-3.7) and median OS was 10.2 months (90% CI: 8.2-13.2). The objective response rate was 14% (90% CI: 5-30%); 2 patients had a complete response, 2 patients had a partial response. Patients who never previously progressed on chemotherapy had a significantly longer median PFS (p=0.02) and OS (p=0.003) than patients who previously progressed on chemotherapy. Three patients with biallelic inactivation of ATM, who never progressed on prior lines of chemotherapy, were on niraparib for over 1 year (range 1 – 4 years). Reversion mutations restoring the reading frame in BRCA2 were identified in cell-free DNA in 3 patients with BRCA2 pathogenic frameshift variants. Additional putative resistance mutations in other DNA repair genes were identified and will be reported. Conclusions: Niraparib demonstrated a promising 6-month PFS rate and provided clinically meaningful benefit in patients with pancreatic cancer. The observation of prolonged benefit of three patients with biallelic ATM inactivation warrants further investigation. Acknowledgment: Funding for this study was provided by GSK. GSK was provided the opportunity to review a preliminary version of this abstract for factual accuracy. The authors are solely responsible for final content and interpretation. Citation Format: Brandon M. Huffman, Jett Crowdis, Matthew B. Yurgelun, Nora Horick, Yvonne Li, Huy Nguyen, Kalindi Parmar, Bose S. Kochupurakkal, Andrea Enzinger, Marios Giannakis, Nadine McCleary, Kimmie Ng, Anuj K. Patel, Kimberly J. Perez, Douglas A. Rubinson, Benjamin L. Schlechter, Harshabad Singh, Helen Lam, Kaitlyn Ramsey, Elizabeth Andrews, Leigh Culnane, Andrea Bullock, Ahmed Rattani, Jeffrey Clark, Mary Linton Peters, Brian M. Wolpin, Alan D. D'Andrea, Geoffrey I. Shapiro, Andrew J. Aguirre, James M. Cleary. Phase 2 Trial Testing The PARP Inhibitor Niraparib In Patients With Advanced Pancreatic Cancer with Pathogenic Variants In BRCA 1, BRCA2, PALB2, ATM and CHEK2 [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 PR-04.

Acalabrutinib in Chinese patients with relapsed/refractory chronic lymphocytic leukemia: Primary analysis from an open-label, multicenter phase 1/2 trial.

Acalabrutinib is a highly selective Bruton tyrosine kinase inhibitor approved in the United States and Europe for chronic lymphocytic leukemia (CLL) based on phase 3 trials with limited representation of Asian populations. This phase 1/2 trial evaluates acalabrutinib in Chinese adults with relapsed/refractory (R/R) CLL receiving acalabrutinib 100mg twice daily in 28-day cycles until disease progression or treatment discontinuation due to adverse events (AEs) presenting substantial clinical risk. The primary endpoint was blinded independent central review (BICR)-assessed overall response rate (ORR). A total of 60 patients from 20 sites in China received acalabrutinib (median age 62years; median 1 prior therapy line; 21.7% with del(17p) and/or TP53 mutation; 51.7% with unmutated IGHV). Median total treatment duration was 19.4months (range 0.6-28.2) with 53 patients (88.3%) receiving acalabrutinib at data cutoff; median study follow-up was 20.2months. BICR-assessed ORR was 85.0% (95% CI, 73.4-92.9). Median duration of response, progression-free survival (PFS), and overall survival (OS) were not reached. Estimated 12-month and 18-month PFS rates were 91.5% (95% CI, 80.9-96.4) and 78.8% (95% CI, 60.9-89.2); OS rates were both 96.7% (95% CI, 87.3-99.2). AEs of grade ≥ 3 occurred in 25 patients (41.7%), most commonly decreased neutrophil count (13.3%, n = 8), pneumonia (6.7%, n = 4), and upper respiratory tract infection (6.7%, n = 4). AEs led to treatment discontinuation in 2 patients (paraneoplastic pemphigus; rectal neoplasm). This study demonstrated high ORR in acalabrutinib-treated Chinese patients with R/R CLL with no unexpected safety concerns. This trial is registered on ClinicalTrials.gov (NCT03932331).

Hepatic Arterial Infusion Chemotherapy Combined Lenvatinib and PD-1 Inhibitor Showed Improved Survival for Infiltrative Hepatocellular Carcinoma: A Multicenter Cohort Study.

