12-month Overall Survival Research Articles

Ketone Bodies Are Potential Prognostic Biomarkers in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Results from the R2-GDP-GOTEL Trial

Background: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for high-dose chemotherapy have limited treatment options and poor life expectancy. The purpose of this study is to identify a serum metabolomic profile that may be predictive of outcome in patients with R/R-DLBCL. Methods: This study included 69 R/R DLBCL patients from the R2-GDP-GOTEL trial (EudraCT 2014-001620-299). Serum samples were collected at baseline, and the mean length of follow-up was 41 months. Serum metabolites were analyzed by nuclear magnetic resonance (NMR). Metabolites were correlated with treatment response, progression-free survival (PFS), and overall survival (OS). Results: Serum levels of 3-hydroxybutyrate (3OHB) and acetone were significantly (p < 0.001) associated with PFS (3OHB: hazard ratio [HR] 7.7, 95% confidence interval [CI] 2.5–24.1; acetone: HR 9.32, 95% CI 2.75–31.6) and OS (3OHB: HR 9.32, 95% CI 2.75–31.6; acetone: HR 1.92, 95% CI 1.36–2.69). Serum values of 141 µM for 3OHB and 40 µM for acetone were the optimal cutoffs associated with the survival outcomes. Elevated 3OHB levels (>141 μM) were specific to the ABC subtype of DLBCL, while acetone levels were elevated in both types of DLCBL but more pronounced in ABC cases. In a multivariate survival analysis, including the International Prognostic Index (IPI) score and refractoriness status (R/R), 3OHB and acetone remained significant. To aid oncologists employing the R2-GDP regime, we constructed PFS and OS nomograms for R/R-DLBCL risk stratification, incorporating 3OHB levels or acetone levels, IPI score, and refractoriness status. The nomogram with 3OHB and refractoriness status showed a time-dependent AUC of 0.86 for 6-month PFS and 0.84 for 12-month OS. These nomograms provide a comprehensive tool for individualized risk assessment and treatment optimization. Conclusions: The ketone bodies 3OHB and acetone are potential prognostic biomarkers of poor outcome in R/R DLBCL patients treated with the R2-GDP regimen, independently of IPI score and chemorefractoriness status.

Re-Irradiation for the Progressive Pediatric Diffuse Intrinsic Pontine Glioma: A Report on 109 Children From a Single Center.

Diffuse intrinsic pontine glioma (DIPG) is a challenging pediatric tumor that frequently progresses within the first year following local radiotherapy. However, several small studies have suggested that re-irradiation may improve quality of life and extend overall survival. This retrospective study included 109 children who experienced disease progression ≥3months after their initial radiotherapy, and subsequently received re-irradiation at a single institution. These patients were compared with a cohort of 60 children, meeting the same criteria, who were treated before adopting the re-irradiation policy and received only the best supportive care (BSC). Most of the re-irradiated children (94%) received first radiation dose as hypofractionation (39Gy/13 fractions). The re-irradiation group demonstrated significantly higher overall survival (OS) rates after the first progression, with a 6-month OS of 42% (95% CI: 34%-53%) compared to 16% (95% CI: 8.9%-32%) in the BSC group (p < 0.001). Re-irradiation reduced the hazard of death by more than half (HR = 0.45, p < 0.001). Clinical response (p < 0.001) and radiological response (p = 0.016) were significant predictors of improved survival. While the time from initial radiotherapy to progression (p = 0.059) and higher re-irradiation doses (p = 0.074) were associated with improved OS, these factors did not reach statistical significance but may represent potential prognostic indicators. Re-irradiation improved the OS in children with progression of DIPG and alleviated their signs and symptoms.

Efficacy and Prognostic Indicators of Isatuximab, Pomalidomide, and Dexamethasone (IsaPd) in Daratumumab-Refractory Multiple Myeloma Patients: A Multicenter Real-World Study.

This multicenter real-world analysis evaluated the efficacy of isatuximab, pomalidomide, and dexamethasone (IsaPd) in 51 patients with multiple myeloma (MM) who were refractory to daratumumab (Dara-R). The majority were under 70years old (60.8%), predominantly female (56.9%), and heavily pretreated, with 74.5% being triple-class refractory (TCR); 32.1% of the 28 patients with cytogenetic data had high-risk abnormalities. The overall response rate (ORR) was 56.9%, including 3 patients with stringent complete response (sCR), 4 with CR, and 7 with very good partial response (VGPR). Neither age, number of prior therapies, TCR status, nor time from Dara refractoriness to IsaPd initiation significantly affected response rates. Median progression-free survival (PFS) was 5.8months, with a 12-month PFS probability of 30.6%. Baseline hemoglobin (Hb) levels were a key predictor of PFS: patients with Hb<11.8g/L had a 3.5-fold increased risk of progression, with a median PFS of 4.6months compared to 22months in those with higher Hb. Median overall survival (OS) was 21.0months, with a 12-month OS probability of 63.4%. Lower Hb levels (<11g/L) were associated with a tenfold increased risk of mortality. Among the 28 patients who underwent FISH analysis, while no significant difference in mortality risk was observed, those with high-risk cytogenetic abnormalities exhibited a nearly tenfold increased risk of disease progression. These results suggest that IsaPd offers a meaningful option for Dara-R patients, with Hb levels serving as a critical predictor of both PFS and OS. However, PFS remains modest, underscoring the need for novel combination therapies.

Immune checkpoint inhibitors (ICIs) in deficient mismatch repair (dMMR)/microsatellite instability (MSI) non-colorectal cancers: Real world Indian data and the use of alternative dosing.

