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Background Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin‐dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. Methods This Phase 2 open‐label study enrolled patients with metastatic PDAC who progressed after 1–2 prior therapies. Patients were enrolled in a safety lead‐in (abemaciclib plus galunisertib) followed by a 2‐stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib‐containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression‐free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. Results One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4–1.8), 1.8 months (95% CI: 1.3–1.9), and 3.3 months (95% CI: 1.1–5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified. Conclusion In patients with pretreated metastatic PDAC, abemaciclib‐based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC. Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This phase 2 randomized study for refractory metastatic PDAC patients showed that the CDK4/6 inhibitor abemaciclib, alone or in combination with the PI3K/mTOR LY3023414, does not improve disease control or progression‐free survival compared to standard chemotherapy.

Background We previously reported results of a pooled analysis of two zanubrutinib studies in relapsed or refractory (R/R) MCL showing better survival outcomes when zanubrutinib is used in second‐line versus later‐line. Here, we present an updated pooled analysis with a longer follow‐up of 35.2 months. Methods Data were pooled from two studies—BGB‐3111‐AU‐003 (NCT02343120) and BGB‐3111‐206 (NCT03206970) of zanubrutinib in R/R MCL. The patients were divided into two groups based on the treatment line of zanubrutinib: the second‐line and the later‐line group. The inverse propensity score weighting method was used to balance the baseline covariates between the groups. The primary outcome was overall survival (OS). Secondary outcomes included progression‐free survival (PFS), PFS, and OS rates, objective response rate (ORR), duration of response (DOR), and safety. Results Among 112 pooled patients, 41 (36.6%) patients received zanubrutinib as second‐line and 71 (63.4%) patients as later‐line therapy. After weighting, OS was significantly improved in the second‐line versus later‐line group (HR, 0.459 [95% CI: 0.215, 0.98]; p = 0.044) with median OS not estimable in both groups. The PFS was similar between the two groups (HR, 0.78 [95% CI: 0.443, 1.373]; p = 0.389) but with numerically longer median PFS in the second‐line versus later‐line group (27.8 vs. 22.1 months). ORR was numerically higher in the second‐line versus later‐line (88.6% vs. 85.7%), and DOR was similar between the two groups (25.2 vs. 25.1 months). Zanubrutinib showed a similar safety profile in both groups. Conclusion Zanubrutinib in second‐line treatment was associated with significantly improved OS compared with later‐line treatment of R/R MCL. This pooled analysis of two studies of zanubrutinib examined its efficacy and safety in the treatment of patients with recurrent/relapsed mantle cell lymphoma (MCL) in two different settings—second‐line and later‐line with long‐term follow‐up. This analysis showed that patients receiving zanubrutinib in the second‐line had significantly better overall survival than those who received it in the later‐line. The finding suggests that earlier use of zanubrutinib in the treatment line may lead to better outcomes in patients with recurrent/relapsed MCL.

Purpose Programmed cell death protein 1 (PD‐1) inhibitor monotherapy is the standard second‐line treatment for esophageal squamous cell carcinoma (ESCC), but the clinical response and survival outcomes still remain unsatisfactory. This systematic review aims to assess the efficacy and safety of combined immunotherapy strategies in previously treated ESCC patients. Methods and Materials Studies involving previously treated ESCC patients treated with either combined immunotherapy or PD‐1 inhibitor monotherapy as second‐ or later‐line treatment were searched up to November 30, 2023. Pooled rates of objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and treatment‐related adverse events (TRAEs) were compared. Results A total of 19 studies involving 3007 ESCC patients were included in the pooled analysis. Among them, 1308 patients received immunotherapy monotherapy. Combination immunotherapy included PD‐1 inhibitor combined with chemotherapy (123 patients), anti‐angiogenesis therapy (291 patients), chemoradiotherapy (49 patients), TIGIT inhibitor (62 patients), and anti‐EGFR antibody (28 patients). Patients receiving combination immunotherapy had significantly higher ORR, DCR, PFS, and OS rates compared to those receiving PD‐1 inhibitor monotherapy or chemotherapy (ORR: 35.5% vs. 19.8% vs. 13.0%, p = 0.000; DCR: 84.8% vs. 51.2% vs. 55.2%, p = 0.000). Subgroup analysis demonstrated that second‐line combination immunotherapy significantly improved response and survival rates compared to PD‐1 inhibitor monotherapy in immunotherapy‐naive ESCC patients. The limited data showed that PD‐1 inhibitors combined with both anti‐angiogenesis agents and chemotherapy as second‐line therapy improved response and survival rates compared to PD‐1 inhibitor monotherapy. Notably, the PD‐1 inhibitor combined with anti‐angiogenesis therapy or chemotherapy also showed high antitumor activity in immunotherapy‐treated ESCC patients. Combination therapy was associated with higher treatment‐related but manageable toxicity compared with PD‐1 inhibitor monotherapy. Conclusions Based on the limited data, combined immunotherapy provides additional clinical benefits over standard PD‐1 inhibitor monotherapy in second‐line treatments for both immunotherapy‐naive and previously immunotherapy‐treated ESCC patients.