Lenvatinib and programmed cell death protein-1 (PD-1) inhibitor on infiltrative hepatocellular carcinoma (HCC) have obtained demonstrated efficacy and still need improvement. Hepatic arterial infusion chemotherapy (HAIC) has shown promising results for advanced HCC. This study aimed to compare the efficacy of HAIC combined Lenvatinib and PD-1 inhibitor versus Lenvatinib combined PD-1 inhibitor for infiltrative HCC. A total of 232 patients were enrolled. There were 114 patients received Lenvatinib combined PD-1 inhibitor (Len+PD-1 group) and 118 patients received HAIC combined Lenvatinib and PD-1 inhibitor (HAIC+Len+PD-1 group). Overall survival (OS), progression-free survival (PFS) and safety of patients were compared between the two groups by propensity score-matching (PSM). The 6-, 12-, and 24-month OS rates were 93.8%, 65.1% and 13.4% in Len+PD-1 group, and 100%, 77.3% and 32.1% in HAIC+Len+PD-1 group, respectively. The 3-, 6-, and 12-month PFS rates were 86.4%, 45.7% and 14.1% in Len+PD-1 group, and 95.1%, 59.3% and 25.9% in HAIC+Len+PD-1 group, respectively. The HAIC+Len+PD-1 group had obviously better survival than the Len+PD-1 group both in OS (P=0.002) and PFS (P=0.004). Subgroup analysis revealed that OS in patients with metastasis was improved with HAIC+Len+PD-1 treatment. Patients with alpha-fetoprotein (AFP) response after treatment showed better survival than the non-response. In addition, HAIC+Len+PD-1 group showed manageable adverse events (AEs). Patient with infiltrative HCC, HAIC+Len+PD-1 treatment had longer OS and PFS than Len+PD-1 treatment. Early AFP response was an effective indicator of better survival and tumor response to therapy.

A pilot study of chlorambucil in pre-treated metastatic pancreatic adenocarcinoma patients bearing germline BRCA or other DNA damage repair system variants

BackgorundPancreatic adenocarcinoma remains a malignancy with a grim prognosis and scarce personalized treatment options. Pathogenic variants of DNA damage repair (DDR) genes are emerging as molecular targets, as they confer a higher sensitivity to DNA-damaging agents. This study aimed at assessing the activity of chlorambucil as salvage therapy in metastatic pancreatic cancer patients bearing a germline pathogenetic variant or variant of uncertain significance on a DDR-related gene. MethodsPlatinum-pretreated metastatic pancreatic cancer patients harbouring a germline variant on a DDR gene received chlorambucil at a daily oral dose of 6 mg/m2 for 42 every 56 days for the first cycle and for 14 every 28 days for the following cycles, until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival rate (PFS-6). Median progression-free survival (PFS) and overall survival (OS) were secondarily described. ResultsTwenty patients were enrolled between December 2020 and September 2022. PFS-6 was 5%, median PFS and OS were 1.6 months and 3.0 months, respectively. Grade-3 adverse events were observed in 25% of patients, while no Grade-4 toxicity was reported. ConclusionsSingle agent chlorambucil did not show sufficient signal of activity to warrant its further investigation in metastatic pancreatic cancer patients bearing a DDR-related germline alteration.

A multicenter, prospective, phase II trial of second-line aflibercept plus FOLFIRI in patients with metastatic colorectal cancer refractory to an anti-EGFR antibody: HGCSG1801.

Aflibercept (AFL) plus FOLFIRI prolongs overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a prospective open-label phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese patients with mCRC failing a prior oxaliplatin-based chemotherapy plus an anti-EGFR agent. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-fluorouracil [5-FU] 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months. Forty three patients were enrolled between November 2019 and October 2022. The primary endpoint was met: 6-month PFS rate was 58.8% (90% confidence interval [CI], 45.7%-72.0%). Median PFS and OS were 7.3 months (95% CI, 5.5-11.0 months) and 18.8 months (95% CI, 12.9-26.6 months), respectively. The overall response rate was 20.9% (95% CI, 10.0-36.0%) and disease control rate was 88.4% (95% CI, 74.9-96.1%). The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%), and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. This study suggests that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese patients with mCRC who failed prior oxaliplatin-based chemotherapy plus an anti-EGFR agent.

Immune checkpoint inhibitors for patients with mismatch-repair deficient or microsatellite instability-high advanced cancers: a meta-analysis of phase I-III clinical trials.

