Breast Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.

Neoadjuvant talazoparib in patients with germline BRCA1/2 mutation-positive, early-stage triple-negative breast cancer: exploration of tumor BRCA mutational status.

BACKGROUND: Talazoparib monotherapy in patients with germline BRCA-mutated, early-stage triple-negative breast cancer (TNBC) showed activity in the neoadjuvant setting in the phase II NEOTALA study (NCT03499353). These biomarker analyses further assessed the mutational landscape of the patients enrolled in the NEOTALA study. METHODS: Baseline tumor tissue from the NEOTALA study was tested retrospectively using FoundationOne®CDx. To further hypothesis-driven correlative analyses, agnostic heat-map visualizations of the FoundationOne®CDx tumor dataset were used to assess overall mutational landscape and identify additional candidate predictive biomarkers of response. RESULTS: All patients enrolled (N = 61) had TNBC. In the biomarker analysis population, 75.0% (39/52) and 25.0% (13/52) of patients exhibited BRCA1 and BRCA2 mutations, respectively. Strong concordance (97.8%) was observed between tumor BRCA and germline BRCA mutations, and 90.5% (38/42) of patients with tumor BRCA mutations evaluable for somatic-germline-zygosity were predicted to exhibit BRCA loss of heterozygosity (LOH). No patients had non-BRCA germline DNA damage response (DDR) gene variants with known/likely pathogenicity, based on a panel of 14 non-BRCA DDR genes. Ninety-eight percent of patients had TP53 mutations. Genomic LOH, assessed continuously or categorically, was not associated with response. CONCLUSION: The results from this exploratory biomarker analysis support the central role of BRCA and TP53 mutations in tumor pathobiology. Furthermore, these data support assessing germline BRCA mutational status for molecular eligibility for talazoparib in patients with TNBC.

Tumor-infiltrating lymphocytes and breast cancer mortality in racially and ethnically diverse participants of the Northern California Breast Cancer Family Registry.

Stromal tumor-infiltrating lymphocyte (sTIL) enrichment in pretreatment breast tumors has been associated with superior response to neoadjuvant treatment and survival. In a population-based cohort, we studied sTIL-survival associations by race and ethnicity. We assessed associations of continuous sTIL scores and sTIL-enriched breast cancers (defined as percent lymphocytic infiltration of tumor stroma or cell nests at cutoffs of 30%, 50%, and 70%) with clinical and epidemiologic characteristics and conducted multivariable survival analyses. Although we identified no difference in sTIL score by race and ethnicity, higher continuous sTIL score was associated with lower breast cancer-specific mortality only among non-Hispanic White and Asian American but not African American and Hispanic women. This finding suggests that complex factors influence treatment response and survival, given that sTIL enrichment was not associated with a survival advantage among women from minoritized groups, who more often experience health disparities. Further study of patient selection for sTIL-guided treatment strategies is warranted.

Generation and characterization of induced pluripotent stem cells from breast cancer patients carrying ATM mutations.

We generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of breast cancer patients carrying germline ATM mutations, a gene associated with a 7% prevalence in breast cancer. These iPSC lines displayed typical morphology, expressed pluripotency markers, maintained a stable karyotype, and retained the ability to differentiate into the three germ layers. These patient-specific iPSC lines hold great potential for mechanistic investigations and the development of drug screening strategies aimed at addressing ATM-related cancer.

Generation of two induced pluripotent stem cell lines from breast cancer patients carrying BRCA2 variants.

Germline pathogenic variants in the BRCA2 gene are strongly correlated with an elevated risk of developing breast cancer. Two specific BRCA2 variants, c.8167G>C (p.Asp2723His) and c.1583del (p.Asn528fs), have been identified from individuals with a family history of breast cancer. Here we generated two iPSC lines from breast cancer patients who are heterozygous carriers of these two variants. These iPSCs exhibit pluripotency and demonstrate the capability to differentiate into three germ layers. These iPSC lines represent a valuable resource for personalized pre-clinical research, offering new opportunities to explore the underlying mechanisms of breast cancer and develop targeted therapeutic approaches.