347 Background: Immune checkpoint inhibitors, predominantly pembrolizumab and dostarlimab, have been approved in deficient mismatch repair (dMMR)/ microsatellite instability (MSI) non-colorectal cancers. There is also an emerging data to suggest significant clinical activity for low-dose ICIs (LD-ICIs) in these cancers. Methods: A multi-institutional retrospective analysis in Indian patients with dMMR/MSI-H advanced/metastatic non-colorectal carcinomas treated with ICIs (irrespective of dose or schedule) between 2017 and 2024 was conducted. The primary objective of the study was to evaluate 12-month Overall survival (OS) for the whole cohort as well as LD-ICI and standard dose ICI (SD-ICI) cohorts, while other secondary objectives included assessment of overall response rates (ORR) (assessed by RECIST v1.1 as per local radiological reporting), 12-month progression free survival (PFS) and incidence of immune related adverse events (IRAEs). Results: A total of 51 patients were available for analysis. The most common tumour types were gastrointestinal (64%, commonly gastric cancer, oesophageal cancer and cholangiocarcinoma) and endometrial cancers (23%). Eighty-four percent of patients received ICI monotherapy, while the remaining 16% received varying combinations of ICIs with chemotherapy and tyrosine kinase inhibitors. Nivolumab was used in 24 patients (47%) while pembrolizumab was used in 17 patients (33%). With a median follow-up of 14 months, 12-month OS was 72% and 12-month PFS was 62% in the entire cohort. The corresponding 12-months OS and 12-month PFS for those receiving SD-ICIs (n=29) was 69% and 62%, while it was 72% and 64%, respectively for the LD-ICIs cohort (n=22). The ORR was 61%, with 10 patients (20%) achieving complete response (CR) and 21 (41%) achieving partial response (PR). The most common IRAEs (all grades) were fatigue (62%), thyroid disturbances (37%), and pruritus (23%). Conclusions: The current study from India highlights the importance of treating non-colorectal dMMR/MSI-H cancers with ICIs and shows outcomes commensurate with published trial data. Within the confines of a small retrospective study with a short follow-up, low dose ICIs should be explored in these patients in scenarios where standard dosing schedules are not feasible due to logistic reasons. Key Words – Low dose immunotherapy; non-colorectal dMMR/MSI-H cancers; Overall survival.

Real-world (RW) treatment patterns and clinical outcomes of patients treated with sequential regorafenib and trifluridine/tipiracil ± bevacizumab (BEV) for metastatic colorectal cancer (mCRC) in the United States (US) community oncology setting: The SEQRT2 study.

62 Background: Both Regorafenib (R) and Trifluridine/Tipiracil (T) ± BEV are widely used treatments for mCRC in later lines. This RW study evaluated optimal sequencing and associated outcomes among patients who initiated R and T in sequential lines of therapy (LOT) between LOT1-LOT6 within community oncology settings in the US. Methods: A retrospective study utilizing electronic medical record data from The US Oncology Network examined adult patients with mCRC who initiated R and T ± BEV sequentially between 09/01/2015 and 11/30/2022 (index date), with follow-up until 05/31/2023. Treatment patterns, overall survival (OS) and time to next treatment (TTNT) after sequence were assessed overall, R first (R-T) and T first (T-R). Multivariable Cox regression adjusting for age, sex, ECOG, tumor stage, and prior medication, assessed the association of factors with OS and TTNT. Results: In total, 308 mCRC patients initiating R and T (R-T, 156 pts [140 R-T and 16 R-T+BEV]; T-R, 152 pts [136 T-R and 16 T+BEV-R]) met study criteria. Baseline demographic (mean age 63 yrs, males 55%) and clinical characteristics (70% colon cancer, 58% ECOG 0-1) were similar between the cohorts. Most patients initiated index therapies at the third line of therapy (LOT3) (49% R-T, 45% T-R). The median (IQR) sequence duration was 7.4 (5.6), 6.7 (4.4), and 7.0 (4.7) months, respectively in patients with R-T, T-R, and overall. The median (95% CI) OS was 12.8 (11.2, 14.1) months among R-T and 10.2 (8.8, 11.9) months among T-R patients. Compared to R-T, the adjusted HR for the T-R sequence was 1.2 (95% CI 0.9–1.6; p=0.2). The median (95% CI) TTNT was 9.3 (8.4, 10.3) and 8.6 (7.8, 9.4) months, for R-T and T-R, respectively; the adjusted HR was 1.1 (95% CI 0.8–1.4; p=0.62). Conclusions: Patients initiating R first appeared to have a longer duration of treatment and survival, although not statistically significant. The one-year median duration of survival in this real-world setting confirms the importance of access to these treatments in patients with mCRC and can inform physicians regarding the choice of medications while sequencing therapies in mCRC. Clinical outcomes among R-T and T-R mCRC patients. Variable Level R-T (± BEV)[N 1 = 156] T (± BEV) -R[N 1 = 152] Adjusted 3,4 HR 5 (95% CI)[R-T Reference] Effect OverallSurvival Months – median (95% CI) 12.8(11.2, 14.1) 10.2(8.8, 11.9) 1.20 (0.91, 1.58) 0.20 TTNT 2 Months – median (95% CI) 9.3(8.4, 10.3) 8.6(7.8, 9.4) 1.07 (0.83, 1.37) 0.62 1 Entire R-T and T-R cohorts are presented since 16 patients in each cohort initiated T+BEV. 2 Time To Next Treatment. 3 Overall Survival adjusting for age, gender, stage at diagnosis, ECOG, prior anti-VEGF treatment. 4 Time To Next Treatment adjusting for age, gender, stage at diagnosis, and line of therapy. 5 Hazard Ratio.