Mismatch-repair deficient (dMMR) and microsatellite instability-high (MSI-H) cancers are associated with an increased number of somatic mutations, which can render tumors more susceptible to immune checkpoint blockade. However, a comprehensive evaluation of the efficacy profile of immune checkpoint inhibitors in this patient population across multiple cancer types is lacking. This study aims to address this knowledge gap by synthesizing data from Phase I-III clinical trials. A systematic search was conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials and Google Scholar from inception until June, 2024. Eligible studies included randomized controlled trials (RCTs), non-randomized comparative studies, and single-arm trials investigating immune checkpoint inhibitors in patients with dMMR/MSI-H advanced cancers. The primary outcome was objective response rate (ORR), and the secondary outcomes included disease control rate (DCR), 1-year, 2-year, and 3-year overall survival (OS) and progression-free survival (PFS) rates. Subgroup analyses were conducted for the primary outcome stratified by major study characteristics. Of the 10802 identified studies, 19 trials in 25 studies totaling 2052 participants met the inclusion criteria and were included in the meta-analysis. The pooled ORR was 41.7% (95% CI, 35.7%-47.7%). The pooled DCR was 68.9% (95% CI, 62.2%-75.7%). The pooled 12-month, 24-month and 36-month OS rates were 29.1% (95% CI, 19.9%-38.3%), 35.8% (95% CI, 23.6%-48.0%), and 35.8% (95% CI, 23.6%-48.0%), respectively. The pooled 12-month, 24-month and 36-month PFS rates were 46.4% (95% CI, 39.1%-53.8%), 67.0% (95% CI, 55.2%-78.8%), and 63.1% (95% CI, 37.3%-88.9%), respectively. The study establishes the therapeutic potential of immune checkpoint inhibitors in dMMR/MSI-H advanced cancers, highlighting the importance of MSI status in this context. Further head-to-head comparisons are needed to conclusively determine MSI's predictive power relative to proficient mismatch-repair/ microsatellite stable (pMMR/MSS) tumors.

Performance of Low-Dose Immunotherapy and Standard-Dose Immunotherapy in Microsatellite Instability-High Metastatic Colorectal Cancer: Real-World Data (CLouD-High Study).

Standard-dose immune checkpoint inhibitors (SD-ICIs) are the standard of care as initial therapy in microsatellite instable-high (MSI-H) advanced/metastatic colorectal adenocarcinomas (mCRC), but there are preclinical data to suggest that low-dose ICIs (LD-ICI) might also have similar efficacy. A retrospective study of patients with MSI-H mCRC receiving ICIs between June 2017 and January 2023 was conducted. The primary end point of the study was 12-month progression-free survival (PFS), which was computed using the Kaplan-Meier method. A total of 65 patients were available for analysis during the study period. Sixty patients (92%) received nivolumab, whereas the remaining received pembrolizumab. First-line ICIs were received by 18 patients (28%), whereas 47 patients (72%) received ICIs during later lines. Thirty patients (47%) received LD-ICIs (all received nivolumab), with the remaining receiving SD-ICIs (53%). At a median follow-up of 16.5 (95% CI, 11.8 to 21.2) months, median PFS was not reached in the entire cohort. The 12-month PFS rate in the LD-ICI cohort was 90%, whereas it was 75.8% in the SD-ICI cohort. There were no statistical differences in patients receiving ICIs as first-line therapy (12 months PFS-94.4%) or during later lines of therapy (12-month PFS-77.9%; P = .56). ICIs in the current study show survivals which are similar to those seen in seminal trials in patients with MSI-H mCRC. Low-dose ICIs appear to work in MSI-H mCRC and should be explored prospectively in clinical trials. Patients with MSI-H status should be exposed to ICIs, whether initially or later during treatment, whenever feasible.

MGMT protein expression is a reliable predictive biomarker for temozolomide-containing chemotherapy in osteosarcoma.