Introduction Regorafenib remains the standard and widely used second‐line strategy for advanced hepatocellular carcinoma (HCC). There is still a lack of large‐scale multicenter real‐world evidence concerning the concurrent use of regorafenib with immune checkpoint inhibitors (ICI). This study aims to evaluate whether combining regorafenib with ICI provides greater clinical benefit than regorafenib monotherapy as second‐line therapy for advanced HCC under real‐world circumstances. Patients and Methods The study included 208 patients from five medical facilities. One hundred forty‐three patients received regorafenib plus ICI combination therapy, while 65 patients received regorafenib monotherapy. Propensity score matching (PSM) analysis was employed. Results The regorafenib plus ICI group demonstrated significantly higher objective response rate (24.3% vs. 10.3%, after PSM, p = 0.030) and disease control rate (79.4% vs. 50.0%, after PSM, p < 0.001) compared to the regorafenib monotherapy group based on mRECIST criteria. Median progression‐free survival (7.9 vs. 3.2 months, after PSM, p < 0.001) and overall survival (25.6 vs. 16.4 months, p = 0.010, after PSM) were also considerably longer in the regorafenib plus ICI group. The incidence of Grades 3–4 treatment‐related adverse events (TRAEs) was marginally greater in the regorafenib plus ICI group than in the regorafenib group (23.8% vs. 20.0%, p = 0.546). Notably, there were no instances of treatment‐related mortality or emergence of new TRAEs in any treatment group. Conclusion The combination of regorafenib and ICI shows potential as a viable second‐line treatment for advanced HCC, exhibiting favorable efficacy while maintaining a tolerable safety profile in contrast to regorafenib monotherapy. Regorafenib+ICI was more effective than regorafenib in second line for advanced HCC. Combining with ICI did not yield a significant increase in TRAEs.

Background The prognosis for patients with relapse of localized rhabdomyosarcoma (RMS) remains poor, with limited evidence for optimal second‐line therapy. This study describes the management and outcomes of relapsed RMS patients in France. Methods We retrospectively reviewed all nonmetastatic RMS patients enrolled in France in the RMS 2005 study who relapsed between 2006 and 2019 after achieving complete local control, defined as complete remission or stable residue ≥ 6 months after treatment completion. Data were extracted from the RMS 2005 database and medical records. Results Ninety‐five patients relapsed at a median age of 6.0 years (range: 1.0–27.0). The median time from diagnosis to relapse was 17.5 months (range: 7.4–82.0). Most patients had embryonal RMS (65.3%) and local/locoregional relapses (71.6%). The first relapse treatment included chemotherapy (all except two patients), radiotherapy (52.6%), and surgery (48.4%). Second‐line chemotherapy yielded a 58.5% objective response rate after 3 ± 1 cycles. Fifty‐five patients achieved second complete remission. With a median follow‐up of 7.2 years from the first relapse (range: 0.3–11.3), 5‐year progression‐free survival was 26% (95% CI: 18–36), and 5‐year overall survival was 35% (95% CI: 25–45). Importantly, no patient survived relapse without receiving locoregional treatment (surgery and/or radiotherapy). Conclusion This study confirmed the inconsistencies in therapy and the poor prognosis for relapsed RMS but highlighted the potential for long‐term survival in patients who received surgery and/or radiotherapy, emphasizing the crucial role of achieving local control in improving outcomes at relapse.

