JCO oncology advances最新文献

Purpose: PD-L1 and PD-L2 are inhibitory ligands that interact with PD-1 receptors, enabling immune escape. Though PD-L1 has been extensively studied, much less is known about PD-L2. PD-L2 expression could lead to incomplete blockade of the PD-1 axis by anti-PD-L1 agents and also influence activity of anti-PD-1 agents.

Methods: We analyzed PD-L2 transcriptomic expression in a pan-cancer cohort (N=514; 489 patients with advanced/metastatic disease and clinical correlates available) for associations with immunomodulatory variables and outcome.

Results: The most common tumors were colorectal (27% [140/514]), pancreatic (11% [55/514]), and breast cancer (9.5% [49/514]). High PD-L2 expression (≥75^th RNA percentile rank) occurred in 19.5% (100/514) of patients; PD-L2 expression varied across and within tumor types. High PD-L2 independently/significantly correlated with high PD-L1, PD-1, CD4, and TIM-3 RNA levels (both as dichotomized and as linear variables), with high tumor mutational burden (TMB) (≥10 mutations/megabase), and with a breast cancer diagnosis. In 217 patients who received immune checkpoint blockade (mainly anti-PD-1-based regimens), high versus moderate/low PD-L2 predicted longer overall survival (OS) (but not progression-free survival) in univariate analysis (median 1.88 years (95% confidence interval [CI] 1.37-not estimable) versus 1.21 years (95% CI 0.95-1.54) (P = 0.02). In 272 patients who never received immunotherapy, high PD-L2 expression was not prognostic for OS.

Conclusions: High PD-L2 transcripts were more common in breast cancer and associated with high expression of other immune-relevant factors: PD-L1, PD-1, CD4, and TIM-3, and with TMB ≥10 mutations/megabase. High PD-L2 levels correlated with longer OS in immunotherapy-treated patients.

Trial registration: NCT02478931.

Purpose: Lack of race- and age-diversity in clinical trials adversely affects generalizability of trial results and equity of trial access. Research on barriers to representative accrual has focused on patient-level factors. We aimed to define site-level factors affecting the diversity of accrual to a multicenter clinical trial.

Methods: Alliance 191901 (GETSET) is a national randomized controlled trial testing interventions to promote breast cancer endocrine therapy adherence, which oversamples Black women and those under age 50 years at 30% thresholds. A secondary study objective is to examine site-level factors associated with accrual of Black and younger participants. At 50% accrual to the parent study, we performed prespecified analyses of association between site characteristics (region, neighborhood racial composition, Alliance membership type, number of recent accruals to cooperative research group trials) and the proportion of Black patients and younger patients accrued. We also examined trajectories of accrual over time for race- and age-specified subgroups.

Results: The analysis included 124 sites. Among 590 participants, 9.7% were Black, and 22.4% were age <50 years. Neither site type nor historical accrual volume was associated with Black participant recruitment. Southern sites recruited higher proportions of Black participants (19.0% v 7.3% for West, P < .001). Neighborhood racial composition was positively associated with recruitment of Black participants (16.2% at sites from highest Black composition v 1.4% in lowest, P < .01). Recruitment trajectories of Black participants were slower than target rates, whereas those among non-Black participants were faster.

Conclusion: Neighborhood composition and geographic region were predictors of proportions of Black participants accrued to A191901 sites, but site type and historical accrual volume were not. When trials must limit site selection, identifying sites based on neighborhood composition and geography may be an appropriate tool for increasing trial diversity.

Purpose: Cancer-associated thrombosis (CAT) is a significant cause of morbidity and mortality. Significant gaps exist in adherence to guidelines suggesting the use of primary thromboprophylaxis in high-risk patients with cancer. Our goal was to understand gaps in patients' awareness of CAT and thromboprophylaxis to better inform future outreach efforts within the framework of shared decision making between patients and providers.

