Targeted Oncology最新文献

Background: Adavosertib (AZD1775) is a small-molecule Wee1 inhibitor. Durvalumab is a PD-L1 inhibitor.

Objective: The safety, tolerability, pharmacokinetics, and preliminary antitumor activity of adavosertib plus durvalumab were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).

Patients and methods: This phase 1, non-randomized, open-label study determined MTD/RP2D using dose-escalation cohorts. Eligible patients had histologically confirmed tumors refractory to standard therapy or for which no standard of care existed.

Results: A total of 55 patients received adavosertib with durvalumab. Overall, 3/52 evaluable patients experienced dose-limiting toxicities (DLTs; two grade 3 nausea, one grade 3 diarrhea that did not respond to care within 48 h). The most frequent (in > 5% of patients) treatment-emergent grade ≥ 3 toxicities were fatigue, diarrhea, nausea, anemia, and abdominal pain. MTD for twice-daily (bid) adavosertib dosing was oral adavosertib 150 mg bid (3 days on/4 days off; treatment days 15-17 and 22-24 of a 28-day cycle) with intravenous durvalumab 1500 mg four times a week (Q4W), which was also the RP2D. MTD for once-daily (qd) adavosertib dosing was oral adavosertib 300 mg qd (5 days on/2 days off; treatment days 15-19 and 22-26 of a 28-day cycle) with intravenous durvalumab 1500 mg Q4W.

Conclusions: This study defined the MTD/RP2D of adavosertib plus durvalumab in patients with advanced solid tumors. The safety profile of adavosertib with durvalumab was consistent with the known safety data of each agent. Findings provide preliminary evidence of limited antitumor activity of adavosertib plus durvalumab.

Trial registration: ClinicalTrials.gov, NCT02617277 (registration: 30 November 2015).

Chondrosarcomas, a rare form of bone sarcomas with multiple subtypes, pose a pressing clinical challenge for patients with advanced or metastatic disease. The lack of US Food and Drug Administration (FDA)-approved medications underscores the urgent need for further research and development in this area. Patients and their families face challenges as there are no systemic therapeutic options available with substantial effectiveness. A significant number (50-80%) of chondrosarcomas have a mutation in the isocitrate dehydrogenase (IDH) genes. This review focuses on IDH-mediated pathogenesis and recent pharmacological advances with novel IDH inhibitors, explores their potential therapeutic value, and proposes potential future avenues for clinical trials combining IDH inhibitors with other systemic agents for chondrosarcomas.

Context: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens.

Objective: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials.

Evidence acquisition: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features.

Evidence synthesis: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival.

Conclusions: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.

Background: Patients with high-risk localized and locally advanced prostate cancer (HR-LPC/LAPC) have increased risk of metastasis, leading to reduced survival rates. Segmenting the disease course [time to recurrence, recurrence to metastasis, and post-metastasis survival (PMS)] may identify disease states for which the greatest impacts can be made to ultimately improve survival.

Objective: Evaluate real-world PMS of patients with HR-LPC/LAPC who received primary radical prostatectomy (RP) or radiotherapy (RT) with or without androgen deprivation therapy (ADT).

Patients and methods: Electronic health records from an oncology database were used to assess PMS. Risk of death was estimated using the Kaplan-Meier method. Hazard ratios (HRs) were used to analyze the impact of treatment and time to metastasis (TTM) on PMS. Standardized mortality ratios (SMRs) were calculated for patients with HR-LPC/LAPC versus the US general male population.

Results: Overall, 5008 patients with HR-LPC/LAPC were identified, and 1231 developed metastases after primary treatment (RP, n = 885; RT only, n = 262; RT+ADT, n = 84). Age-adjusted PMS HR between the RP and RT only cohorts was 1.19 (p = 0.077) and between RP and RT+ADT cohorts was 1.32 (p = 0.078). TTM was unrelated to PMS in unadjusted (HR 1.01, p = 0.2) and age-adjusted models (HR 0.99, p = 0.3). Relative to pre-metastasis SMRs, post-metastasis SMRs increased eightfold and fivefold in patients treated with RP and RT±ADT, respectively.

Conclusions: PMS was unrelated to TTM in patients with HR-LPC/LAPC, suggesting PMS may be independent of the trajectory to development of metastases. Given PMS may be a fixed length of time, delaying the development of metastasis may improve survival in patients with HR-LPC/LAPC.

Background: Immune checkpoint inhibitor (ICI) Kaplan-Meier (KM) curves often show delayed survival benefit followed by long-term survival in a subgroup of patients. Such outcomes can violate the proportional hazards assumption, leading to a loss of statistical power.

Objective: We aimed to determine common trends in delayed separation to inform future ICI clinical trials.