Background Lenvatinib (LEN) is the recommended first‐line therapy for unresectable hepatocellular carcinoma (uHCC), but resistance frequently develops, and limited data exist on second‐line treatments. This study evaluated the efficacy and safety with a focus on the sorafenib (SOR) or regorafenib (REG)‐ based monotherapy or combination therapy in patients with uHCC after failure of first‐line LEN. Methods Patients with first‐line LEN failure between May 2018 and December 2023 were retrospectively collected. Based on second‐line regimens, 70 patients were divided into two groups: the TKI group (n = 21) and the TKI‐ICI group (n = 49). Overall survival (OS) and progression‐free survival (PFS) were analyzed by Kaplan–Meier methods, and multivariate analysis was performed to identify prognostic factors. Results In the TKI‐ICI group, median PFS was 5.27 months and median OS was 12.53 months. In the TKI group, median PFS was 3.10 months and median OS was 7.50 months. The objective response rate (ORR) was 19.1% in the TKI group and 16.3% in the TKI‐ICI group. The disease control rate (DCR) was 85.7% in the TKI‐ICI group and 61.9% in the TKI group. In the TKI‐ICI cohort, multivariable Cox analysis revealed the high albumin to neutrophil ratio index (ANRI) was an independent predictor for PFS, while alpha‐fetoprotein > 400 ng/mL was the independent predictor for OS. Safety profiles in both cohorts showed manageable toxicity, with no treatment‐related deaths. Conclusions The combination of TKI and ICI presents a promising second‐line treatment option after LEN failure, regardless of the specific second‐line TKI used. The combination of TKI and ICI for uHCC after LEN failure demonstrated great survival benefits and was well tolerated, irrespective of the second‐line TKI administered.

Background Currently there is no standard therapy recommended for second‐line treatment for thymic carcinoma. Our study compared multidrug chemotherapy, single‐agent chemotherapy, and PD‐1 inhibitors in patients diagnosed with advanced thymic carcinoma who had previous platinum‐based chemotherapy at the clinic. Methods The study included patients with thymic carcinoma who failed first‐line platinum‐based chemotherapy. Kaplan–Meier methods were applied in the study for estimating the progression‐free survival (PFS) and overall survival (OS) curves. Pearson chi‐square or Fisher's exact chi‐square test was adopted to make comparisons of the objective response rate (ORR) between treatment groups. Cox regression was used for the multivariate analyses in PFS and OS. Results Among the 92 patients enrolled, multidrug chemotherapy was used in 51 (55.4%) patients for second‐line therapy. Thirty‐six patients (35.9%) received single‐agent chemotherapy, and eight patients (8.7%) underwent PD‐1 inhibitors. The multidrug chemotherapy group showed better efficacy than the other two groups, with an ORR of 35.3% (p = 0.006). The median PFS of multidrug chemotherapy, single‐agent chemotherapy and PD‐1 inhibitors were 5.0 months, 3.0 months, and 4.0 months, respectively (p = 0.008). Patients in the multidrug chemotherapy group also showed an advantage in OS in comparison with the other two treatment groups (p = 0.045), with a median OS of 30.4 months. Multivariate analysis showed that second‐line treatment was independent factor for both PFS (p = 0.035) and OS (p = 0.037). Grade 3–4 AEs were mostly detected in patients receiving multidrug chemotherapy and were primarily hematologic. Treatment‐related mortality was not found in any of the groups. Conclusions Multidrug chemotherapy had a trend toward a more positive response rate and outcomes in longer survival time than single‐agent chemotherapy and PD‐1 inhibitors. Multidrug chemotherapy is a choice worth considering for second‐line therapy in patients with thymic carcinoma if tolerable. (1) In 92 patients, the multidrug chemotherapy group showed better efficacy than the single‐agent chemotherapy group and the PD‐1 inhibitors group, with an ORR of 35.3%, 6.0%, and 12.5%, respectively (p = 0.006). (2) In second‐line therapy, the median PFS was 5.0 months for multidrug chemotherapy, 3.0 months for monotherapy and 4.0 months for PD‐1 inhibitors (p = 0.008). (3) The multidrug chemotherapy group had an advantage over the other groups in OS (p = 0.045), with median OS of 30.4 months.