Preliminary results of the ALTER-E009 study: Efficacy and safety of anlotinib combined with radiotherapy in patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC)—A multicenter, multi-cohort retrospective exploratory study.

361 Background: Therapeutic options for metastatic esophageal squamous cell carcinoma (ESCC) primarily involve immunotherapy combined with chemotherapy. For locally advanced ESCC, concurrent chemoradiotherapy (CRT) or radiotherapy is the standard, though outcomes remain suboptimal. Targeted therapies, particularly anti-angiogenic agents, hold promise to enhance CRT efficacy. Anlotinib, a multi-target anti-angiogenic agent inhibiting VEGFR, PDGFR, FGFR, and c-KIT, has shown potential to enhance radiotherapy by alleviating tumor hypoxia. This multicenter, retrospective study evaluates the efficacy and safety of anlotinib combined with radiotherapy in locally advanced or metastatic ESCC. Methods: This study screened patients (pts) with locally advanced or metastatic ESCC treated with anlotinib (8-12 mg, p.o., qd, d1-14, q3w) and radiotherapy from June 2018 to June 2024. Two cohorts were included: Cohort 1 (metastatic ESCC) and Cohort 2 (locally advanced ESCC). Cohort 2 was divided into an observational group (OG, anlotinib + radiotherapy ± chemotherapy) and a control group (CG, radiotherapy ± chemotherapy). Radiotherapy doses for primary lesions were 45-60 Gy (1.8-2.2 Gy per fraction), while metastatic lesions received either standard fractionation (≥45 Gy) or stereotactic body radiotherapy (SBRT, ≥3 Gy per fraction, total dose ≥30 Gy). Chemotherapy regimens were not restricted. Cohort 1 aimed to enroll 50 pts, while Cohort 2 included 100 in the OG and 200 in the CG. The primary endpoint was overall survival (OS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and safety. Results: By September 10, 2024, 128 pts had been enrolled: 34 in Cohort 1 and 94 in the OG of Cohort 2. In Cohort 1, all 34 pts (100%) were stage IVB, with a median OS of 24.0 months (95% CI: 12.44-35.60) and a median PFS of 9.2 months (95% CI: 7.60-10.80). The 24-month OS and PFS rates were 54.0% (95% CI: 27.20-74.73) and 30.8% (95% CI: 10.21-54.53), respectively. ORR was 52.9% (95% CI: 35.1-70.2), with 1 complete response (CR) and 17 partial responses (PR), DCR was 88.2% (95% CI: 72.5-96.7). In Cohort 2, 50 pts (53.2%) were stage III, and 28 (29.8%) were stage IVA. The median OS is not yet mature, but the median PFS was 20.1 months. The 36-month OS and PFS rates were 61.9% (95% CI: 46.12-74.34) and 48.4% (95% CI: 29.58-64.87). ORR was 46.8% (95% CI: 36.4-57.4), with 6 CRs and 38 PRs, DCR was 95.7% (95% CI: 89.5-98.8). Safety data collection is ongoing. Conclusions: Anlotinib combined with radiotherapy exhibited promising efficacy in locally advanced or metastatic ESCC, though further data are needed to confirm these preliminary findings.

Bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 plus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Survival results of a phase II trial.

411 Background: Recently, several clinical trials have demonstrated synergistic efficacy by combining immune checkpoint inhibitors (ICIs) with chemotherapy. However, only a subset of patients (pts) derived benefits. Combining ICIs with agents blocking immunosuppressive pathway may expand the clinical benefit of ICIs to more pts. Transforming growth factor β (TGF-β) participates in tumor immune escape. SHR-1701, a novel bifunctional fusion protein consisting of a monoclonal antibody targeting PD-L1 fused with the extracellular domain of TGF-β receptor II, was evaluated in a phase II trial (ChiCTR2000039909) to assess its efficacy and safety when combined with chemotherapy for pts with unresectable locally advanced, recurrent or metastatic ESCC in China. Methods: This trial enrolled treatment-naive pts with histologically or cytologically confirmed unresectable locally advanced, recurrent, or metastatic ESCC. Eligible pts received SHR-1701 (30mg/kg, iv, d1, q3w) in combination with up to six cycles of albumin-bound paclitaxel (125mg/m 2 , iv, d1, d8, q3w) and cisplatin (75mg/m 2 , iv, d1, q3w). For those without progressive disease, maintenance treatment was administered with SHR-1701 monotherapy until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: At the data cut-off, March 1, 2024, 24 pts had received at least one dose of the study treatment and were included in both the intention-to-treat (ITT) analysis and safety analysis sets. 3 and 12 pts achieved confirmed complete and partial responses, respectively. The confirmed ORR was 62.5% and DCR was 87.5%. With a median follow-up of 20.8 months (95% CI, 15.5-NR), the median duration of response was 9.1 months (95% CI, 6.9-NR). The median PFS was 10.8 months (95% CI, 7.8-NR) and the median OS was 26.1 months (95% CI, 8.6-NR). 12-month PFS and OS rates were 41.4% (95% CI, 22.5-76) and 64.8% (95% CI, 47.8-87.9), respectively. Grade 3-4 treatment-related adverse events occurred in 11 (45.8%) pts and no treatment-related death was observed. Conclusions: The results highlighted that SHR-1701 plus chemotherapy as first-line therapy maintained long-term, durable survival benefit in pts with advanced ESCC. Clinical trial information: ChiCTR2000039909.