Patients and methods: A bilingual (in English and Spanish) questionnaire was designed for individuals with a history of cancer or active cancer by a multidisciplinary expert group including patient advocates, pilot tested and electronically circulated through nonprofit patient advocacy groups for thrombosis and cancer in the United States. Survey domains included (1) risk factor awareness, (2) clinical presentation/diagnosis, (3) treatment, and (4) prevention. We received responses from 140 patients, 41% of whom were actively receiving cancer treatment.

Results: Patients demonstrated significant knowledge gaps with regard to CAT, with 61% of patients being unaware of the higher risk of thrombosis in cancer. Patients were open to receiving more information about CAT, including 80% who would like to receive more information from their clinician. A total of 71% of patients would consider the use of thromboprophylaxis if discussed with their provider; however, patients endorsed several concerns about its use including bleeding risk, polypharmacy, and medication interactions.

Conclusion: Our study demonstrated that there remain significant knowledge gaps regarding CAT and thromboprophylaxis in American patients with cancer. Clinicians remain a trusted source of information about clotting, and a majority of patients are willing to consider thromboprophylaxis if discussed with their provider. Patient education will be an important aspect of increasing adherence to thromboprophylaxis guidelines in high-risk patients with cancer.

Background: There are limited data on response and survival outcomes for patients who receive the combination of anti-PD-1 and anti-CLTA-4 after prior failure of an anti-PD-1/L1, in particular among patients with less common cancers. We analyzed a unique trial resource, an NCI-sponsored basket trial for participants with rare solid tumors conducted by SWOG that was open at over 1,000 sites across the USA (S1609/DART). Participants received Ipilimumab (1mg/kg every six weeks) plus nivolumab (240 mg every two weeks) (both intravenously). The trial eligibility allowed prior exposure to anti-PD-1/L1, and our objective was to compare response and survival outcomes for patients with and without prior anti-PD-1/PDL-1.

Methods: Logistic and Cox regression models were used to evaluate associations between prior anti-PD-1/PDL-1 exposure and the endpoints of clinical benefit rate (CBR) (includes stable disease of at least six months and objective response by RECISTv1.1), progression-free survival (PFS), and overall survival (OS).

Results: CBR was not significantly different between those with and without prior anti-PD-1/L1 exposure, 26% in both groups. There were no significant differences in PFS and OS between patients with and without prior anti-PD-1/L1 exposure on either univariate and multivariable analysis (multivariable hazard ratio, 95% confidence interval and p-value: PFS: 1.18, 0.83-1.68, p=0.36; OS: 1.11, 0.76-1.63, p=0.58).

Conclusions: There were no statistically or clinically significant differences in outcomes with and without prior anti-PD-1/L1 exposure for patients with a variety of rare cancers treated with nivolumab and ipilimumab. Patients with prior anti-PD-1/L1 exposure should be eligible for clinical trials evaluating combination immunotherapy.

Purpose: Impaired homologous recombination-mediated DNA repair is common in head and neck squamous cell carcinoma (HNSCC) and in preclinical models and sensitizes HNSCC to poly (ADP-ribose) polymerase (PARP) inhibitors and platinum therapy. PARP inhibitors and anti-PD-1 antibodies have synergistic antitumor activity. The primary hypothesis of this phase II trial was that olaparib, a PARP inhibitor, given with pembrolizumab and carboplatin as first-line treatment for biomarker-unselected recurrent or metastatic (RM)-HNSCC, would result in a higher objective response rate (ORR) than that historically reported with fluorouracil, pembrolizumab, and platinum therapy.

