IO102-IO103 immune-modulatory cancer vaccine and pembrolizumab in melanoma.

Differential expression of PD-L1 and IDO1 in association with the immune microenvironment in resected lung adenocarcinomas

9503 Background: Immune checkpoint inhibitor therapy has revolutionized the treatment of patients with advanced melanoma. However, novel combinations are needed to optimize the benefit-risk profile. Lymphocyte-activation gene 3 (LAG-3) regulates an immune checkpoint pathway, which inhibits T-cell activity, and is upregulated in many tumor types including melanoma. Relatlimab (RELA), a human IgG4 LAG-3-blocking antibody, restores effector function of exhausted T cells. RELA in combination with nivolumab (NIVO; anti-programmed death [PD]-1) modulates potentially synergistic immune checkpoint pathways and can enhance antitumor immune responses. RELATIVITY-047 is a global, randomized, double-blind, phase II/III study evaluating a novel immune checkpoint inhibitor combination of RELA+NIVO as a fixed-dose combination (FDC) treatment in first-line advanced melanoma. Methods: Patients with previously untreated advanced melanoma were randomized 1:1 to receive RELA 160 mg + NIVO 480 mg FDC intravenously (IV) every 4 weeks (Q4W) or NIVO monotherapy 480 mg IV Q4W, stratified by LAG-3 expression, programmed death ligand 1 expression, BRAF mutation status, and AJCC (v8) M stage. The primary endpoint was progression-free survival (PFS) per RECIST v1.1 as assessed by blinded independent central review. Secondary endpoints were overall survival and objective response rate. PFS in prespecified subgroups and safety were additional objectives. Results: 714 patients were randomized to RELA+NIVO FDC (n = 355) or NIVO (n = 359). Patient characteristics were well balanced between treatment groups. Median follow-up was 13.2 months. Median PFS in the RELA+NIVO FDC group (10.1 months [95% CI, 6.4–15.7]) was significantly longer than in the NIVO group (4.6 months [95% CI, 3.4–5.6]; hazard ratio, 0.75 [95% CI, 0.6–0.9]; P = 0.0055). PFS rates at 12 months were 47.7% (95% CI, 41.8–53.2) and 36.0% (95% CI, 30.5–41.6) for RELA+NIVO FDC and NIVO, respectively. PFS favored RELA+NIVO FDC across key prespecified subgroups. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was higher in the RELA+NIVO FDC group (18.9%) versus NIVO (9.7%). There were 3 treatment-related deaths with RELA+NIVO FDC and 2 with NIVO. TRAEs (any grade) led to treatment discontinuation in 14.6% and 6.7% of patients in the RELA+NIVO FDC and NIVO groups, respectively. Conclusions: First-line treatment with RELA+NIVO FDC demonstrated a statistically significant PFS benefit compared to NIVO monotherapy in patients with advanced melanoma. RELA+NIVO FDC was well tolerated with a manageable safety profile and without unexpected safety signals. This is the first phase III study of a novel FDC to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways. Clinical trial information: NCT03470922.