Updated survival results of ZL-IRIAN: Irinotecan plus anlotinib or in combination with penpulimab as second-line treatment of metastatic colorectal cancer.

167 Background: The irinotecan based chemotherapy in combination with bevacizumab had become the standard second-line treatment for metastatic colorectal cancer (mCRC), but the efficacy was limited. Anlotinib, an oral anti-angiogenic tyrosine kinase inhibitor, had initially shown promising clinical effects when combined with chemotherapy in the first-line treatment of mCRC. Whether anlotinib could bring clinical benefit in the second line treatment warrants further exploration. The PD-1 antibody might have partial effects when combined with anti-angiogenic agents with or without chemotherapy in first- and third-line treatment for proficient mismatch repair (pMMR)/microsatellite stable (MSS) mCRC. Our study was to explore the rationality of anlotinib plus chemotherapy or further combined with a novel anti-PD-1 IgG1 antibody—penpulimab in the second line treatment of mCRC. Methods: This study was an open label, non-randomized, multi-cohorts, phase II prospective clinical trial that included pts with pMMR/MSS mCRC who were eligible for the second-line systemic treatment. Two cohorts were established as follows: Cohort A consisted of anlotinib(10mg daily, d1-10, q2w) + irinotecan (180mg/m d6, q2w) (n = 23); Cohort B consisted of anlotinib (8mg daily, d1-10, q2w)+irinotecan (180mg/m d6, q2w) + penpulimab (200mg, d6, q2w) (n = 23). The primary endpoint was ORR. Secondary endpoints included progress free survival (PFS), overall survival (OS), duration of response (DoR), disease control rate (DCR) and safety. The ORR was reported at 2024 ASCO, and PFS and OS have been updated in this report. Results: At the cutoff date on August 2024, a total of 23 Pts were enrolled in A cohort, and 23 pts were enrolled B cohort but 21 pts received at least one dose of treatment. The median PFS was 7.87 months (95% CI 5.52-10.22) in A cohort, compared to 7.4 months (95% CI 3.17-11.63) in B cohort, p=0.141. The 6-month, 12-month and 18-month PFS rates in A cohort and B cohort were 69.3% vs 80.7%, 27.5% vs 40.3% and 5.5% vs 22.4%, respectively. The median OS of A cohort was 21.73 months (95% CI 9.43-34.03), compared to 19.17 months (95% CI 11.44-26.90 months) in B cohort, p=0.987. The 12-month and 24-month OS rates in A cohort and B cohort were 64.7% vs 73.1% and 20.2% vs 54.8%, respectively. Safety profile indicated that 65.2% (15/23) and 66.7% (14/21) experienced grade≥3 adverse events in A cohort and B cohort, respectively. Common grade ≥ 3 adverse reactions (≥ 20%) mainly include hypertension (4.35% vs 14.29%), diarrhea (13.04% vs 9.52%), neutrophilopenia (39.13% vs 33.33%), and leukopenia (26.09% vs 9.52%). Conclusions: There was no statistically significant difference in overall efficacy between the two cohorts, but the long-term PFS and OS rates were higher in group B cohort, indicating that immunotherapy may bring long-term survival benefits to certain patients. Clinical trial information: NCT05229003 .

A phase IIa clinical trial of first-line cyclical therapy alternating gemcitabine, cisplatin, and durvalumab with pemigatinib for advanced biliary tract cancers with FGFR2 -alterations.

TPS645 Background: Unresectable biliary tract cancer (BTC) has a poor prognosis. Frontline chemo-immunotherapy (C-IO) for advanced BTC leads to ~25% overall survival (OS) at 24-month, but 93-99% of patients reported adverse events (AEs), and 13-19% of patients stopped treatment drugs due to AEs. FGFR kinase inhibitors (FGFRi) are second-line therapy for 10% of BTC with FGFR2 fusions. However, clinical trials of upfront FGFRi have not accrued well. Cumulative toxicities frequently interrupt treatment and limit feasibility of concurrent C-IO + FGFRi. Over time, side effects from each of therapies have a negative impact on patients’ quality of life (QoL). We previously treated two FGFR2 -altered BTC patients with cyclical chemotherapy (CT) and FGFRi and observed prolonged survival with better QoL. By monitoring serial circulating tumor DNA (ctDNA), we observed development of FGFRi-resistant subclones while on FGFRi and their subsequent clearance after resuming CT. Thus, we have developed a clinical trial to validate our hypothesis that upfront cyclical therapy alternating between C-IO and FGFRi can improve therapeutic efficacy and QoL. Alternating therapy is hypothesized to avoid accumulating toxicities and treat emerging resistance subclones. Methods: In this single-center, single-arm, Phase IIa trial, all treatment-naive patients with FGFR2 -altered advanced BTCs, PS ≤ 1, are eligible. Patients will receive cyclical therapy alternating between two therapy-blocks, starting from C-IO block (2 cycles of gemcitabine, cisplatin and durvalumab, 28-day/cycle), then FGFRi block (3 cycles of pemigatinib on day 1-14 of 21-day/cycle). Block-switch continues until progressive disease (PD), and then we will continue alternated block until the next PD. A sample size of 30 is calculated based on an expected 12-month OS rate of ≥ 55%. The trial is anticipated to enroll the first patient in early 2025. Results: The primary objective is 12-month OS rate. Secondary objectives are overall response rate, progression-free survival, AEs. We will stratify patients to PD-L1 CPS &lt;1 or ≥ 1 to assess if cyclical therapy can enhance IO. Exploratory objectives are (1) assessing dynamics of FGFR2 -ctDNA variants throughout therapy correlating with clinical outcomes, using a custom liquid biopsy (FGFR-Dx) developed at the Ohio State University; (2) assessing QoL scores with EORTC-QLQ-C30 and -BIL21 questionnaires, correlating with clinical outcomes. Results will be compared to historical controls from TOPAZ-1 trial. Conclusions: Cyclical therapy will be one of the first to combine alternating C-IO and targeted therapy in cancer. This strategy can be validated in other tumors if it is proven effective in our trial. Cyclical therapy holds great promise to introduce FGFRi earlier into treatment for BTC and improve both efficacy and QoL.