Genomic analysis of advanced breast cancer tumors from talazoparib-treated gBRCA1/2mut carriers in the ABRAZO study.

These analyses explore the impact of homologous recombination repair gene mutations, including BRCA1/2 mutations and homologous recombination deficiency (HRD), on the efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor talazoparib in the open-label, two-cohort, Phase 2 ABRAZO trial in germline BRCA1/2-mutation carriers. In the evaluable intent-to-treat population (N = 60), 58 (97%) patients harbor ≥1 BRCA1/2 mutation(s) in tumor sequencing, with 95% (53/56) concordance between germline and tumor mutations, and 85% (40/47) of evaluable patients have BRCA locus loss of heterozygosity indicating HRD. The most prevalent non-BRCA tumor mutations are TP53 in patients with BRCA1 mutations and PIK3CA in patients with BRCA2 mutations. BRCA1- or BRCA2-mutated tumors show comparable clinical benefit within cohorts. While low patient numbers preclude correlations between HRD and efficacy, germline BRCA1/2 mutation detection from tumor-only sequencing shows high sensitivity and non-BRCA genetic/genomic events do not appear to influence talazoparib sensitivity in the ABRAZO trial.ClinicalTrials.gov identifier: NCT02034916.

Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes.

PURPOSE: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer. METHODS: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. RESULTS: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. CONCLUSIONS: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.

NCCN Guidelines® Insights: Breast Cancer, Version 4.2023.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.

Neoadjuvant Talazoparib in Patients With Germline BRCA1/2 Mutation-Positive, Early-Stage Triple-Negative Breast Cancer: Results of a Phase II Study.

BACKGROUND: The undetermined efficacy of the current standard-of-care neoadjuvant treatment, anthracycline/platinum-based chemotherapy, in patients with early-stage triple-negative breast cancer (TNBC) and germline BRCA mutations emphasizes the need for biomarker-targeted treatment, such as poly(ADP-ribose) polymerase inhibitors, in this setting. This phase II, single-arm, open-label study evaluated the efficacy and safety of neoadjuvant talazoparib in patients with germline BRCA1/2-mutated early-stage TNBC. PATIENTS AND METHODS: Patients with germline BRCA1/2-mutated early-stage TNBC received talazoparib 1 mg once daily for 24 weeks (0.75 mg for moderate renal impairment) followed by surgery. The primary endpoint was pathologic complete response (pCR) by independent central review (ICR). Secondary endpoints included residual cancer burden (RCB) by ICR. Safety and tolerability of talazoparib and patient-reported outcomes were assessed. RESULTS: Of 61 patients, 48 received ≥80% talazoparib doses, underwent surgery, and were assessed for pCR or progressed before pCR assessment and considered nonresponders. pCR rate was 45.8% (95% confidence interval [CI], 32.0%-60.6%) and 49.2% (95% CI, 36.7%-61.6%) in the evaluable and intent-to-treat (ITT) population, respectively. RCB 0/I rate was 45.8% (95% CI, 29.4%-63.2%) and 50.8% (95% CI, 35.5%-66.0%) in the evaluable and ITT population, respectively. Treatment-related adverse events (TRAE) were reported in 58 (95.1%) patients. Most common grade 3 and 4 TRAEs were anemia (39.3%) and neutropenia (9.8%). There was no clinically meaningful detriment in quality of life. No deaths occurred during the reporting period; 2 deaths due to progressive disease occurred during long-term follow-up (>400 days after first dose). CONCLUSIONS: Neoadjuvant talazoparib monotherapy was active despite pCR rates not meeting the prespecified threshold; these rates were comparable to those observed with combination anthracycline- and taxane-based chemotherapy regimens. Talazoparib was generally well tolerated. CLINICALTRIALS.GOV IDENTIFIER: NCT03499353.

Antimicrobial exposure is associated with decreased survival in triple-negative breast cancer.