8551 Background: Similar to programed death ligand 1 (PD-L1), indoleamine 2,3-Dioxygenase 1 (IDO1) is known to exert immunosuppressive effects and be variably expressed in human lung cancer. However, IDO1 expression has not been well-studied in lung adenocarcinoma (ADC). Methods: PD-L1 and IDO1 expression were evaluated in 261 resected ADC using tissue microarrays and H-scores (cutoff 5). We compared IDO1 with PD-L1 expression in association with clinical features, tumor-infiltrating lymphocytes (TILs), HLA class I (β-2 microglobulin; B2M) expression, molecular alterations, and patient outcomes. Results: There was expression of PD-L1 in 89 (34.1%) and IDO1 in 74 (28.5%) cases, with co-expression in 49 (18.8%). Both PD-L1 and IDO1 were significantly associated with smoking, aggressive pathologic features, and abundant CD8+ and T-bet+ (Th1 marker) TILs. PD-L1 expression and abundant CD8+ were inversely associated with a loss of B2M membranous expression (p = 0.0019 and p < 0.001, respectively). Compared to PD-L1+/IDO1+ and PD-L1+ only cases, significantly fewer IDO1+ only cases had abundant CD8+ and T-bet+ TILs (p < 0.001, respectively). PD-L1 expression was significantly associated with EGFR wild-type (p < 0.001) and KRAS mutants (p = 0.021), whereas there was no difference in IDO1 expression between different molecular alterations. As for survival, PD-L1 was significantly associated with decreased progression-free (PFS) and overall survival (OS), while IDO1 was associated only with decreased OS. Interestingly, there was a significant difference in the 5-year PFS and OS (p = 0.004 and 0.038, respectively), where cases without PD-L1 or IDO1 expression had the longest survival, and those with PD-L1 alone had the shortest survival. Conclusions: While PD-L1 +/- IDO1 expression is observed in association with B2M expression, CTL/Th1 microenvironments, EGFR wild-type, and KRAS mutations, isolated IDO1 expression does not demonstrate these associations, suggesting that IDO1 may serve a distinct immunosuppressive role in ADC. Thus, blockade of IDO1 may represent an alternative and/or complementary therapeutic strategy to reactivate anti-tumor immunity.

BackgroundThe phase 2/3 RELATIVITY-047 clinical trial (NCT03470922) in patients with previously untreated metastatic or unresectable melanoma met its primary endpoint of improved progression-free survival with a combination of nivolumab plus...

Background: Rucaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved in the United States for treatment of women with deleterious BRCA mutation (germline and/or somatic) associated advanced OC who have been treated with two or more chemotherapies. Rucaparib has also demonstrated antitumor activity in the treatment setting in patients (pts) with BRCA wild-type associated recurrent OC whose tumor has high genomic loss of heterozygosity (LOH). ARIEL3 evaluated rucaparib vs placebo as maintenance treatment in pts with recurrent platinum-sensitive OC. Methods: Eligible pts received ≥2 prior platinum-based therapies, had platinum-sensitive OC (disease progression ≥6 mo after penultimate platinum), and achieved a complete response (RECIST v1.1) or partial response (RECIST v1.1 or Gynecologic Cancer InterGroup CA-125 criteria) to their most recent platinum. All pts were required to have CA-125 less than the upper limit of normal. Pts were randomized 2:1 to receive oral rucaparib 600 mg BID or placebo. Investigator-assessed progression-free survival (PFS) (primary endpoint) was assessed in a step-down procedure for 3 nested cohorts: (1) BRCA mutant (deleterious germline or somatic BRCA mutation); (2) homologous recombination deficient (HRD) (BRCA mutant or BRCA wild type/LOH high); and (3) intent-to-treat (ITT) population. PFS was also assessed by blinded independent central review (BICR) (secondary endpoint) and LOH status in pts with BRCA wild type OC (exploratory endpoint). Adverse events (AEs) were summarized descriptively. Results: ARIEL3 enrolled 564 pts (375, rucaparib; 189, placebo). Nearly 200 pts (n=196) had BRCA mutation-associated OC. Of these pts, 130 had a germline BRCA mutation (82 [21.9%], rucaparib; 48 [25.4%], placebo), 56 had a somatic BRCA mutation (40 [10.7%], rucaparib; 16 [8.5%], placebo), and 10 pts had tumors with germline and/or somatic BRCA status unknown (8 [2.1%], rucaparib; 2 [1.1%], placebo). Median investigator-assessed PFS in the BRCA-mutant cohort (130, rucaparib; 66 placebo) was 16.6 mo vs 5.4 mo (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.16-0.34; P<0.0001). In the HRD cohort (236, rucaparib; 118, placebo), median PFS was 13.6 mo vs 5.4 mo (HR, 0.32; 95% CI, 0.24-0.42; P<0.0001), and in the ITT population, median PFS was 10.8 mo vs 5.4 mo (HR, 0.37; 95% CI, 0.30-0.45; P<0.0001). Median PFS by BICR in the BRCA-mutant cohort was 26.8 mo vs 5.4 mo (HR, 0.20; 95% CI, 0.13-0.32; p<0.0001). In the HRD cohort, median PFS by BICR was 22.9 mo vs 5.5 mo (HR, 0.34; 95% CI, 0.24-0.47; p<0.0001), and in the ITT population, median PFS by BICR was 13.7 mo vs 5.4 mo (HR, 0.35; 95% CI, 0.28-0.45; p<0.0001). In the safety population (372, rucaparib; 189, placebo), the most common treatment-emergent AEs (≥35% of pts in either arm) included nausea (75.3% and 36.5%), asthenia/fatigue (69.4% and 43.9%), dysgeusia (39.2% and 6.9%), anemia (37.4% and 5.8%), constipation (36.6% and 23.8%), and vomiting (36.6% and 14.8%). The most common grade 3 or higher treatment-emergent AEs were anemia (18.8% and 0.5%) and alanine/aspartate aminotransferase increase (10.5% and 0%). At the visit cutoff date (15 April 2017), 13.4% and 1.6% of pts discontinued maintenance treatment due to treatment-emergent AEs (excluding disease progression), and 1.6% and 1.1% of pts died due to treatment-emergent AEs (including disease progression). Conclusion: Rucaparib significantly improved PFS vs placebo in pts with platinum-sensitive, recurrent OC in all primary analysis groups of pts with platinum-sensitive, recurrent OC. Additionally, rucaparib significantly improved PFS vs placebo in pts with BRCA wild-type OC (LOH high and LOH low). Clinical trial identification: NCT01968213. This abstract is also being presented as Poster A47. Citation Format: Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Johanne I. Weberpals, Andrew Clamp, Giovanni Scambia, Alexandra Leary, Robert W. Holloway, David M. O’Malley, Terri Cameron, Lara Maloney, Sandra Goble, Kevin Lin, James Sun, Heidi Giordano, Jonathan A. Ledermann. ARIEL3: A phase 3, randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian cancer (OC). [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR06.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