Outcomes and Prognostic Indicators in Daratumumab-Refractory Multiple Myeloma: A Multicenter Real-World Study of Elotuzumab, Pomalidomide, and Dexamethasone in 247 Patients

Daratumumab-refractory multiple myeloma (Dara-R MM) presents a significant treatment challenge. This study aimed to evaluate the efficacy and survival outcomes of elotuzumab, pomalidomide, and dexamethasone (EloPd) in a large, real-world cohort of patients with Dara-R MM, with particular focus on progression-free survival (PFS) and overall survival (OS). This retrospective analysis included 247 Dara-R MM patients treated with EloPd. All patients were also refractory to lenalidomide, with 51.4% to a proteasome inhibitor, thus classified as triple-class refractory (TCR). Survival risk-scoring systems for PFS (progression-free risk score-PRSDaraR) and OS (survival risk score-SRSDaraR) were developed to stratify patients based on their risk profiles. The overall response rate was 52.6%, with a median PFS and OS of 6.6 and 17.0 months, respectively. The International Staging System (ISS) stages II and III, low hemoglobin (Hb) levels, the last therapy being daratumumab, and symptomatic relapse were identified as significant independent predictors of shorter PFS in multivariable analysis. In addition to advanced ISS stages, low Hb levels (<10.6 g/dl), symptomatic relapse, and refractory disease exhibited an independent negative impact on OS. Importantly, no significant differences in both PFS and OS were observed between TCR and non-TCR patients. Based on these multivariable analyses, we developed PRSDaraR and SRSDaraR according to the magnitude of the hazard ratio. In PRSDaraR, 10.1% were low-risk, 41.3% intermediate, 43.3% high, and 5.3% very high-risk. The 12-month PFS probabilities were 86.3% (low), 67.6% (intermediate), 52.9% (high), and 31.8% (very high). For SRSDaraR, 6.1% were low-risk, 47.8% intermediate, 19.4% high, and 26.7% very high. The 12-month OS probabilities were 90.9% (low), 75.7% (intermediate), 55.9% (high), and 32.6% (very high). This study supports EloPd as an effective treatment option in Dara-R MM patients, providing valuable disease control and acting as a potential bridge to newer therapies, such as CAR-T and bispecific antibodies.

Dual anti-CTLA-4 and anti-PD-1 blockade in metastatic basal cell carcinoma

We report the basal cell cancer (BCC) cohort of the SWOG/NCI 1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART), a phase II prospective, multicenter basket trial of nivolumab and ipilimumab. The primary endpoint was objective response rate (ORR) (RECIST v1.1). Overall survival (OS), progression-free survival (PFS), and toxicity were secondary endpoints. Sixteen patients with advanced/metastatic BCC were evaluable. The ORR was 31% (95% CI, 19–50%), and the 12-month OS, 75% (95% CI, 57–100%). Median PFS was 9.3 months (95% CI, 3.3–NA). Of 15 patients evaluable for clinical benefit, five partial responses (PRs) and five stable disease >6 months (total = 10/15 (66.7%)) were seen. The most common toxicities included fatigue (37.5%), pruritis (31.3%), and diarrhea (25%). In patients with advanced/metastatic BCC, ipilimumab and nivolumab produced an ORR of 31% and prolonged (>6 months) PFS in 73% of patients, with seven PFS/iPFS of >1 year, including one with prior anti-PD-1. ClinicalTrials.gov ID: NCT02834013 (Registered 7/15/2016; https://clinicaltrials.gov/ct2/show/NCT02834013).

Nomogram for prognosis prediction in metastatic pancreatic cancer patients undergoing intra-arterial infusion chemotherapy: incorporating immune-inflammation scores and coagulation indicators