Methods: Patients received up to six 21-day cycles of olaparib (200 mg twice daily orally on days 1-10), pembrolizumab, and carboplatin followed by 29 cycles of olaparib (300 mg twice a day on days 1-21) and pembrolizumab. The primary end point was independent radiologist-assessed confirmed objective response per RECIST v1.1. A Simon optimal two-stage design tested the null (H₀: ORR ≤36%) versus the alternative hypothesis (ORR ≥62%) at a type I error rate of 10% and a power of 90%. H₀ would be rejected if ≥14 responses occurred among 29 patients. Secondary end points included duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

Results: Between July 08, 2021, and October 11, 2023, 30 patients were enrolled. Among the 29 evaluable patients, the ORR was 51.7% (90% CI, 35.2 to 68.0; v H₀, one-sided P = .04). The median DoR was 14.1 months (IQR, 6.8 to 21.2), and the median PFS and OS were 7.8 (95% CI, 4.1 to 15.4) and 24.5 months (95% CI, 8.8 to 25.3), respectively. The most common study drug-related grade 3 to 4 adverse events included neutropenia (50%) and anemia (23%). Febrile neutropenia and treatment-related deaths did not occur.

Conclusion: Olaparib, pembrolizumab, and carboplatin given as first-line treatment of RM-HNSCC resulted in a higher ORR than that historically reported with fluorouracil, pembrolizumab, and platinum therapy.

Purpose: The vast majority of cervical cancer is preventable through human papillomavirus vaccination and screening with cytology or DNA testing. After decades of progress, recent cervical cancer trends in Western populations show a plateau or modest increase in incidence rates. Further investigation is required to understand the drivers of these emerging trends. In this study, we examined age-specific cervical cancer incidence rates in Canada from 1992 to 2022.

Methods: Data were obtained from the Canadian Cancer Registry maintained by Statistics Canada, which included cancer cases, population counts, and incidence rates of cervical cancer by age and province for the period 1992 to 2022. Joinpoint regression analysis was used to estimate temporal incidence trends across age groups.

Results: Cervical cancer incidence rates in Canada decreased among women age 25-34 years and those 65 years and older since 1992. Incidence rates among women age 35-44 years and 45-54 years have increased by 1.1% (95% CI, 0.5 to 2.5) and 1.6% (95% CI, -0.1 to 8.6) per year since 2001 and 2012, respectively. In 2022, the highest incidence rate of cervical cancer was among women age 35-44 years (18.1 per 100,000 women), which is comparable with rates in 1992.

Conclusion: Cervical cancer incidence rates have been increasing in recent years among women age 35-54 years. This cohort may be falling into a cancer prevention gap. Targeted public health interventions are warranted to address the rising incidence of cervical cancer among this cohort of Canadian women.

Purpose: Intralesional vinblastine can induce regression of Kaposi sarcoma (KS), but it is often painful. We conducted a phase I trial to evaluate the safety and tolerability of intralesional injections of nivolumab to treat cutaneous KS.

Patients and methods: We enrolled participants with limited cutaneous KS and injected 1 mL (10 mg) of nivolumab into target KS lesions once every 2 weeks for four doses, with optional extension to total of eight doses. Skin biopsy of a target KS lesion was performed at screening and at week 26. The primary end point was safety; the secondary end point was KS response by AIDS Clinical Trials Group criteria.

Results: Between May 2018 and December 2020, 12 cis-gender men (six living with HIV and six without HIV) were enrolled. Baseline median CD4⁺ T-cell count was 550 and 706 cells/uL for those with and without HIV, respectively. No grade 3 or higher treatment-related adverse events (including autoimmune events) were reported. Three participants without HIV had complete resolution of the injected lesion(s). All participants had a reduction of HHV-8-positive cells in their skin biopsies at week 26. Four participants had a relative increase in the infiltrating CD8⁺ T cells in skin biopsies after treatment. PD-1 and PD-L1 by immunohistochemistry did not change between the pre- and post-treatment skin biopsies. The percentage of circulating CD4⁺ and CD8⁺ T cells expressing PD-1 decreased from 23.8% to 19.2% before treatment to 10.9% and 9.4% before the third intralesional nivolumab injection, respectively. The frequency of PD-1 expressing lymphocytes returned to baseline level at 26 weeks after the last injection.