PURPOSENivolumab and relatlimab activity in advanced melanoma with prior progression on anti–programmed death-1/programmed death ligand 1 (PD-(L)1)-containing regimens is under investigation. RELATIVITY-047 demonstrated significantly improved progression-free survival (PFS) for nivolumab and relatlimab over nivolumab in previously untreated advanced melanoma.METHODSThe phase I/IIa, open-label RELATIVITY-020 trial part D assessed efficacy and safety of nivolumab and relatlimab in advanced melanoma with progression during, or within 3 months of, 1 (D1) or ≥ 1 (D2) anti–PD-(L)1-containing regimens. Safety was a primary end point. Objective response rate (coprimary end point) and PFS by blinded independent central review (BICR) were assessed.RESULTSFive hundred eighteen patients (D1 = 354; D2 = 164) received nivolumab and relatlimab. Among evaluable patients, the objective response rate by BICR was 12.0% (95% CI, 8.8 to 15.8) in D1 (n = 351) and 9.2% (95% CI, 5.2 to 14.7) in D2 (n = 163). Responses appeared to be enriched among patients with tumors expressing programmed death ligand 1 or lymphocyte activation gene 3; however, responses were observed regardless of programmed death ligand 1 and lymphocyte activation gene 3 expression (1%). The median duration of response was not reached (95% CI, 12.9 to not reached) in D1 and 12.8 months (95% CI, 6.9 to 12.9) in D2. The median PFS by BICR was 2.1 months (95% CI, 1.9 to 3.5) in D1 and 3.2 months (95% CI, 1.9 to 3.6) in D2; the 6-month PFS rate was 29.1% (95% CI, 24.2 to 34.1) and 27.7% (95% CI, 20.5 to 35.4), respectively. The grade 3-4 treatment-related adverse event incidence was 15.0% in D1 and 12.8% in D2. One case of grade 3 myocarditis and no treatment-related deaths occurred across part D.CONCLUSIONNivolumab and relatlimab had a manageable safety profile and demonstrated durable clinical activity in a proportion of patients with heavily pretreated advanced melanoma with prior progression on anti–PD-(L)1-containing regimens.