Antimicrobial exposure during curative-intent treatment of triple-negative breast cancer (TNBC) may lead to gut microbiome dysbiosis, decreased circulating and tumor-infiltrating lymphocytes, and inferior outcomes. Here, we investigate the association of antimicrobial exposure and peripheral lymphocyte count during TNBC treatment with survival, using integrated electronic medical record and California Cancer Registry data in the Oncoshare database. Of 772 women with stage I-III TNBC treated with and without standard cytotoxic chemotherapy - prior to the immune checkpoint inhibitor era - most (654, 85%) used antimicrobials. Applying multivariate analyses, we show that each additional total or unique monthly antimicrobial prescription is associated with inferior overall and breast cancer-specific survival. This antimicrobial-mortality association is independent of changes in neutrophil count, is unrelated to disease severity, and is sustained through year three following diagnosis, suggesting antimicrobial exposure negatively impacts TNBC survival. These results may inform mechanistic studies and antimicrobial prescribing decisions in TNBC and other hormone receptor-independent cancers.

Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial.

Importance: Preclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types or molecular subtypes may benefit from this combination. Objective: To investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes. Design, Setting, and Participants: In this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non-small cell lung cancer (NSCLC); DNA damage response (DDR)-positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2)-negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021. Interventions: All patients in phases 1b and 2 received avelumab plus talazoparib. Main Outcomes and Measures: The phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers. Results: A total of 223 patients (mean [SD] age, 63.2 [11.0] years; 117 [52.5%] men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median [range] DOR, 11.1 [3.4-20.4] months); HR-positive, ERBB2-negative, and DDR-positive BC (median [range] DOR, 15.7 [3.9 to ≥20.6] months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to ≥18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients [33.6%]), thrombocytopenia (48 patients [21.5%]), and neutropenia (31 patients [13.9%]). Conclusions and Relevance: This nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations. Trial Registration: ClinicalTrials.gov Identifier: NCT03330405.

Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial.

Importance: Nonclinical studies suggest that the combination of poly(ADP-ribose) polymerase and programmed cell death 1/programmed cell death-ligand 1 inhibitors has enhanced antitumor activity; however, the patient populations that may benefit from this combination have not been identified. Objective: To evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type. Design, Setting, and Participants: In this pan-cancer tumor-agnostic phase 2b nonrandomized controlled trial, patients with advanced BRCA1/2-altered or ATM-altered solid tumors were enrolled into 2 respective parallel cohorts. The study was conducted from July 2, 2018, to April 12, 2020, at 42 institutions in 9 countries. Interventions: Patients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily. Main Outcomes and Measures: The primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review. Results: A total of 200 patients (median [range] age, 59.0 [26.0-89.0] years; 132 [66.0%] women; 15 [7.5%] Asian, 11 [5.5%] African American, and 154 [77.0%] White participants) were enrolled: 159 (79.5%) in the BRCA1/2 cohort and 41 (20.5%) in the ATM cohort. The confirmed OR rate was 26.4% (42 patients, including 9 complete responses [5.7%]) in the BRCA1/2 cohort and 4.9% (2 patients) in the ATM cohort. In the BRCA1/2 cohort, responses were more frequent (OR rate, 30.3%; 95% CI, 22.2%-39.3%, including 8 complete responses [6.7%]) and more durable (median duration of response: 10.9 months [95% CI, 6.2 months to not estimable]) in tumor types associated with increased heritable cancer risk (ie, BRCA1/2-associated cancer types, such as ovarian, breast, prostate, and pancreatic cancers) and in uterine leiomyosarcoma (objective response in 3 of 3 patients and with ongoing responses greater than 24 months) compared with non-BRCA-associated cancer types. Responses in the BRCA1/2 cohort were numerically higher for patients with tumor mutational burden of 10 or more mutations per megabase (mut/Mb) vs less than 10 mut/Mb. The combination was well tolerated, with no new safety signals identified. Conclusions and Relevance: In this phase 2b nonrandomized controlled trial, neither the BRCA1/2 nor ATM cohort met the prespecified OR rate of 40%. Antitumor activity for the combination of avelumab and talazoparib in patients with BRCA1/2 alterations was observed in some patients with BRCA1/2-associated tumor types and uterine leiomyosarcoma; benefit was minimal in non-BRCA-associated cancer types. Trial Registration: ClinicalTrials.gov Identifier: NCT03565991.