BackgroundPancreatic cancer is one of the most malignant tumors with an inferior prognosis. This study aims to determine the prognostic significance of immune-inflammatory scores and coagulation indices in patients with metastatic pancreatic cancer(MPC) and develop a predictive nomogram.MethodsThis study retrospectively analyzed the clinical data of 384 patients with MPC who underwent intra-arterial infusion chemotherapy (IAIC). Patients were randomly divided into training and validation cohorts. Firstly, the optimal cutoff values for continuous variables were obtained in the training cohort. Then, survival analysis was performed to evaluate the impact of immune-inflammatory scores neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and coagulation indicators prothrombin time (PT), fibrinogen (FIB), and D-dimer on the overall survival (OS) of patients. Next, univariate analysis was utilized to identify prognostic factors, and a stepwise regression method was employed for variable selection to construct a nomogram based on the Cox proportional hazards model. Additionally, the predictive performance of the nomogram was assessed by the concordance index (C-index), the area under the ROC curve (AUC), and calibration curves. Finally, patients were stratified into risk groups based on the total score of the nomogram.ResultsThe Kaplan–Meier survival curves indicated that immune-inflammatory scores NLR, PLR, SII, and coagulation indicators PT, FIB, and D-dimer were associated with OS. Through Cox regression analysis, a nomogram was ultimately constructed incorporating NLR, PLR, PT, alkaline phosphatase (ALP), carbohydrate antigen 125 (CA125), age, and ablation. The model demonstrated good discriminative ability, with a C-index of 0.722, and the AUC values at 6- and 12-month OS predictions were 0.828 and 0.851 in the training cohort, while in the validation cohort, the corresponding AUC values were 0.754 and 0.791, respectively. The calibration curves showed a good fit, confirming the stability of the model. A cutoff value of 353.3 was identified as optimal for risk stratification, with a statistically significant difference in OS between the high- and low-risk groups.ConclusionThe nomogram based on immune-inflammatory scores, coagulation indicators, and other clinicopathological factors can effectively predict the OS of patients with MPC.

Multicenter Phase 2 Trial of Second-Line Regorafenib in Patients with Unresectable Hepatocellular Carcinoma After Progression on Atezolizumab Plus Bevacizumab (REGONEXT)

Introduction: Atezolizumab-bevacizumab (Atezo-Bev) has become the standard first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). However, data on subsequent treatment after Atezo-Bev failure are lacking. We aimed to investigate the efficacy and safety of regorafenib for uHCC progression after first-line Atezo-Bev. Methods: This investigator-initiated, single-arm, phase 2 trial involved two academic centers in Korea. Eligibility criteria included a diagnosis of HCC, prior treatment with at least 2 cycles of Atezo-Bev, and Child-Pugh A liver function. Eligible patients received regorafenib 160 mg once daily for 3 weeks of every 4-week cycle (i.e., 3 weeks on, 1 week off) until progressive disease or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, disease control rate according to RECIST v1.1, overall survival (OS), and treatment-related adverse events. Results: Forty patients were enrolled from December 2021 through May 2023. The median follow-up duration was 10.1 months (95% confidence interval [CI], 8.3-12.0). The median PFS was 3.5 months (95% CI, 3.0-3.9). The median OS was 10.5 months (95% CI, 7.1-13.8), and the 6-month OS rate was 65.0%. The objective response rate and disease control rate were 10.0% and 82.5%, respectively. The most common grade 3-4 treatment-related adverse event was thrombocytopenia (5.0%). When stratified according to time to progression on prior Atezo-Bev (first quartile [&lt; 2.3 months] vs. second to fourth quartiles [≥ 2.3 months]), patients with longer time to progression on prior Atezo-Bev had better OS (15.0 vs. 3.6 months, p&lt;0.001), objective response rate (13.3% vs. 0%, p=0.009), and a tendency toward better PFS with regorafenib (3.8 vs. 2.5 months; p=0.054). Conclusions: Second-line regorafenib was effective for treating uHCC progression after first-line Atezo-Bev. The efficacy and safety outcomes from our study were consistent with those observed in the pivotal phase 3 RESORCE trial, which included sorafenib-tolerant/progressed patients.

Pembrolizumab ± paricalcitol in metastatic pancreatic cancer postmaximal cytoreduction.

Intravenous paricalcitol did not improve the efficacy of pembrolizumab, likely related to the short half-life. Immunotherapy has limited benefit in the treatment of advanced pancreatic cancer with the tumor microenvironment playing a key role in immune resistance. In preclinical studies, vitamin D receptor (VDR) agonists have been shown to sensitize pancreatic tumors to PD-1 blockade. This was a randomized, double-blinded, placebo-controlled, phase II trial to evaluate pembrolizumab with or without paricalcitol as maintenance therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants were ≥18 years; histologically or cytologically confirmed metastatic PDAC showing no disease progression after frontline systemic therapy, and achieving maximal cytoreduction (eg, with no further antitumor effect), Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; adequate organ function. Study treatment included: pembrolizumab 200mg IV every 3 weeks and either paricalcitol 25 mcg IV 3 times per week or placebo. The primary objective was to evaluate 6-month progression free survival (PFS). Secondary objectives include evaluating the toxicity of the combination and overall survival (OS). There was no significant difference in 6-month PFS, median PFS, median OS, nor treatment-related AEs between the 2 arms. Paricalcitol did not improve the efficacy of pembrolizumab likely related to its short half-life of only 5-7 hours. Microbiome analysis revealed significant difference between long-term (>12 weeks) and short-term (<12 weeks) survival groups across treatment arms. Modulation of the tumor microenvironment will likely require more sustained VDR activity. Clinicaltrials.gov, ID: NCT03331562.