Although Nivolumab is one of the immune-checkpoint inhibitors that improves the prognosis of lung cancer, it is known to cause immune-related adverse events (irAEs). It has recently been reported that patients with irAEs have a longer progression-free survival (PFS) than those without irAEs. However, there are few detailed reports on irAEs in patients with NSCLC. We previously reported the association between single nucleotide polymorphisms (SNPs) of programmed death ligand 1 (PD-L1) and PFS for nivolumab treatment. Therefore, we hypothesized that the SNPs of programed death 1 (PD-1) and PD-L1 were associated with irAEs and PFS. Between January 2016 and March 2017, 95 consecutive patients with advanced NSCLC were treated with nivolumab and 80 of these patients participated in this study. Patients who did not provide informed consent, patients without follow-up blood tests, patients with double cancer history, and patients diagnosed with disease progression within 15 days were excluded. The prevalence of genotypes between patients with adverse events and those without adverse events was evaluated. PFS was calculated in 59 out of 80 patients excluding liver metastasis at baseline imaging. The response rate was 15% and the median PFS was 85 days in this cohort. For all adverse events, hypothyroidism, which is defined as a low free T4 level, was associated with SNPs of PD-L1: rs1411262 and rs822339. Moreover, patients with hypothyroidism had a significantly longer PFS than those without hypothyroidism (67 days vs N.R.; P= 0.0055). The T/T genotype of rs1411262 and the A/A genotype of rs822339 were significantly associated with longer PFS than the C/T and C/C genotypes of rs1411262, and the A/G and G/G genotypes of rs822339, respectively (82 versus 175 days; P = 0.0468). In conclusion, the T allele of rs1411262 and the A allele of rs822339 were significantly associated with hypothyroidism and longer PFS. SNPs of PD-L1 may be associated with functions of the PD-1 and PD-L1 pathway. Hypothyroidism and SNPs of PD-L1hypothyroidism (-)hypothyroidism (+)P value(n=7)(n=73)rs14112620190.0386CC336CT418TTrs822339AA0190.0386AG336GG418 Citation Format: Tomoko Funazo, Hiroaki Ozasa, Takashi Nomizo, Takahiro Tsuji, Yuto Yasuda, Hironori Yoshida, Yuichi Sakamori, Hiroki Nagai, Toyohiro Hirai, Young Hak Kim. Clinical impact of hypothyroidism and PD-L1 SNPs in patients having non-small cell lung cancer treated with nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5541.

Bempegaldesleukin plus nivolumab in first-line advanced/metastatic urothelial carcinoma: Results from a phase II single-arm study (PIVOT-10)

PURPOSEDespite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma.METHODSPatients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and exploratory end points included additional efficacy measures, safety, and pharmacokinetics (PKs) and pharmacodynamics analyses.RESULTSIn 783 patients (n = 391, BEMPEG plus NIVO; n = 392, NIVO monotherapy), the median follow-up was 11.6 months in the intent-to-treat population. The ORR with BEMPEG plus NIVO was 27.7% versus 36.0% with NIVO (two-sided P = .0311). The median PFS with BEMPEG plus NIVO was 4.17 months (95% CI, 3.52 to 5.55) versus 4.99 months (95% CI, 4.14 to 7.82) with NIVO (hazard ratio [HR], 1.09; 97% CI, 0.88 to 1.35; P = .3988). The median OS was 29.67 months (95% CI, 22.14 to not reached [NR]) with BEMPEG plus NIVO versus 28.88 months (95% CI, 21.32 to NR) with NIVO (HR, 0.94; 99.929% CI, 0.59 to 1.48; P = .6361). Grade 3-4 treatment-related adverse events (AEs) and serious AE rates were higher with the combination (21.7% and 10.1%, respectively) versus NIVO (11.5% and 5.5%, respectively). BEMPEG PK exposure and absolute lymphocyte count changes after BEMPEG plus NIVO were comparable between PIVOT IO 001 and PIVOT-02.CONCLUSIONThe PIVOT IO 001 study did not meet its primary end points of ORR, PFS, and OS. Increased toxicity was observed with BEMPEG plus NIVO versus NIVO.