The prognosis of patients with osteosarcoma who experience recurrence or progression (R/P) is extremely poor, and more effective and less toxic therapies are needed. In the current study, the clinical data of osteosarcoma patients who experienced R/P were retrospectively analyzed to verify the reliability of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression or MGMT promoter methylation for predicting the response to off-label temozolomide (TMZ)-containing chemotherapy. Of the 30 evaluable patients, 9 (30%) showed no/low MGMT protein expression, whereas all 16 evaluable patients had unmethylated MGMT promoter irrespective of MGMT protein expression levels. Twenty-three patients received TMZ-containing chemotherapy for measurable lesions (n = 14) or as adjuvant therapy following resection of recurrent lesions (n = 9). Among 14 patients with radiologically measurable lesions, the objective response rate was higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group with borderline significance (0%, p = 0.066). The 6-month progression-free survival (PFS) rate in patients with radiologically measurable lesions was significantly higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group (0%, p = 0.036). In the multivariate analysis of the 23 patients receiving TMZ-containing chemotherapy, MGMT expression and disease status before TMZ-containing chemotherapy were significantly associated with PFS. No severe adverse effects were observed during TMZ-containing chemotherapy. MGMT protein expression, but not MGMT promoter methylation, could predict a favorable outcome in patients receiving TMZ-containing chemotherapy.

Efficacy of Ipilimumab and Nivolumab in Patients with Melanoma and Brain Metastases-A Danish Real-World Cohort.

Combination immunotherapy using ipilimumab/nivolumab is the golden standard treatment for patients with melanoma and asymptomatic brain metastases (MBM). However, it remains uncertain if real-world patients have the same treatment effects compared to patients enrolled in clinical trials. The aim of this study was to compare clinical benefits between real-world patients and patients enrolled in clinical trials when administering ipilimumab/nivolumab in treatment-naive patients with asymptomatic MBM. Using data from the Danish Metastatic Melanoma Database (DAMMED), 79 patients with clinical parameters similar to the inclusion criteria from two phase II trials, the ABC and the CheckMate-204 trials, were included in the analyses. Thirteen patients (16.5%) achieved complete response (CR) and an overall response rate (ORR) of 46.9%. We found an overall 6-month Progression-Free Survival (PFS) rate of 53.5% and a median PFS of 6.5 months. Median overall survival (mOS) was not reached during the 5-year follow-up. These results were comparable to the phase II trials. In conclusion, clinical benefits from phase II studies were comparable to Danish real-world data regarding OS, PFS, and CR. Confirming that combination immunotherapy can be recommended as first-line treatment for patients with asymptomatic, treatment-naive melanoma brain metastases.

Serplulimab combined with gemcitabine, nab-paclitaxel and stereotactic body radiotherapy as the first-line treatment for patients with metastatic pancreatic adenocarcinoma in China: a multicentre, single-arm, phase II trial (ICSBR) protocol

IntroductionPatients with pancreatic ductal adenocarcinoma (PDAC) remain a poor prognosis despite the development of chemotherapy. Although programmed cell death 1 (PD-1) blockade has shown great efficacy in various solid tumours,...

Validation of the 10-gene expression profile for prediction of response to checkpoint inhibitor in patients with advanced NSCLS

Purpose: individualization of the use of immune checkpoint inhibitors in patients with inoperable NSCLC potentially sensitive to immunotherapy based on the level of the combined expression index as a predictive marker of effectiveness.Methods: in 146 patients with inoperable NSCLC, the level of the combined expression index in a tumor tissue sample was determined using PCR, which included studies of ten genes (CCL5, CXCL9, CXCR6, HLA-DQA1, TIGIT, EOMES, CTLA4, PD-L2, GZMB, PRF1). The patients were divided into cohorts depending on the level of the combined expression index and randomized into chemotherapy or immunotherapy groups. The null hypothesis of the study was that the group with a low combined expression index would have a 6-month progression-free survival of 35%, and with a high combined expression index – 75%, with α-error probability of 0.05, a power of 90%. Results: the use immune checkpoint inhibitors in the first line of the therapy for patients with a high level of the combined expression index leads to a significant increase in the rate of objective responses from 18% to 43%, the median overall survival from 10 to 21 months, and the median time to progression from 7.3 to 14.8 months. The 6-month progression-free survival rate in the group with a high combined expression index was 79%, versus 35% in the group with a low combined expression index. Conclusion: analysis of the gene expression signature can become one of the reliable predictive markers that predict the real effectiveness of therapy with immune checkpoint inhibitors, which will improve the results of treatment of patients with unresectable or metastatic NSCLC. Key words: NSCLC, immune checkpoint inhibitors, gene expression signature, predictive markers

Multicenter phase I/II trial of gemcitabine, oxaliplatin and nab-paclitaxel as first-line treatment for patients with advanced biliary tract cancer