The efficacy and safety of induction chemotherapy combined with sintilimab followed by concurrent chemoradiotherapy plus sintilimab sequencing maintaining with sintilimab for patients with unresectable locally advanced esophageal squamous cell carcinoma

PurposeTo evaluate the efficacy and safety of induction chemotherapy combined with programmed death protein 1 (PD-1) inhibitor (sintilimab) followed by concurrent chemoradiotherapy (CCRT) plus sintilimab, and subsequent maintenance with sintilimab (IC-ICCRT-IO) for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) in a retrospective study.MethodsData from patients with histologically confirmed, locally advanced, inoperable ESCC who received IC-ICCRT-IO were retrospectively analyzed. Treatment effects were evaluated after 2 cycles of induction therapy and after CCRT by contrast-enhanced CT scans and esophagograms, followed by subsequent evaluations every 3 months post-treatment. The primary endpoints included progression-free survival (PFS) and PFS rates at 6, 12, and 18 months. Secondary endpoints involved overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The influence of the expression level of programmed death ligand-1 (PD-L1) as well as neutrophil-to-lymphocyte ratio (NLR) on efficacy of the IC-ICCRT-IO was analyzed.ResultsIn total, 29 eligible patients were enrolled and analyzed. The median follow-up time was 20.5 months. The median PFS was not reached; the 6-, 12-, and 18-month PFS rates were 100.0%, 93.1%, and 82.8%, respectively. The median OS was not reached, and the 6-, 12-, and 18-month OS rates were all 100.0%. The ORR and DCR were 89.7% and 100.0%. Adverse events (AEs) were manageable, with grade 3 or higher AEs observed in 48.2% of patients, primarily nonimmune-related and clinically manageable. Hematologic toxicity was predominant. Two patients developed grade 3 immune-related rash, and two patients developed grade 3 radiation pneumonitis, all of whom were managed with appropriate symptomatic treatment. No significant differences in survival outcomes were observed with respect to PD-L1 and NLR.ConclusionOur results indicated that the IC-ICCRT-IO regimen for unresectable locally advanced ESCC provided a survival benefit with manageable safety profile. More prospective clinical studies should be warranted.Trial registration2024-04-22, No. QYFY WZLL 28,684, retrospectively registered.

Olaparib as treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency: Phase 2 LIGHT study final overall survival analysis.

LIGHT (oLaparib In HRD-Grouped Tumor types; NCT02983799) prospectively evaluated olaparib treatment in patients with platinum-sensitive relapsed ovarian cancer (PSROC) assigned to cohorts by known BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive non-BRCAm, and HRD-negative. At the primary analysis, olaparib treatment demonstrated activity across all cohorts, with greatest efficacy in terms of objective response rate and progression-free survival observed in the g/sBRCAm cohorts. The authors report final overall survival (OS). In this phase 2, open-label, noncomparative study, patients with PSROC and one or more prior line of platinum-based chemotherapy were assigned to cohorts by BRCAm and HRD status. OS was a secondary end point. Tumors were analyzed using Myriad BRACAnalysis CDx and MyChoice CDx assays; HRD-positive tumors were defined using a genomic instability score of ≥42. Of 272 enrolled patients, 271 received olaparib and 270 met the inclusion criteria for the efficacy analysis. At data cutoff, 18-month OS rates in the gBRCAm, sBRCAm, HRD-positive non-BRCAm, and HRD-negative cohorts were 86.4%, 88.0%, 78.6%, and 59.6%, respectively. No new safety signals were observed. In a post hoc analysis, patients on treatment for >18 months were most frequently present in g/sBRCAm cohorts (31.0%). Olaparib treatment continued to demonstrate benefit across all cohorts. Consistent with the primary analysis, the highest OS rates were observed in the BRCAm cohorts, regardless of g/sBRCAm. In patients without a BRCAm, a higher OS rate was observed in the HRD-positive non-BRCAm than the HRD-negative cohorts. These results highlight the importance of biomarker testing in this treatment setting.

Avelumab + axitinib treatment in older patients with advanced renal cell carcinoma in Japan: Subgroup analyses of post-marketing surveillance data by age.

Avelumab + axitinib was approved in Japan in December 2019 for the treatment of curatively unresectable or metastatic renal cell carcinoma (RCC) based on results from the JAVELIN Renal 101 trial. To evaluate the safety and effectiveness of avelumab + axitinib in older patients in general clinical practice in Japan, an ad hoc analysis of data from post-marketing surveillance (PMS) by age group was conducted. The analysis population included 328 patients who had received ≥1 dose of avelumab and were enrolled between December 2019 and May 2021. In total, 100 patients (30.5%) were aged ≤64 years, 130 (39.6%) were aged 65-74 years, and 98 (29.9%) were aged ≥75 years. Within these age groups, adverse drug reactions (ADRs) of safety specifications of any grade occurred in 46 (46.0%), 71 (54.6%), and 56 (57.1%), and of grade ≥3 in 13 (13.0%), 23 (17.7%), and 20 (20.4%), respectively. The most common ADRs of safety specifications across all age groups were thyroid dysfunction, infusion reactions, and hepatic function disorders. Median overall survival (OS) was not reached in any age group; 12-month OS rates in patients aged ≤64, 65-74, or ≥75 years were 83.8%, 86.2%, and 80.0%, and objective response rates were 31.0%, 43.8%, and 30.6%, respectively. Analyses of PMS data show the safety and effectiveness of avelumab + axitinib across all age groups of patients with RCC in general clinical practice in Japan. The favorable benefit-risk profile was generally consistent with that observed in previous clinical trials.

Final Analysis of Post-Marketing Surveillance for Avelumab + Axitinib in Patients With Renal Cell Carcinoma in Japan.