Patients and methods: A literature search was performed using Trialtrove^® to identify phase III trials of antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) agents in locally advanced/metastatic solid tumors published between January 2010 and September 2021. The frequency of delayed separation of overall survival (OS) and progression-free survival (PFS) KM curves, correlation between duration of delayed separation in OS/PFS KM curves, and correlation between duration of delayed separation in OS/PFS KM curves with corresponding hazard ratios (HRs) were assessed in all-comer and PD-L1 enriched populations.

Results: Eighty-five studies with OS/PFS KM curves were identified. Most studies showed delayed separation of OS (> 67.9%) and PFS (> 54.5%) KM curves. The correlation between the duration of delayed separation in OS/PFS KM curves was strongest in the PD-L1 enriched population (adjusted R² = 0.66). No correlation was seen between the duration of delayed separation of OS KM curves and OS HR. A modest correlation was seen between the duration of delayed separation of PFS KM curves and PFS HR in all-comer and PD-L1 enriched populations (adjusted R² = 0.24 and 0.31, respectively).

Conclusions: Delayed separation of KM curves was common in clinical trials of anti-PD-(L)1 agents. Understanding delayed separation is key to clinical study designs and assessing outcomes with ICIs.

Background: Although durvalumab has shown promise in improving survival rates in patients with locally advanced non-small cell lung cancer (NSCLC), the ideal duration of treatment has yet to be established.

Objective: The primary objective of this study was to determine the optimal number of durvalumab cycles following definitive chemoradiotherapy for locally advanced NSCLC.

Patients and methods: A total of 178 patients who received chemoradiotherapy for stage III NSCLC at 15 institutions were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were assessed according to the number of consolidation durvalumab cycles by landmark analysis. Landmark analyses were performed at 3-month intervals from the start of durvalumab treatment to 9 months.

Results: The median number of durvalumab cycles was 16 (range 1-27). PFS and OS were significantly better in patients who received ≥20 cycles of durvalumab than in those who did not (p < 0.001 and p < 0.001, respectively). In landmark analysis, significant differences were observed in PFS from 0 to 6 months and OS from 3 to 6 months between patients who continued durvalumab after the time point and those who did not. However, there were no significant differences in PFS or OS between patients who received 13-19 or ≥20 cycles of durvalumab at 9 months.

Conclusions: Durvalumab should be administered for more than 6 months to contribute to the main benefits of consolidation therapy following chemoradiotherapy.

Background: Concurrent chemoradiotherapy (cCRT) followed by 1 year of the immune checkpoint inhibitor (ICI) durvalumab is standard of care for patients with unresectable stage III nonsmall cell lung cancer (NSCLC).

Objectives: The purpose of this study was to evaluate survival outcomes of (1) cCRT followed by durvalumab in patients older versus younger than 75 years of age and (2) post-progression treatment with ICI alone versus chemotherapy alone versus combined ICI and chemotherapy.

Patients and methods: Patients with unresectable stage III NSCLC treated between January 2018 and July 2023 with cCRT followed by durvalumab were identified retrospectively. Progression-free survival (PFS) and overall survival (OS) from ICI start were analyzed in three cohorts aged < 65, 65-74, and ≥ 75 years. Multivariable Cox proportional hazard regression modelling of factors associated with OS was undertaken. Logistic regression analysis identified risk factors of early durvalumab discontinuation for toxicity. Time from first salvage drug treatment to death (OS-2) was described.

Results: A total of 472 patients were analyzed: the proportions aged < 65, 65-74, and ≥ 75 years were 34.3%, 42.8%, and 22.9%, respectively. Odds of early durvalumab discontinuation was 2.2-fold greater in the oldest (versus youngest) cohort. Age associated differences in median PFS (26.7 months, 20.3 months, and 14.2 months; p < 0.001) and OS (60.8 months, 44.4 months, and 27.6 months; p < 0.001) were observed. On multivariable analysis, factors associated with shorter OS were age ≥ 75 years (versus < 65), performance status 2/3 (versus 0/1), stage IIIC (versus IIIA), neutrophil to lymphocyte ratio (per 7.43 unit increase), Charlson comorbidity index (per 1 unit increase), tumoral PD-L1 expression < 1% (versus ≥ 50%, 1-49%, or unknown), and squamous histology (versus non-squamous). Of 264 patients with disease progression, 48.5% received subsequent drug therapy. Median OS-2 was longer with ICI alone (9.9 months) or ICI-chemotherapy (11.8 months) than platinum doublet chemotherapy (6.7 months.) For recurrences < 6 months from the last durvalumab infusion, OS-2 were similar across treatment groups.

Conclusions: In the studied cohort, OS was significantly shorter for patients ≥ 75 years of age treated with cCRT followed by durvalumab compared to those < 65 years. Post-progression systemic therapy was associated with modest efficacy, underscoring the need for new therapies.

Background: Osimertinib shows higher effectiveness than first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in the initial treatment of EGFR-mutated non-small cell lung cancer. However, its superiority in terms of overall survival in the Asian population, especially Japanese patients, remains uncertain.