IntroductionThe prognosis of patients with advanced biliary tract cancer (BTC) is still poor, and new strategies improving patients’ outcome are needed. In our trial we investigated safety and activity of nab-paclitaxel in combination with gemcitabine and oxaliplatin as first-line systemic treatment for patients with advanced BTC. MethodsIn this investigator-initiated, multicenter, dose-escalation, single-arm phase I/II trial, patients were accrued into cohorts of 3 patients and dose escalation was performed following the standard 3 + 3 rule. Primary endpoint was the proportion of patients free from progression at 6 months. Secondary endpoints included safety and tolerability of the combination; progression-free survival (PFS); overall survival (OS); objective response rate (ORR); duration of response. ResultsBetween July 2017 and December 2020, 67 patients were treated. Among the 10 patients in the phase I, no dose-limiting toxicity was observed, and dose level 2 was defined as recommended phase II dose for the phase II part. At data cutoff, the 6-month PFS rate was 49.1 % (95 % CI 40.8–57.5 %) with 28 patients out of 57 free from progression or death at 6 months. Median PFS was 6.3 months (95 % CI 3.6–10.1) and median OS was 12.4 months (95 % CI 8–23). ORR was 20.89 %. Most common grade 3 and grade 1–2 drug-related adverse events were neutropenia and peripheral neuropathy, respectively. ConclusionTriple chemotherapy demonstrated a favorable safety profile. However, the study did not meet its primary endpoint. Future studies will clarify the benefit of chemotherapy combinations in different settings.This trial is registered with ClinicalTrials.gov, NCT03943043.

Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Primary Results From AMEERA-5.

AMEERA-5 investigated amcenestrant (oral selective estrogen receptor [ER] degrader) plus palbociclib versus letrozole plus palbociclib as first-line treatment for ER-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced/metastatic breast cancer (aBC). In AMEERA-5 (ClinicalTrials.gov identifier: NCT04478266), a double-blind, double-dummy, international phase III trial, adult pre-/post-menopausal women and men without previous systemic therapy for ER+/HER2- aBC were randomly assigned 1:1 to amcenestrant 200 mg once daily + standard palbociclib dosage (125 mg once daily, 21 days on/7 days off) or letrozole 2.5 mg once daily + standard palbociclib dosage, stratified by de novo metastatic disease, postmenopausal women, and visceral metastasis. The primary end point was progression-free survival (PFS), compared using a stratified log-rank test with one-sided type I error rate of 2.5%. Secondary end points included overall survival (key secondary), pharmacokinetics, and safety. Between October 14, 2020, and December 2, 2021, 1,068 patients were randomly assigned to amcenestrant + palbociclib (N = 534) or letrozole + palbociclib (N = 534). At the interim analysis (median follow-up 8.4 months), the stratified hazard ratio for PFS was 1.209 (95% CI, 0.939 to 1.557; one-sided P value = .9304); therefore, the study was stopped for futility. The 6-month PFS rate was 82.7% (95% CI, 79.0 to 85.8) with amcenestrant + palbociclib versus 86.9% (95% CI, 83.5 to 89.6) with letrozole + palbociclib. In the amcenestrant + palbociclib versus letrozole + palbociclib groups, treatment-emergent adverse events (any grade) occurred in 85.6% versus 85.4% of patients and grade ≥3 events in 46.3% versus 60.8%, respectively. The AMEERA-5 study was discontinued on the basis of the recommendation of the data monitoring committee at the interim futility analysis. No new safety signals were identified.

Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM).

