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Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458. Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8–11·6) in the experimental group and 11·3 months (8·1–11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7–3·8) in the experimental group versus 2·0 months (1·8–2·1) in the control group (hazard ratio 0·88, 95% CI 0·65–1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3–4 adverse events (p=0·30). The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy. Institut Curie.

Purpose of Review The purpose of the review is to summarize the data regarding PD-L1 expression in breast cancer and the results of first clinical trials with PD-1 or PD-L1 inhibitors in patients with metastatic breast cancer. Recent Findings PD-L1 expression is heterogeneous across primary breast cancers, and is generally associated with the presence of tumor-infiltrating lymphocytes and the presence of poor-prognosis features such as high grade, and aggressive molecular subtypes (triple-negative (TN), basal, HER2-enriched). Early phase clinical trials using PD-1 or PD-L1 inhibitors alone or in combination have shown objective tumor responses and durable long-term disease control, in heavily pre-treated patients, notably in the TN subtype. Summary Blockade of PD-1 or PD-L1 shows impressive antitumor activity in some subsets of breast cancer patients. Many clinical trials are ongoing in the metastatic and neoadjuvant setting, alone and in combination with chemotherapy, targeted therapy, radiotherapy, and/or other immune therapy. The identification of biomarkers predictive for a clinical benefit is warranted.

Recently, the development of immunotherapy through the immune checkpoint blockade led to long-lasting responses in several types of cancers that are refractory to conventional treatments, such as melanoma or non-small cell lung cancer. Immunotherapy has also demonstrated significant improvements in various other types of cancers. However, breast cancer remains one of the tumors that have not experienced the explosion of immunotherapy yet. Indeed, breast cancer was traditionally considered as being weakly immunogenic with a lower mutational load compared to other tumor types. In the last few years, anti-PD1/PD-L1 (Programmed death-ligand 1) agents have been evaluated in breast cancer, particularly in the triple negative subtype, with promising results observed when delivered as monotherapy or in combination with conventional treatments. In this review, we will report the results of the most recent studies evaluating immune checkpoint inhibitors in breast cancer. In addition, we will discuss the concomitant development of possible biomarkers, which is required for improving the selection of patients with the highest probability of benefiting from these agents.

Among patients with breast cancer and germline mutations in the BRCA DNA repair pathway genes, the poly(adenosine diphosphate–ribose) inhibitor talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival.

The phosphatidylinositol 3-kinase (PI3K) pathway is one of the most altered pathways in human cancers, and it plays a central role in cellular growth, survival, metabolism, and cellular mobility, making it a particularly interesting therapeutic target. Recently, pan-inhibitors and then selective p110α subunit inhibitors of PI3K were developed. Breast cancer is the most frequent cancer in women and, despite therapeutic progress in recent years, advanced breast cancers remain incurable and early breast cancers are at risk of relapse. Breast cancer is divided in three molecular subtypes, each with its own molecular biology. However, PI3K mutations are found in all breast cancer subtypes in three main “hotspots”. In this review, we report the results of the most recent and main ongoing studies evaluating pan-PI3K inhibitors and selective PI3K inhibitors in each breast cancer subtype. In addition, we discuss the future of their development, the various potential mechanisms of resistance to these inhibitors and the ways to circumvent them.

Brain metastases occur in 30–50% of patients with metastatic HER2-positive breast cancer. In the case of diffuse brain metastases, treatment is based on whole brain radiotherapy (WBRT). Few systemic options are available. We aimed to investigate the combination of lapatinib plus capecitabine for the treatment of previously untreated brain metastases from HER2-positive breast cancer. In this single-arm phase 2, open-label, multicentre study, eligible patients had HER2-positive metastatic breast cancer with brain metastases not previously treated with WBRT, capecitabine, or lapatinib. Tretament was given in 21 day cycles: patients received lapatinib (1250 mg, orally) every day and capecitabine (2000 mg/m2, orally) from day 1 to day 14. The primary endpoint was the proportion of patients with an objective CNS response, defined as a 50% or greater volumetric reduction of CNS lesions in the absence of increased steroid use, progressive neurological symptoms, and progressive extra-CNS disease. All responses had to be confirmed 4 weeks after initial response. Efficacy analyses included all patients who received the study drugs and were assessable for efficacy criteria. This trial is registered with ClinicalTrials.gov, number NCT00967031. Between April 15, 2009, to Aug 2, 2010, we enrolled 45 patients, 44 (98%) of whom were assessable for efficacy, with a median follow-up of 21·2 months (range 2·2–27·6). 29 patients had an objective CNS response (65·9%, 95% CI 50·1–79·5); all were partial responses. Of all 45 treated patients, 22 (49%) had grade 3 or grade 4 treatment-related adverse events, of which the most common were diarrhoea in nine (20%) patients and hand-foot syndrome in nine (20%) patients. 14 (31%) patients had at least one severe adverse event; treatment was discontinued because of toxicity in four patients. No toxic deaths occurred. The combination of lapatinib and capecitabine is active as first-line treatment of brain metastases from HER2-positive breast cancer. A phase 3 trial is warranted. GlaxoSmithKline-France and UNICANCER.