Objective: To evaluate the survival benefit of osimertinib over other EGFR-TKIs in Japanese patients, using real-world data. METHODS : As part of the Tokushukai REAl-world Data project, a retrospective multi-institutional study across 46 hospitals in Japan was conducted to evaluate the overall survival of patients with advanced EGFR-mutated non-small cell lung cancer using propensity score matching. The study involved patients receiving osimertinib as the first-line treatment (1L-Osi), those initially treated with other EGFR-TKIs (1L-non-Osi), and those receiving osimertinib after initial EGFR-TKI treatment (2L/later-Osi) between April 2010 and December 2022 and followed up until April 2023.

Results: Among 1062 Japanese patients with EGFR-mutated non-small cell lung cancer, 416 (39.2%) received 1L-Osi, while 646 (60.8%) received 1L-non-Osi, including 139 (13.1%) who received 2L/later-Osi. Within these groups, 416 (39.2%), 293 (27.6%), and 75 (7.1%) patients received first-line EGFR-TKI treatment post-osimertinib approval as a later-line treatment in Japan (March 2016). After propensity score matching, the overall survival of the 1L-Osi group was comparable to that of the 1L-non-Osi group in the post-March 2016 subset (n = 283, 42.0 vs 42.4 months). Similar trends were observed in the Del19 and L858R subgroups. The median overall survival of the 2L/later-Osi group was notably long: 60.2 months post-March 2016 (n = 75). A subgroup analysis based on initial EGFR-TKI treatment in the 1L-non-Osi and 2L/later-Osi groups revealed no significant differences among the gefitinib, erlotinib, and afatinib groups.

Conclusions: Based on real-world data, osimertinib did not show a significant improvement in overall survival compared to other EGFR-TKIs as a first-line treatment for EGFR-mutated advanced non-small cell lung cancer in the Japanese (Asian) population.

Clinical trial registration: This study was registered at the University Hospital Medical Information Network Clinical Trials Registry on 9 March, 2023 (identification UMIN000050552).

Background: Tumors harboring two or more PIK3CA short variant (SV) ("multi-hit") mutations have been linked to improved outcomes with anti-PIK3CA-targeted therapies in breast cancer. The landscape and clinical implications of multi-hit PIK3CA alterations in clinically advanced prostate cancer (CAPC) remains elusive.

Objective: To evaluate the genomic landscape of single-hit and multi-hit PIK3CA genomic alterations in CAPC.

Patients and methods: The Foundation Medicine FoundationCore database was used to identify 19,978 CAPC tumors that underwent hybrid capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA) and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, single-base substitution mutational signatures, and homologous recombination deficiency signature (HRDsig). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3).

Results: 18,741 (93.8%) tumors were PIK3CA wild type (WT), 1155 (5.8%) featured single PIK3CA SV, and 82 (0.4%) featured multi-hit PIK3CA SVs. Single-hit (6.6 versus 3.8; p < 0.0001) and multi-hit (12.8 versus 3.8; p < 0.0001) featured more driver GA per tumor than PIK3CA WT CAPC, as well as higher prevalence of MMR mutational signature, MSI high status, and TMB levels versus PIK3CA WT (p < 0.0001). Other differences in GA included higher frequencies of GA in BRCA2 in multi-hit versus WT (18.3% versus 8.5%; p = 0.0191), ATM in multi-hit versus WT (13.4% versus 5.6%; p = 0.02) and PTEN in single-hit versus WT (40.2% versus 30.1%; p < 0.0001). Homologous recombination deficiency signatures were higher in PIK3CA WT versus single-hit (11.2% versus 7.6%; p = 0.0002). There were no significant differences in PD-L1 expression among the three groups.

Conclusions: Identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique phenotype that may be associated with response to anti-PIK3CA targeted therapy and checkpoint inhibition, supporting relevant clinical trial designs.

For the past two decades, cisplatin-based adjuvant chemoradiotherapy (CRT) has remained the standard of care for patients with resected, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) who are at high risk of disease recurrence. However, many patients are deemed ineligible for cisplatin-based CRT because of poor performance status, advanced age, poor renal function, or hearing loss. Outcomes with radiotherapy alone remain poor, so patients at high risk of disease recurrence who are ineligible to receive cisplatin represent a population with a significant unmet medical need. Although clinical guidelines and consensus documents have provided definitions for cisplatin ineligibility, there are still areas of debate, including thresholds for age and renal impairment as well as criteria for hearing loss. Treatment selection for patients with resected, high-risk LA SCCHN who are deemed ineligible to receive cisplatin is often based on clinical judgment, as treatment options are not clearly specified in international guidelines. Therefore, there is an urgent need to develop alternative systemic treatments to be used in combination with radiotherapy. In this podcast, we share our clinical experience and provide our perspectives related to cisplatin ineligibility in patients with LA SCCHN, discuss the limited clinical evidence for adjuvant treatment of patients with resected, high-risk disease, and highlight ongoing clinical trials that have the potential to provide new treatment options in this setting.