A combination of immune-checkpoint inhibitors that target the programmed cell death 1 (PD1)/programmed cell-death ligand 1 (PDL1) pathway and indoleamine 2,3-dioxygenase 1 (IDO1) is a promising treatment for non-small-cell lung cancer. Herein, we investigated clinical features of IDO1+/PDL1+ primary lung adenocarcinoma. IDO1 and PDL1 expression in 388 resected primary lung adenocarcinoma samples was evaluated using immunohistochemistry, and the radiological features of patients with IDO1+/PDL1+ lung adenocarcinoma were analyzed. Of 388 specimens, 229 (59.0%) were IDO1+, 131 (33.8%) were PDL1+, and 109 (28.1%) were IDO1+/PDL1+ In multivariate analysis, vascular convergence and the absence of surrounding ground glass opacity were significantly associated with IDO1+/PDL1+ tumors. Fisher's exact test showed high consolidation/tumor ratio was also significantly associated with IDO1+/PDL1+ tumors. Moreover, maximum standardized uptake in 18F-fluorodeoxyglucose positron-emission tomography/computed tomography was significantly higher in patients with IDO1+/PDL1+ tumors than in those with IDO1- or PDL1- tumors. IDO1/PDL1 co-expression was significantly related to radiological invasiveness and malignancy in lung adenocarcinoma. This study may help select patients likely to benefit from combination therapy using immune-checkpoint inhibitors.

Background: Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing EGFR, thereby limiting associated toxicities. Zongertinib was granted Fast Track and Breakthrough Therapy Designations by the FDA for patients (pts) with advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 mutations and who have received prior systemic therapy. Beamion LUNG-1 (NCT04886804) is a Phase (Ph) Ia/Ib study evaluating zongertinib in pts with HER2-mutant advanced/metastatic NSCLC in Ph Ib. At the primary analysis (May 2024) of Ph Ib Cohort 1, the primary endpoint, confirmed response by blinded independent central review (BICR), was met in pts with pretreated HER2-mutant NSCLC within the tyrosine kinase domain (TKD). Here, we report the previously unreported median duration of response (DoR) and median progression-free survival (PFS) for Cohort 1, and first data from Cohorts 3 and 5. Methods: In Cohort 1, pts with pretreated HER2-mutant NSCLC within the TKD were initially randomized to receive zongertinib 120 mg or 240 mg once-daily; the 120 mg dose was selected at an interim analysis. In exploratory Cohort 3, pts had pretreated HER2-mutant NSCLC with TKD or non-TKD mutations. In Cohort 5, pts had HER2-mutant NSCLC within the TKD and were pretreated with a HER2-directed antibody-drug conjugate. In Cohorts 3 and 5, pts initially received zongertinib 240 mg. Once the 120 mg dose was selected in Cohort 1, all newly recruited pts received zongertinib 120 mg. Primary endpoint was objective response (best overall response of complete or partial response; RECIST v1.1) by BICR (Cohorts 1 and 5) and investigator review (Cohort 3). Secondary endpoints included DoR and PFS. Results: As of November 29, 2024, 75 pts in Cohort 1, 20 pts with non-TKD mutations in Cohort 3, and 31 pts in Cohort 5 had received zongertinib 120 mg; treatment was ongoing in 33 (44%), 4 (20%), and 13 (42%) pts, respectively. In Cohort 1, the objective response rate (ORR) by BICR was 71% (95% CI: 60-80) and disease control rate (DCR) was 96% (95% CI: 89-99). In Cohort 3, the ORR was 30% (95% CI: 15-52) and DCR was 65% (95% CI: 43-82). In Cohort 5, the ORR was 48% (95% CI: 32-65) and DCR was 97% (95% CI: 84-99). Median (95% CI) DoR and PFS were 14.1 (6.9-not evaluable [NE]) months and 12.4 (8.2-NE) months in Cohort 1 and 5.3 (2.8-NE) months and 6.8 (5.4-NE) months in Cohort 5. DoR and PFS in Cohort 3 were not yet mature. Drug-related adverse events (all/grade [G] ≥3) were reported in 97%/17%, 80%/25%, and 77%/3% of pts in Cohorts 1, 3, and 5, respectively, most commonly diarrhea in all cohorts (mainly G1). There were no cases of drug-related interstitial lung disease (ILD). Conclusions: Zongertinib demonstrated significant and clinically meaningful activity with a manageable safety profile in pts with pretreated advanced NSCLC harboring HER2 mutations. Citation Format: John V. Heymach, Gerrina Ruiter, Myung-Ju Ahn, Nicolas Girard, Egbert Smit, David Planchard, Yi-Long Wu, Byoung Chul Cho, Noboru Yamamoto, Joshua K. Sabari, Yanqiu Zhao, Hai-Yan Tu Kiyotaka Yoh, Ernest Nadal, Behbood Sadrolhefazi, Maren Rohrbacher, Ute von Wangenheim, Sabina Eigenbrod-Giese, Jon Zugazagoitia. Zongertinib in patients with pretreated HER2-mutant advanced NSCLC: Beamion LUNG-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT050.