Avelumab, an anti-programmed death ligand 1 antibody, was approved in combination with axitinib for curatively unresectable or metastatic renal cell carcinoma (RCC) in Japan in December 2019. Because the pivotal JAVELIN Renal 101 study included a limited number of Japanese patients, post-marketing surveillance (PMS) was required to evaluate outcomes (safety and effectiveness) in patients with RCC who received avelumab + axitinib treatment in clinical practice in Japan. We report data from prospective, noncomparative, multicenter, observational PMS in patients with RCC who received ≥ 1 dose of avelumab. Patients were enrolled between December 2019 (date of regulatory approval) and May 2021. The primary objective was to evaluate safety, defined as adverse drug reactions (ADRs) of safety specifications occurring during an observation period of ≤ 52 weeks for each patient. The secondary objective was to evaluate effectiveness, including best overall response and overall survival (OS). In total, 328 patients were included in the safety and effectiveness analysis sets. Overall, 173 patients (52.7%) had ADRs of safety specifications of any grade, most commonly thyroid dysfunction (n = 69 [21.0%]), infusion reaction (n = 65 [19.8%]), and hepatic disorders (n = 45 [13.7%]). Objective responses occurred in 118 patients (36.0%), including complete or partial responses in 13 (4.0%) and 105 (32.0%), respectively; the disease control rate was 75.6%. The 12-month OS rate was 83.7% (95% CI, 78.9%-87.4%). This PMS confirmed the safety, tolerability, and effectiveness of avelumab + axitinib in patients with RCC in clinical practice in Japan, with a benefit-risk profile comparable to that observed in clinical trials.

Superior 125-month outcome through cetuximab in the larynx organ preservation trial DeLOS-II: a single study center's experience.

The larynx organ preservation (LOP) trial DeLOS-II enrolled n = 173 patients with advanced laryngeal/hypopharyngeal squamous cell carcinoma (LHSCC) amenable (only curatively resectable) through total laryngectomy (TL) to receive induction chemotherapy (IC) with TPF [docetaxel (T), cisplatin (P), and 5-fluorouracil (F)] (arm A, 85 patients) or additional cetuximab (E) weekly (arm B, 88 patients). Responders with endoscopic estimated tumor surface shrinkage (ETSS) ≥30% after 1 cycle IC (IC-1) received a further two cycles of IC followed by radiotherapy (RT), whereas TL was recommended for non-responders. Arm B failed to show superior 24-month laryngectomy-free survival (LFS) and overall survival (OS), the protocol-specified primary and secondary endpoints. Ten years after the last per-protocol visit, we are interested in the long-term outcome of our clinic's DeLOS-II patients. Our cohort of 52 DeLOS-II patients accrued between 2007 and 2012 included 27 and 25 patients randomized to arms A and B, respectively. F was omitted because of severe toxicity with amendment 2 of the DeLOS-II protocol, leading to 21 and 31 patients receiving TPF and TP IC backbone, respectively. Follow-up data were collected using electronic health records and information from the German Centre for Cancer Registry Data to evaluate long-term LFS and OS in treatment groups. According to ETSS ≥ 30%, 42 patients (80.8%; 21 and 21 corresponding to 77.8% and 84.0% in arms A and B, respectively) were responders to IC-1 and underwent the LOP attempt. Recommending early TL to non-responders (ETSS < 30%), eight patients (five and three in A and B, respectively) underwent early TL. At 125 months, 22 (eight and 14) patients were alive: 17 (six and 11) with a functioning larynx and five (two and three) without a larynx. Arm B had superior OS (p = 0.023). Disease-specific survival (DSS) and tumor-specific survival were not different, whereas non-cancer-related survival (NCRS) was impaired in arm A (p = 0.018). Receiving TP or TPF IC did not significantly influence survival. Pairwise comparing OS of patients receiving TP, TPF, TPE, and TPFE revealed a benefit from cetuximab in TPE vs. TP (p = 0.020). While the per-protocol DeLOS-II results earlier reported comparable 24-month LFS and OS in arms A and B, our subcohort's long-term follow-up data demonstrate a superior 125-month outcome in arm B.

Outcomes of CD19 CAR T in Transformed Indolent Lymphoma Compared to De Novo Aggressive Large B-Cell Lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of aggressive large B-cell lymphoma (aLBCL). Patients with transformed indolent non-Hodgkin lymphoma (tiNHL) were included in key CAR trials, but outcomes of CAR for this distinct, historically high-risk group are poorly understood. We conducted a multicenter retrospective study of 1182 patients with aLBCL receiving standard-of-care CAR T between 2017 and 2022, including 338 (29%) with tiNHL. Rates of grade ≥ 3 cytokine release syndrome (CRS) were similar between tiNHL and de novo cohorts (7% vs. 8%, p = 0.6), while grade ≥ 3 immune effector cell-associated neurotoxicity syndrome was lower in tiNHL (21% vs. 27%, p = 0.02). Overall response rate was similar in both cohorts (83% vs. 81%, p = 0.3), while complete response rate was higher in tiNHL (67% vs. 59%, p = 0.017). With a median follow-up of 22.3 months, the progression/relapse-free (PFS) and overall survival (OS) were similar between the tiNHL and de novo cohorts (24-month PFS 41% [95% CI: 35%-46%] vs. 38% [95% CI: 35%-42%]; 24-month OS 58% [95% CI: 52%-63%] vs. 52% [95% CI: 48%-56%], respectively). After adjusting for key risk factors, there was a trend toward a lower hazard of disease progression, relapse or death post-CAR for tiNHL patients compared to de novo aLBCL patients (HR: 0.84 [95% CI: 0.69-1.0], p = 0.07). Elevated LDH, advanced stage, prior bendamustine within 12 months of CAR, receipt of bridging therapy, CNS involvement, and ≥ 3 prior lines of therapy were each associated with inferior PFS. In conclusion, CAR T therapy is highly effective with an acceptable toxicity profile in patients with tiNHL.