Emerging strategies: PARP inhibitors in combination with immune checkpoint blockade in BRCA1 and BRCA2 mutation-associated and triple-negative breast cancer.

Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor monotherapy in germline BRCA1 and BRCA2 mutation-associated metastatic breast cancer is a well-tolerated and an effective therapeutic strategy, however, the durability of response can be limited. Checkpoint inhibitors targeting the PD-1/PD-L1 axis as monotherapy in metastatic triple-negative breast cancer (mTNBC) have a limited role due to low response rates, but are capable of long, durable responses. Combination PARP inhibition with checkpoint blockade is an emerging area of investigation with potential synergy to produce robust responses with durability. Mechanistically, PARP inhibition activates the stimulator of interferon gene (STING) pathway to promote dendritic cell and T lymphocyte recruitment, increases tumor neoantigens, and upregulates PD-L1 expression to increase the immunogenicity of the tumor and thereby potentially enhance responses to immunotherapy. Several clinical trials have reported early results on PARP inhibitor and PD-1/PD-L1 checkpoint inhibitor combinations. All studies have shown safety and tolerability of this combination regimen. In advanced breast cancer associated with a germline BRCA1 or BRCA2 mutation, response rates have been high and similar to what is observed with PARP inhibitor monotherapy. Additional follow-up is needed to see if combination with a checkpoint inhibitor can lead to a clinically meaningful extension of durability of response in patients with germline mutations in BRCA1 and BRCA2. In unselected mTNBC in the 1st-3rd line setting, response rates of combined PARP inhibitor and PD-1/PD-L1 inhibitors have ranged from 18-21%, with higher rates of response among those with alterations in homologous recombination DNA repair pathway genes. Multiple ongoing studies will report additional data on combinations of PARP inhibitors and checkpoint blockade in the future and this combination strategy remains an active area of investigation.

A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes.

Talazoparib, a PARP inhibitor, is active in germline BRCA1 and BRCA2 (gBRCA1/2)-mutant advanced breast cancer, but its activity beyond gBRCA1/2 is poorly understood. We conducted Talazoparib Beyond BRCA ( NCT02401347 ), an open-label phase II trial, to evaluate talazoparib in patients with pretreated advanced HER2-negative breast cancer (n = 13) or other solid tumors (n = 7) with mutations in homologous recombination (HR) pathway genes other than BRCA1 and BRCA2. In patients with breast cancer, four patients had a Response Evaluation Criteria in Solid Tumors (RECIST) partial response (overall response rate, 31%), and three additional patients had stable disease of ≥6 months (clinical benefit rate, 54%). All patients with germline mutations in PALB2 (gPALB2; encoding partner and localizer of BRCA2) had treatment-associated tumor regression. Tumor or plasma circulating tumor DNA (ctDNA) HR deficiency (HRD) scores were correlated with treatment outcomes and were increased in all gPALB2 tumors. In addition, a gPALB2-associated mutational signature was associated with tumor response. Thus, talazoparib has been demonstrated to have efficacy in patients with advanced breast cancer who have gPALB2 mutations, showing activity in the context of HR pathway gene mutations beyond gBRCA1/2.

Integrating Immunotherapy Into the Treatment Landscape for Patients With Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive histologic subtype of breast cancer for which, until recently, treatment options have been limited to chemotherapy. In recent years, an improved understanding of the importance of tumor-infiltrating lymphocytes and the tumor microenvironment in TNBC has led to investigation of immune checkpoint inhibitors for treatment. There is now evidence from several randomized controlled trials that supports the addition of immune checkpoint inhibitors to first-line treatment of advanced TNBC and to neoadjuvant chemotherapy for stage II-III TNBC. In parallel, the PARP inhibitors have emerged as a targeted therapy option for patients with HER2-negative breast cancer harboring mutations in BRCA1, BRCA2, and PALB2. Here, we review the recent clinical trials that inform the integration of immune checkpoint inhibitors into treatments for TNBC and discuss ongoing challenges-including patient selection, management of resistance to post-checkpoint inhibitor therapy, and combining immunotherapy with targeted therapies, including PARP inhibitors.