BackgroundHead and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting.MethodsThe phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria.ResultsFrom November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III–IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3–4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR.ConclusionsNeoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach.Trial registration numberClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759.

We proposed in 2005 that androgens replace oestrogens as the driver steroids in a subgroup of triple-negative breast cancer (TNBC) with androgen receptor (AR) expression called molecular apocrine (MA) or luminal androgen receptor (LAR). Here, we report the analysis of a clinical trial evaluating the antitumour activity of the anti-androgen darolutamide in MA breast cancer. Our aim was to assess the clinical benefit in patients with AR-positive TNBCs defined by immunohistochemistry and by RNA profiling. In this multicentre, non-comparative, randomised, phase 2 trial, women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–1 and with advanced TNBC that was previously treated with a maximum of one line of chemotherapy were recruited from 45 hospitals in France. After central confirmation of TNBC status and AR positivity (≥10%; SP107 antibody), participants were randomly assigned (2:1) to receive darolutamide 600 mg orally twice daily or capecitabine minimum 1000 mg/m2 twice daily for 2 weeks on and 1 week off, until disease progression, unacceptable toxicity, lost to follow-up, or withdrawal of consent. Randomisation was done centrally using the minimisation procedure and was stratified according to the number of previous lines of chemotherapy. Transcriptomic analysis was used to classify tumours into groups with high and low AR activity (MAhigh and MAlow). The primary clinical endpoint was clinical benefit rate at 16 weeks (confirmed complete response, partial response, or stable disease). The primary translational endpoint was clinical benefit rate in the darolutamide group in MAhigh tumours versus all other tumours. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov (NCT03383679), and is closed to recruitment. Between April 9, 2018, and July 20, 2021, 254 women were screened and 94 were randomly assigned to darolutamide (n=61) or capecitabine (n=33), of whom 90 were evaluable for efficacy analyses. Median follow-up at the data cutoff on July 20, 2022, was 22·5 months (IQR 16·5–30·5). The clinical benefit rate was 29% (17 of 58; 90% CI 19–39) with darolutamide and 59% (19 of 32; 90% CI 45–74) with capecitabine. In patients treated with darolutamide, the clinical benefit rate was 57% (12 of 21; 95% CI 36–78) in MAhigh tumours, and 16% (five of 31; 95% CI 3–29; p=0·0020) in other tumours. The most common grade 3 adverse events were palmar-plantar erythrodysaesthesia syndrome (none of 60 in the darolutamide group vs two [6%] of 33 in the capecitabine group), and headache (three [5%] vs none). No grade 4 or 5 adverse events were observed. Drug-related serious adverse events occurred in three (5%) patients in the darolutamide group and three (9%) in the capecitabine group, which were toxicoderma (n=1) and headache (n=2) in the darolutamide group, and diarrhoea, general physical deterioration, and hepatic cytolysis in the capecitabine group (n=1 each). This study did not reach its prespecified endpoint for darolutamide activity in patients with triple-negative breast cancer selected on the basis of immunohistochemistry for AR. Further studies selecting patients based on RNA profiling might allow better identification of tumours sensitive to anti-androgens. Bayer and Fondation Bergonié.

Exquisitely exploiting defects in homologous recombination process, poly(ADP-ribose) polymerase (PARP) inhibitors have recently emerged as a promising class of therapeutics in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with germline breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) mutations (gBRCA1/2m). In this setting, PARP inhibitors, either as single agent or in combination with platinum-based chemotherapy, significantly increased progression-free survival, as compared to conventional chemotherapy. Accordingly, further therapeutic advances are expected at an earlier stage of the disease. In the neoadjuvant setting, veliparib failed to increase the pathological complete response rate when added to a carboplatin-based regimen, in unselected triple-negative breast cancer patients. Similarly, when administered before anthracycline-cyclophosphamide, the neoadjuvant olaparib-paclitaxel combination was not superior to carboplatin–paclitaxel, in patients with HER2-negative breast cancer and BRCA1/2 mutation, or homologous recombination defect. Yet, neoadjuvant talazoparib, administered as a single-agent in patients with HER2-negative breast cancer and germline BRCA1/2 mutation, achieved an impressive pathological complete response rate of nearly 50%. In the adjuvant setting, the results from the OlympiA phase III study, evaluating adjuvant olaparib in HER2-negative early breast cancer and germline BRCA1/2 mutations, are eagerly awaited. Ongoing trials should clarify whether PARP inhibitors might improve outcome when administered in the adjuvant or neoadjuvant setting in early breast cancer patients with BRCA1/2 mutation or homologous recombination defect.