Conclusion: Intralesional nivolumab was safe and well-tolerated in this population of men with limited cutaneous KS.

Purpose: The onset of the COVID-19 pandemic in early 2020 disrupted the conduct of cancer clinical trials. In response, federal agencies allowed more flexibility for trial recruitment and patient follow-up. A key question is whether the benefits of adopting these strategies outweigh the potential detriments to quality metrics.

Methods: A joint ASCO and Friends of Cancer Research task force invited industry and National Cancer Institute trial sponsors to contribute deidentified trial-level aggregate data on enrollment, major protocol deviations, dropouts, and severe adverse events (Common Terminology Criteria for Adverse Events grade 3-5). These quality metrics were examined as proportions of participants at risk during the pre-COVID-19 (January 2017-February, 2020), initial wave (March-April, 2020), initial recovery (May-December, 2020), and secondary recovery (January 2021-December 2022) periods. Multilevel beta-regression was used, adjusting for phase; study and sponsor were treated as random effects. Indicator variables were used with pre-COVID-19 as the reference.

Results: Ten sponsors contributed 67 analyzable trials with N = 12,000 US-based participants. Enrollment odds decreased 49% in the initial wave (odds ratio [OR], 0.51 [95% CI, 0.30 to 0.86], P = .01) but recovered to pre-COVID-19 levels by 2021-2022 (OR, 1.01 [95% CI, 0.56 to 1.81], P = .97). Major protocol deviations, dropouts, and severe toxicity all had a lower incidence in the initial wave compared with pre-COVID-19; these outcomes were also less frequent (P < .05) in the initial recovery period but returned to pre-COVID-19 levels by 2021-2022.

Conclusion: In this multicollaborator evaluation, large declines in enrollment, major protocol deviations, dropouts, and severe toxicity during the acute phase of the pandemic all returned to pre-COVID-19 levels by 2021-2022. These findings highlight the impact of the temporary disruption to trial conduct during the pandemic's peak, but suggest that pandemic-related procedural flexibility did not result in long-term reduced data quality. Sponsors and regulators should consider broader adaptation of trial flexibilities moving forward.

Purpose: NRG-RTOG 1203 reported that intensity-modulated radiation therapy (IMRT) reduced patient-reported GI toxicities in patients with cervical/endometrial cancer receiving postoperative RT, compared with 3-dimensional conformal radiation therapy (3DRT). We conducted a secondary analysis of patient-reported sexual function (PR-SF) among treatment groups to identify factors associated with sexual dysfunction.

Methods and materials: Patients on NRG-RTOG 1203 were randomly assigned to 3DRT versus IMRT and completed Patient-Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) and FACT-Cx surveys at baseline, week 5 of RT, and at 4-6 weeks, 1 year, and 3 years after RT. Patient responses to FACT-Cx sexual function questions were analyzed. The between-arm frequency and severity of responses and their comparison with PRO-CTCAE GI toxicity were tested using chi-square tests. A repeated-measures logistic regression model was used to determine the impact of clinical and treatment factors on PR-SF.

Results: Two hundred thirty-six patients completed PR-SF questions; 125 (53%) received 3DRT and 111 (47%) IMRT. There were no significant differences in PR-SF between groups (P > .05). After RT, responses to "I am afraid to have sex" and "I am interested in sex" significantly improved over time (P = .007 and P = .03, respectively). At 1 year after RT, women with interference from abdominal pain were more bothered by odor from the vagina versus women with no interference of abdominal pain (5% v 0%, P = .006). Additionally, at 1 year after RT, women with no severity of abdominal pain or no interference from abdominal pain liked their body appearance more versus women with at least some abdominal pain or some interference from abdominal pain (34% v 13%, P = .003 and 32% v 6%, P = .001, respectively).

Conclusion: PR-SF was similar between treatment groups. After RT, fear of sex declined and interest in sex improved over time. Women with GI toxicity after RT completion are at risk for worse sexual function.