Objective Few studies have evaluated disparities in race, ethnicity, and health insurance in real‐world health outcomes for patients with diffuse large B‐cell lymphoma (DLBCL). This study aimed to evaluate association between racial disparities and health insurance with real‐world health outcomes. Methods Patients with DLBCL (January 2011–July 2021) treated with first‐line therapy were selected from a real‐world database. Variables of interest included race/ethnicity, health insurance type (Medicaid, Commercial) by patient age (<65, ≥65 years), stage at diagnosis, overall survival (OS), and time to second‐line therapy or death due to any cause (TTNTD). Results Among 5362 patients with DLBCL (82% White, 7% Black, 8% Hispanic/Latino, 3% Asian), White patients were older (mean age, 66.7 vs. 59.3–62.5 years) and less likely to have Medicaid insurance (1.7% vs. 3.4%–5.9%). Adjusted hazard ratios (aHR) for OS (Black, 0.88 [95% confidence interval, 0.72–1.07]; Hispanic/Latino, 0.84 [0.70–1.03]; Asian, 0.82 [0.59–1.16]) and TTNTD (Black, 0.89 [0.75–1.05]; Hispanic/Latino, 0.85 [0.73–1.00]; Asian, 1.11 [0.86–1.43]) were similar to those of White patients. Among patients aged <65 years, Medicaid‐insured versus Commercially insured patients had more advanced disease (stage III–IV, 66% vs. 48%), worse OS (aHR, 0.52 [0.34–0.80]; p = 0.003), and shorter TTNTD (aHR, 0.70 [0.49–0.99]; p = 0.044). Conclusions There was no statistically significant difference in these variables/outcomes between Medicaid‐insured and commercially insured patients aged ≥65 years. Medicaid‐insured status was significantly associated with poorer OS and TTNTD in patients with DLBCL aged <65 years but not in those aged ≥65 years, with or without adjusting for other baseline characteristics. Race was not significantly associated with these outcomes. The large real‐world EHR dataset Flatiron has shown that race was not significantly associated with poorer survival in patients with DLBCL. Medicaid insurance status was significantly associated with poorer overall survival and time to second‐line therapy or death due to any cause in patients with DLBCL aged <65 years.

Background Several options for second‐line therapy are available for patients with advanced non‐small cell lung cancer (NSCLC); however, the optimal therapy remains unclear. Docetaxel (DTX) monotherapy and DTX plus ramucirumab (RAM) are the recommended second‐line treatment options. However, the efficacy of these treatments remains unsatisfactory. The aim of this study was to identify the clinical characteristics of patients with NSCLC who respond to DTX or DTX + RAM and factors that predict response. Methods Patients with NSCLC treated with DTX or DTX + RAM after second‐line therapy were retrospectively analyzed. Patients were compared with those who responded or did not respond to the post‐treatment efficacy assessment. Results Of 53 patients, 12 (22.6%) had lung cancer that responded to DTX or DTX + RAM therapy (response group). Multivariate analysis identified the absence of immune checkpoint inhibitors (ICIs) in the immediate prior therapy and a reduced dose of DTX after the second cycle as significant independent risk factors predicting nonresponse to DTX and DTX + RAM therapy in patients with NSCLC. The overall survival was significantly longer in the response group compared to the nonresponse group (p = 0.016). Conclusions Our results suggest that DTX and DTX + RAM therapies immediately after treatment with ICI‐containing regimens as well as continuation of DTX without dose reduction after the second cycle may increase the response rate and prolong survival in patients with NSCLC. Several options for second‐line therapy are available for patients with advanced non‐small cell lung cancer (NSCLC); however, the optimal therapy remains unclear. Our results suggest that DTX and DTX + RAM therapies immediately after treatment with ICI‐containing regimens as well as continuation of DTX without dose reduction after the second cycle may increase the response rate and prolong survival in patients with NSCLC.

Background Immune‐checkpoint inhibitors are now used more commonly in combination than monotherapy as the first‐line choice in patients with unresectable advanced melanoma. Nevertheless, for cases that progressed after the initial combination therapy, the subsequent regimen option can be very difficult. Herein, we reported the efficacy and safety of a triple combination regimen in Chinese unresectable advanced melanoma patients who had poor responses to the first‐line immune therapy. Methods We reviewed the clinical profiles of patients diagnosed with stage IIIC‐IV melanoma between June 1, 2020, and September 30, 2023. The patients who failed the prior immune therapies and received anti‐PD‐1 mono antibody plus interferon(IFN)‐alpha 1b and anlotinib hydrochloride as the second‐line therapy were enrolled in the retrospective analysis. Additionally, we examined the exhaustion of T‐cells using mIHC staining in available tumor samples. Results Fifty‐five patients were included in this study. The median follow‐up period was 13.6 months. The objective response rate evaluated by the investigators was 9.1%(1CR, 4PR). The disease control rate was 47.3%. The median overall survival was 17.6 months, and the median progression‐free survival was 2.8 months. The adverse events rate of any grade was 100%. Grade 3 or 4 irAEs were observed in 29.1% of cases. Multiplex immunohistochemical staining revealed an increased trend of TIM3 expression on tumor‐infiltrating T cells in patients without objective response. Conclusion PD‐1 monoclonal antibody plus interferon‐alpha 1b plus anlotinib showed acceptable tolerability and anticancer benefits in Chinese metastatic melanoma patients as a second‐line therapy.