Breast Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.

Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update.

PURPOSE: To update the ASCO Biomarkers to Guide Systemic Therapy for Metastatic Breast Cancer (MBC) guideline. METHODS: An Expert Panel conducted a systematic review to identify randomized clinical trials and prospective-retrospective studies from January 2015 to January 2022. RESULTS: The search identified 19 studies informing the evidence base. RECOMMENDATIONS: Candidates for a regimen with a phosphatidylinositol 3-kinase inhibitor and hormonal therapy should undergo testing for PIK3CA mutations using next-generation sequencing of tumor tissue or circulating tumor DNA (ctDNA) in plasma to determine eligibility for alpelisib plus fulvestrant. If no mutation is found in ctDNA, testing in tumor tissue, if available, should be used. Patients who are candidates for poly (ADP-ribose) polymerase (PARP) inhibitor therapy should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine eligibility for a PARP inhibitor. There is insufficient evidence for or against testing for a germline PALB2 pathogenic variant to determine eligibility for PARP inhibitor therapy in the metastatic setting. Candidates for immune checkpoint inhibitor therapy should undergo testing for expression of programmed cell death ligand-1 in the tumor and immune cells to determine eligibility for treatment with pembrolizumab plus chemotherapy. Candidates for an immune checkpoint inhibitor should also undergo testing for deficient mismatch repair/microsatellite instability-high to determine eligibility for dostarlimab-gxly or pembrolizumab, as well as testing for tumor mutational burden. Clinicians may test for NTRK fusions to determine eligibility for TRK inhibitors. There are insufficient data to recommend routine testing of tumors for ESR1 mutations, for homologous recombination deficiency, or for TROP2 expression to guide MBC therapy selection. There are insufficient data to recommend routine use of ctDNA or circulating tumor cells to monitor response to therapy among patients with MBC.Additional information can be found at www.asco.org/breast-cancer-guidelines.

Phase 1b study of berzosertib and cisplatin in patients with advanced triple-negative breast cancer.

Platinum derivatives are commonly used for the treatment of patients with metastatic triple-negative breast cancer (TNBC). However, resistance often develops, leading to treatment failure. This expansion cohort (part C2) of the previously reported phase 1b trial (NCT02157792) is based on the recommended phase 2 dose of the combination of the ataxia-telangiectasia and Rad3-related (ATR) inhibitor berzosertib and cisplatin observed in patients with advanced solid tumors, including TNBC. Forty-seven patients aged ≥18 years with advanced TNBC received cisplatin (75 mg/m2; day 1) and berzosertib (140 mg/m2; days 2 and 9), in 21-day cycles. Berzosertib was well tolerated, with a similar toxicity profile to that reported previously for this combination. The overall response rate (90% confidence interval) was 23.4% (13.7, 35.8). No relevant associations were observed between response and gene alterations. Further studies combining ATR inhibitors with platinum compounds may be warranted in highly selected patient populations.

Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial.

PURPOSE: Dual inhibition of glucose and glutamine metabolism results in synergistic anticancer effects in solid tumor models. Telaglenastat, an investigational, small-molecule, glutaminase inhibitor, exhibits modest single-agent activity in renal cell carcinoma (RCC) patients. This phase Ib trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC). PATIENTS AND METHODS: mRCC patients received escalating doses of telaglenastat [400-800 mg per os (p.o.) twice daily] in a 3 + 3 design, plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and antitumor activity. RESULTS: Twenty-seven patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grades 1 to 2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No maximum tolerated dose (MTD) was reached for either combination, leading to a recommended phase II dose of 800-mg telaglenastat twice daily with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% [20/21, including 1 partial response (PR)] among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies [5/10 PRs as best response (3 confirmed) in clear cell]. CONCLUSIONS: TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients.