Clinical factors associated with prolonged response and survival under olaparib as maintenance therapy in BRCA mutated ovarian cancers.

OBJECTIVE: To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in daily practice. METHODS: Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy. RESULTS: One hundred and fifteen patients were included. Median age was 54 years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21 months, median PFS was 12.7 months and median OS was 35.4 months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI) ≥ 12 months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFI ≥ 12 months, CR and normalization of CA-125. CONCLUSIONS: Platinum-free interval ≥ 12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA1/BRCA2 mutated ovarian cancer patients who received olaparib as maintenance therapy.

Nivolumab in recurrent/metastatic head and neck cancers.

Head and neck cancer is an immunosuppressive disease, with a high proportion expressing PD-L1. Until recently, options were lacking in second line. Prognosis is poor especially for patients who progress during chemotherapy with survival often inferior to 6 months. Nivolumab is the only anti-PD-1 agent to prolong survival in the second-line setting and is now the standard option since the CheckMate-141 trial. Treatment is generally well tolerated, patients seem to have a better quality of life when compared with chemotherapy. Markers of efficacy are lacking even if some data are emerging. Different combinations of immunotherapy are ongoing. Hyperprogression is a phenomenon associated with poor outcome and might be the consequence of anti-PD-1 treatment but this is yet to be proven.

What contributes to promote sexual health in cancer palliative care? A realist review.

INTRODUCTION: Sexuality is an important determinant of the overall health of a population and remains so at the end of life and in patients with advanced cancers. Despite the abundant literature on sexuality and intimacy, these topics have been rarely discussed in the context of cancer palliative care, and very few interventions to promote sexual health in patients undergoing cancer palliative care have been explored. OBJECTIVES: In this study we sought to identify which factors and mechanisms contribute to promoting sexual health in cancer palliative care. METHODS: A realist review was performed according to the guidelines of the realist and meta-narrative evidence synthesis method guidelines. Articles published between January 2010 and June 2021 were searched in 4 databases. Records were screened for their relevance regarding a predefined list of context-mechanism-outcome (CMO) configurations. Abstracts were independently screened by 2 authors before the data were extracted from the full-text articles selected for inclusion. With the use of abductive and retroductive reasoning techniques, each article was examined for evidence of its contribution to one of the CMO configurations, which could be refined when relevant. The data were summarized according to the final CMO configurations. RESULTS: Of the 2056 articles identified, 38 articles were included in the review. The data reported in these articles contributed to 7 CMO hypotheses: (1) improving communication skills, (2) healthcare provider training, (3) reorganizing the patient environment in care settings or at home, (4) managing sexual symptoms and also general symptoms, (5 and 6) patient-centered counseling or couple counseling, and (7) lifting the taboo. CONCLUSIONS: The findings reported here highlight various ways to improve sexual health for patients in cancer palliative care but are limited to genital cancers. Further research should consider all types of cancer rather than being restricted to genital cancers.

Analysis of the benefit of salvage chemotherapy after progression on nivolumab in patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Checkpoint inhibitor (CI) therapies have shown benefit in the treatment of locally recurrent or metastatic head and neck squamous cell carcinoma (R L/M HNSCC). Previous studies have suggested a superior benefit of salvage chemotherapy (SCT) in R/M HNSCC after progression on CI. We aimed to describe the benefit of SCT after progression on nivolumab. PATIENTS AND METHODS: Patients were eligible if they received at least one injection of SCT in the treatment of R/M HNSCC after progression on nivolumab between 2017 and 2022. The present work was a retrospective and monocenter study. Primary endpoint was the objective response rate (ORR) on first regimen of salvage chemotherapy (SCT1). Secondary endpoints were disease-control rate (DCR), ORR on second course of SCT (ORR2), progression-free survival (PFS) on SCT1 and SCT2 (PFS2) and overall survival (OS). RESULTS: Eighty-three patients received an SCT. The ORR on STC1 was 32%. Median progression-free survival (PFS) was 2.20 months (CI 95% 2.06-3.71). Median OS was 5.55 months (CI 95% 4.82-10.20). The ORR to the first line of treatment in the relapse setting was an independent prognostic factor for SCT1 PFS and OS. CONCLUSION: In R/M HNSCC, SCT following nivolumab is associated with ORRs of 32%. These results are consistent with other publications that suggest a superior benefit of SCT after CI treatment, independent of the tumor outcome on previous immunotherapy.

HER2-Positive Metastatic Breast Cancer: Available Treatments and Current Developments.

For several years, the overexpression of the HER2 receptor in breast cancer has been correlated with a poor prognosis and an increased risk of developing brain metastases. Currently, the combination of anti-HER2 double blockade and taxane and trastuzumab emtansine (T-DM1) are considered the standard treatments for metastatic breast cancer overexpressing these receptors in the first and second line. Very recently, the development of a new antidrug conjugate, trastuzumab-deruxtecan, has improved the overall survival of patients, even in second-line treatment. However, trastuzumab-deruxtecan has become a new standard. Despite the benefits of these antidrug conjugates, this benefit in patients with brain metastases remains unclear. Tucatinib is a new tyrosine kinase inhibitor that has given hope for the treatment of these patients. The objective of this article was to review data on the established drugs and novel agents for HER2-positive MBC and to discuss how to incorporate anti-HER2 therapies in first and later-line settings.

Methods and Designs of Modern Breast Cancer Confirmatory Trials.

BACKGROUND: The benefit-risk assessments of new drugs for breast cancer (BC) face several challenges, as all stakeholders do not agree on the evidence bar required for market authorization, and by the fragmentation of breast cancer diagnosis. The aim of this study was to describe the changes in methods and designs of breast cancer confirmatory trials. METHODS: All phase III randomized trials published between 2001 and 2020 and assessing systemic BC therapies were included. Trials' main characteristics, endpoints, and statistical methods were collected using a standardized data extraction form. RESULTS: A total of 347 randomized controlled trials (RCTs) met the inclusion criteria. While most older trials (79%) included all subtypes of breast cancer, most recent trials populations were limited to one large intrinsic BC subgroup (69%). The use of gatekeeping testing strategies increased dramatically from 9% to 71%. The use of overall survival (OS) as an endpoint in the trials increased over time, but its use as a primary endpoint remained infrequent. The inclusion of OS testing in a hierarchical sequence in case of positive testing of a tumor-centered or composite endpoint appeared to have become the new standard. CONCLUSION: Our findings indicate some improvements in the quality of the evidence-base supporting new breast cancer drugs. The rigorous assessment of patient-relevant endpoints has increased over time, but this improvement is mainly related to the analysis of OS as a secondary endpoint analyzed in a hierarchical sequence.

Using Breast Cancer Gene Expression Signatures in Clinical Practice: Unsolved Issues, Ongoing Trials and Future Perspectives.

The development of gene expression signatures since the early 2000's has offered standardized assays to evaluate the prognosis of early breast cancer. Five signatures are currently commercially available and recommended by several international guidelines to individualize adjuvant chemotherapy decisions in hormone receptors-positive/HER2-negative early breast cancer. However, many questions remain unanswered about their predictive ability, reproducibility and external validity in specific populations. They also represent a new hope to tailor (neo)adjuvant systemic treatment, adjuvant radiation therapy, hormone therapy duration and to identify a subset of patients who might benefit from CDK4/6 inhibitor adjuvant treatment. This review will highlight these particular issues, address the remaining questions and discuss the ongoing and future trials.

Investigating the Impact of Immune-Related Adverse Events, Glucocorticoid Use and Immunotherapy Interruption on Long-Term Survival Outcomes.

It remains unclear whether immune-related adverse events (irAEs) and glucocorticoid use could impact long-term outcomes in patients treated for solid tumors with immune checkpoint inhibitors (ICI). All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective unicentric study. The objectives were to assess the impact of grade ≥3 irAEs, glucocorticoid use and the interruption of immunotherapy on progression-free survival (PFS) and overall survival (OS). In this 828-patient cohort, the first occurrence of grade ≥3 irAEs had no significant impact on PFS or OS. Glucocorticoid administration for the irAEs was associated with a significantly shorter PFS (adjusted HR 3.0; p = 0.00040) and a trend toward shorter OS. ICI interruption was associated with a significantly shorter PFS (adjusted HR 3.5; p < 0.00043) and shorter OS (HR 4.5; p = 0.0027). Glucocorticoid administration and ICI interruption were correlated. In our population of patients treated with single agent ICI, grade ≥3 irAEs did not impact long-term outcomes. However, the need for glucocorticoids and the interruption of immunotherapy resulted in poorer long-term outcomes. The impact of grade ≥3 irAEs reported in other studies might then be explained by the management of the irAEs.

Front-Line Maintenance Therapy in Advanced Ovarian Cancer-Current Advances and Perspectives.

Ovarian tumor is the gynecological cancer associated with the highest mortality. Most diseases are diagnosed at an advanced stage, which impairs the chances of prolonged complete remission. The standard front-line treatment of advanced stages combines surgery in an expert center with platinum-based chemotherapy. Most patients experience a relapse in the years following the initial treatment. During the last decade, anti-angiogenic agents used in the maintenance setting improved progression free survival (PFS) over chemotherapy alone. More recently, PARP inhibitors demonstrated substantial efficacy, mainly in patients with germinal or somatic BRCA mutations or other homologous recombination deficiencies (HRD), all involved in double strand DNA Damage Repair (DDR). Other therapeutic paradigms are currently being explored, including combinations of immune-checkpoints inhibitors, chemotherapy, bevacizumab and PARP inhibitors. In addition to these clinical advances, molecular characterization of the tumors and their correlations with drugs efficacy are needed to better understand which patient will benefit the most from the various treatments available to date.

Induction chemotherapy in head and neck cancers: Results and controversies.

Standard treatment for locally advanced head and neck squamous cell carcinoma (LAHNSCC) consists mainly of concurrent chemoradiation (CCR) but induction chemotherapy (IC) by docetaxel-cisplatin-fluorouracil (TPF), followed by CCR, is a strong option. Comparative trials suggest that IC and CCR are equivalent, and some trials suggest superiority of IC, whereas none shows inferiority. IC might have less interest in oropharyngeal cancer (more often linked to HPV infection). When functional laryngeal preservation is the patient's priority, essays strongly suggest that IC is the best treatment. There is little data about a less toxic regimen of IC, but several schemes are promising and need to be developed. An early selection of responders to IC by metabolic imaging must be considered. Intensification attempts with cetuximab were too toxic and unsafe, but trials with immunotherapy are ongoing to enhance TPF efficacy. After IC, CCR either with cetuximab or cisplatin seems to be equally effective.

L'immunothérapie dans les cancers ORL.

IMMUNOTHERAPY IN HEAD AND NECK CANCERS: Immunotherapy wave has also touched head and neck cancer. In recurrent or metastatic disease, checkpoint inhibitors (anti PD-1/PD-L1) are approved in 2nd line with a clear benefit on overall survival and quality of life. Multiple clinical studies are in progress in both palliative and curative intent, combined or not with other checkpoint inhibitor (anti-CTLA4) or other standard therapies (radiotherapy, chemotherapy). It is essential to define which patients will benefit from immunotherapy, according to robust biomarkers, in order to increase risk benefit balance by decreasing side effects and selecting those who respond the most. Here we present an overview of immunotherapy in 2018 in head and neck squamous cell cancer.