BackgroundPatients with previously untreated, locally advanced, unresectable or metastatic triple-negative breast cancer who are not candidates for inhibitors of programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) have limited treatment options.MethodsIn this international, phase 3, open-label, randomized trial, we enrolled patients with previously untreated, advanced triple-negative breast cancer who were not candidates for PD-1 or PD-L1 inhibitors owing to previous use or coexisting conditions. Patients had either PD-L1–negative tumors with a combined positive score (CPS; the number of PD-L1–staining tumor cells, lymphocytes, and macrophages divided by the total number of viable tumor cells, multiplied by 100) of less than 10 or PD-L1–positive tumors with a CPS of 10 or higher and were assigned in a 1:1 ratio to receive sacituzumab govitecan or chemotherapy (paclitaxel, nanoparticle albumin-bound paclitaxel, or gemcitabine plus carboplatin). The primary end point was progression-free survival, assessed by blinded independent central review. Secondary end points included overall survival, objective response, the duration of response, and safety.ResultsAmong 558 patients, median progression-free survival was 9.7 months (95% confidence interval [CI], 8.1 to 11.1) with sacituzumab govitecan and 6.9 months (95% CI, 5.6 to 8.2) with chemotherapy (stratified hazard ratio for disease progression or death, 0.62; 95% CI, 0.50 to 0.77; P<0.001). An objective response was confirmed in 48% of patients (95% CI, 42 to 54) who received sacituzumab govitecan and 46% (95% CI, 40 to 52) who received chemotherapy; the median response duration was 12.2 months (95% CI, 9.7 to 13.8) and 7.2 months (95% CI, 5.7 to 8.4), respectively. Adverse events of grade 3 or higher occurred in 66% of patients who received sacituzumab govitecan (most frequently neutropenia [in 43%], diarrhea [in 9%], and leukopenia [in 7%]) and in 62% of patients who received chemotherapy (most frequently neutropenia [in 41%], anemia [in 16%], and leukopenia [in 13%]). The incidence of adverse events that led to discontinuation of sacituzumab govitecan or at least one chemotherapy drug was 4% and 12%, respectively.ConclusionsSacituzumab govitecan led to significantly longer progression-free survival than chemotherapy among patients with advanced triple-negative breast cancer who were not candidates for treatment with PD-1 or PD-L1 inhibitors. The incidence of adverse events of grade 3 or higher with sacituzumab govitecan was similar to that with chemotherapy, but adverse events were common. (Funded by Gilead Sciences; ASCENT-03 ClinicalTrials.gov number, NCT05382299.)