LBA105 Background: Use of triplet/quadruplet therapies for 1L MM raises the need for novel combinations at first relapse, which belantamab mafodotin (belamaf) combos may address. In DREAMM-7, BVd led to a significant improvement in progression-free survival (PFS) and a strong trend in improved overall survival (OS) vs daratumumab-Vd in patients (pts) with ≥1 prior therapy. We report results from DREAMM-8 (NCT04484623), which tested a different belamaf combo (BPd) and met its primary endpoint of independent review committee–assessed PFS at a prespecified interim analysis. Methods: DREAMM-8 is a phase 3, open-label, randomized, multicenter trial evaluating the efficacy and safety of BPd vs PVd in RRMM pts who received ≥1 prior line of therapy (LoT), including lenalidomide. Pts were randomly assigned 1:1 to BPd (28-d cycles): belamaf 2.5 mg/kg IV (D1, C1), 1.9 mg/kg (D1, C2+) + pom 4 mg (D1-21, all C) + dex 40 mg (D1, QW, all C), or PVd (21-d cycles): pom 4 mg (D1-14, all C) + bortezomib 1.3 mg/m2 SC (D1, 4, 8, 11 [C1-8]; and D1, 8 [C9+]) + dex 20 mg (day of and 1 day after bortezomib dose). Results: 155 pts were randomly assigned to BPd and 147 to PVd. With a median (range) follow-up of 21.78 mo (0.03-39.23), median PFS (95% CI) was not reached (NR; 20.6-NR) with BPd vs 12.7 mo (9.1-18.5) with PVd (HR, 0.52; 95% CI, 0.37-0.73; P<0.001). 12-month PFS rate (95% CI) was 71% (63-78%) with BPd vs 51% (42-60%) with PVd. ORR (95% CI) was 77% (70.0-83.7%) with BPd vs 72% (64.1-79.2%) with PVd; rate of complete response or better (95% CI) was 40% (32.2-48.2%) with BPd vs 16% (10.7-23.3%) with PVd. Median duration of response (95% CI) was NR (24.9-NR) with BPd vs 17.5 mo (12.1-26.4) with PVd. A positive trend favoring BPd was seen for OS (HR, 0.77; 95% CI, 0.53-1.14); follow up for OS is ongoing. Adverse events (AEs) were reported in >99% and 96% of pts in the BPd and PVd arms, respectively. Of pts treated with BPd, 89% had ocular AEs (CTCAE grade 3/4, 43%) vs 30% (grade 3/4, 2%) in the PVd arm. AEs were generally manageable, and broadly consistent with known safety profile of individual agents. Conclusions: The DREAMM-8 study demonstrated a statistically significant and clinically meaningful PFS benefit with BPd vs PVd in RRMM with >1 prior LoT. BPd also led to deeper and more durable responses, showed a favorable OS trend, and had a manageable safety profile. Clinical trial information: NCT04484623 . [Table: see text]

Ipilimumab and nivolumab plus UV1, an anticancer vaccination against telomerase, in advanced melanoma.

LBA9519 Background: The combination of ipilimumab (IPI) and nivolumab (NIVO) remains a standard of care for patients with advanced melanoma, especially those with poor prognostic factors, albeit with a significant risk of toxicity. Therapeutic cancer vaccines are ideally positioned to improve outcomes without significantly increasing toxicity. UV1 is a therapeutic cancer vaccine generating T-cell responses against the universal cancer antigen telomerase. In a Phase I trial in melanoma (N = 30), UV1 plus pembrolizumab demonstrated a tolerable safety profile, a complete response rate of 33%, median PFS of 18.9 months, and 2-year OS rate of 73.3%. Recently, results from a randomized Phase II trial indicated a longer overall survival and a higher response rate for previously treated patients with advanced mesothelioma receiving UV1 in combination with IPI-NIVO (1). Methods: In this Phase II, open-label, multicenter study, we randomly assigned treatment-naïve patients with unresectable or metastatic melanoma (stage IIIb-IIId or IV) to IPI 3mg/kg + NIVO 1mg/kg for 4 cycles, followed by NIVO 480 mg as maintenance, with or without 8 intradermal injections of 300 µg UV1 (+GM-CSF). The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) according to RECIST 1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response, and safety. Results: A total of 156 patients underwent randomization; 78 patients were assigned to the IPI-NIVO-UV1 arm and 78 patients to the IPI-NIVO arm. The median age was 60, 48% had M1C or D disease, 38% had LDH >upper limit of normal, and 42% had a positive BRAF mutation status. With a minimum follow-up of 18 months, the 12-month PFS rate was 57% in both arms (HR 0.95, 95% CI 0.59-1.55, p value 0.845). The ORR was similar with IPI-NIVO-UV1 compared to IPI-NIVO, at 60% vs 59%, respectively (Odds ratio 1.12, 95% CI 0.58-2.16, p value 0.867). The 12-month OS rate was 87% and 88%, respectively (HR 1.15, 95% CI 0.60-2.20, p value 0.674). The occurrence of grade >3 adverse events was similar in both treatment arms. Conclusion: UV1 did not improve on outcomes of IPI-NIVO, in terms of PFS. Longer follow-up is required for the accurate assessment of OS. No significant toxicity increases were observed with the addition of UV1. Data from a biomarker driven cohort are awaited. 1. Helland et al, Eur J Cancer 2024. Clinical trial information: NCT04382664 .