African American women with high-grade serous ovarian carcinoma have worse outcomes compared with women of European descent. Although the discrepancy is partially attributed to differences in access to care, the tumor immune microenvironment may also contribute. Expression of targetable immune regulatory molecules such as programmed cell death ligand-1 (PD-L1) and indoleamine 2,3 dioxygenase (IDO) is of particular interest as it may help guide therapy in this population. Using cases from the largest study of African American women with ovarian cancer, the African American Cancer Epidemiology Study, we characterized PD-L1 and IDO expression in 112 high-grade serous ovarian carcinomas. Immunohistochemistry for PD-L1, IDO, CD8, FOX3p, and CD68 was performed. PD-L1 and IDO were scored as the percentage of positive tumor cells and tumor-associated immune cells. CD8 and FOX3p counts were averaged across 10 high-power fields. Cox proportional hazards regression was used to evaluate the association between PD-L1 and IDO expression and survival. Tumor cells were positive for PD-L1 and IDO in 29% and 58% of cases, respectively. The majority showed <10% staining, and no cases exceeded 25% positivity. The majority of PD-L1-positive cases coexpressed IDO. PD-L1 and IDO expression was associated with higher CD8 and FOX3p counts (P<0.05). No association was observed between PD-L1 and IDO and survival. In summary, expression of PD-L1 and IDO is seen in a subset of high-grade serous ovarian carcinoma from African American women and is correlated with elevated lymphocyte infiltration. While PD-L1 and IDO co-expression suggests a role for dual immunotherapy, diffuse expression of PD-L1 and IDO is rare, invoking caution regarding the potential for immunotherapeutic response.

The immune microenvironment is a prognostic factor for various malignancies. The significance of key players of this immune microenvironment, including tumour-infiltrating lymphocytes (TILs) and expression of programmed death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase (WARS) in gastrointestinal stromal tumours (GISTs) is largely unknown. Tissue microarrays were constructed from pathology files, 1996-2016. Immunohistochemistry for PD-L1, IDO and WARS was correlated with tumour size, mitoses and outcomes. TILs expressing CD3, CD4, CD8, FoxP3 and GBP5 were counted. A total of 129 GISTs were analysed. Mean patient age was 62.5 years; 52.0% were male. Tumour location included 89 stomach (69.0%), 33 small bowel (25.6%) and seven other (5.4%). Mean tumour size was 5.6 cm; mean mitoses were 7.2 per 50 high-power field. Nineteen patients (15.0%) developed disease progression, to abdominal wall (n = 8), liver (n = 6) and elsewhere (n = 5). Median progression-free survival was 56.6 months; five patients died of disease. PD-L1 was positive in 88 of 127 tumour samples (69.0%), 114 of 127 tumours were IDO-positive (89.8%) and 60 of 127 were positive for WARS (47.2%). PD-L1 was associated with increased size (P = 0.01), necrosis (P = 0.018) and mitoses (P = 0.006). Disease progression was not associated with PD-L1 (P = 0.44), IDO (P = 0.14) or WARS (P = 0.36) expression. PD-L1-positive GISTs with CD8+ or CD3+ TILs were significantly smaller than tumours with CD8+ or CD3+ TILs. PD-L1 expression was associated with increased size and mitoses. High CD8+ or CD3+ TIL counts were associated with decreased PD-L1/IDO+ GIST size. PD-L1 and IDO could be significant in GIST tumour biology, which invites consideration of immunotherapy as a potential treatment option.