Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer.

BACKGROUND: Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population. METHODS: From November 2015 to November 2016, patients receiving in our institution palbociclib + fulvestrant according to the Temporary Authorization for Use were prospectively analyzed. RESULTS: 60 patients were treated accordingly; median age was 61 years; 50 patients (83.3%) had visceral metastasis, and 10 (16.7%) had bone-only disease. Patients had previously received a median of 5 (1-14) lines of treatment, including ET (median 3) and chemotherapy (median 2); 28 (46.7%) received previously fulvestrant and all everolimus. With a median follow-up of 10.3 months, median progression-free survival (mPFS) was 5.8 months (95% CI 3.9-7.3). Patients pretreated with fulvestrant had a similar PFS of 6.4 months (HR 1.00; 95% CI 0.55-1.83; P = 1.00). The most common AEs (adverse events) were neutropenia (93%), anemia (65%), and thrombocytopenia (55%). CONCLUSION: In this heavily pretreated population including everolimus, fulvestrant plus palbociclib provides an mPFS of 5.8 months with the same magnitude of benefit for fulvestrant-pretreated patients.

Totally implantable venous access ports: a prospective long-term study of early and late complications in adult patients with cancer.

PURPOSE: Totally implantable venous access ports (TIVAP) have been widely used for many years in the management of patients suffering from cancer. The implantation and long-term use of TIVAPs are associated with mechanical, thrombotic, and infectious complications. This is the first exhaustive prospective study of all complications occurring in a whole population on long-term follow-up and therefore allows an objective assessment to be made of the safety of TIVAPs. METHODS: We carried out a prospective single-center observational study. All adult patients with cancer who had a TIVAP implanted between January 1 and December 31, 2006 were registered. Early and late complications were recorded until the removal of the device, the patient's death, or until December 31, 2013. Exhaustive data concerning patients and TIVAP was recorded at time of implantation. RESULTS: Four hundred and ninety-three TIVAPs were implanted in 483 adult cancer patients and were followed during a period from 1 to 94 months (median = 18 months) representing a global quantity of 367,359 catheter-days. Eighty-seven complications were recorded (0.237/1000 catheter-days), including 37 infections (0.101/1000 catheter-days), 17 thrombotic events (0.046/1000 catheter-days), and 9 extravasations. Out of the 87 events, 62 (71.3%) occurred during the first year after implantation. Events were therefore extremely rare after 1 year. Thromboembolic and infectious complications were rare and no risk factors for these were found. CONCLUSIONS: This study demonstrates excellent tolerability, with only occasional complications. Most of these occurred during the year following implantation. A TIVAP may also be left in place for an extremely long time.

Real-World Survival Impact of New Treatment Strategies for Lung Cancer: A 2000-2020 French Cohort.

Over the past 20 years, several innovative therapies have been implemented in the treatment of lung cancer that have had reported survival benefits in clinical trials. Whether these improvements translate into the clinic setting has not been studied yet. We retrospectively analyzed all patients consecutively treated at Institute Curie for metastatic lung cancer. Diagnosis date was used to define three periods, based on the approvals of novel treatment strategies in the first-line setting, including targeted therapies in 2010 and immunotherapy in 2018. Endpoints included Overall survival (OS), survival rate of 2 years and 5 years, and a conditional survival rate of 2 years (if still alive at 6 months from treatment initiation). A total of 673 patients were identified for Period 1-2000 to 2009, 752 for Period 2-2010 to 2017, and 768 for Period 3-2018 to 2020. Median OS in the whole cohort was 11.1, 15.5, and 16.2 months, respectively. Median OS for patients with NSCLC or SCLC was 11.2, 17.2, and 18.2 months, or 10.9, 11.7, and 11.2 months, respectively. The two-year conditional survival was more favorable for NSCLC than SCLC patients. Outcomes were statistically higher for women as compared to men in all periods and all subgroups. Survival of patients with metastatic lung cancer has improved over the past 20 years, mostly in NSCLC, along with the implementation of novel treatment strategies.

Capmatinib efficacy for METex14 non-small cell lung cancer patients: Results of the IFCT-2104 CAPMATU study.

BACKGROUND: Capmatinib is a selective MET inhibitor with demonstrated efficacy in a phase II study of non-small cell lung cancer (NSCLC) patients harboring METex14 mutations. However, the real-world outcomes of capmatinib are largely unknown. From June 2019, the French Early Access Program (EAP) provided capmatinib to METex14 NSCLC patients who were ineligible for or for whom first-line standard therapies had failed. METHODS: IFCT-2104 CAPMATU was a multicenter study that included all METex14 NSCLC patients who received capmatinib as part of the EAP until August 2021. The primary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). RESULTS: A total of 146 patients were included. The median age was 74.9 years, 56.6 % were never-smokers, and 32.4 % had brain metastases. The median TTF, median PFS and median OS from capmatinib initiation were 5.1 months (95 % CI 4.2-6.0), 4.8 months (95 % CI 4.0-6.0) and 10.4 months (95 % CI 8.3-13.2), respectively. Evaluation of the best response to capmatinib was available for 134 patients and resulted in an ORR of 55.3 % (95 % CI 46.8 %-63.6 %). The median PFS was 7.7 months for treatment-naïve patients and 6.0 and 4.1 months for patients who had received one or 2 + prior lines of treatment, respectively. For patients with brain metastases, the median PFS was 3.0 months. Capmatinib had a known and manageable safety profile, with grade 3 to 4 adverse events, mostly peripheral edema (8.2 %), occurring in 17.8 % of patients. CONCLUSION: In this large real-world study of METex14 NSCLC patients, the efficacy of capmatinib was confirmed, with a manageable safety profile, even in patients with brain metastases and in those who received several lines of treatment. This study reinforces the key role of capmatinib for these patients.

Accelerated subsequent lung cancer after post-operative radiotherapy for breast cancer.

BACKGROUND: Post-operative whole breast radiotherapy for breast cancer (BC) may increase the risk of subsequent lung cancer (LC). The impact of radiotherapy intensification (boost) has not been specifically explored in this context. We investigated the role of radiation modalities on the development of subsequent LC among our patients treated by radiotherapy for localized BC. METHODS: All patients with a diagnosis of LC between 2000 and 2020 with a history of prior localized BC treated by surgery and post-operative radiotherapy were retrospectively reviewed. Primary endpoint was time to first diagnosis of LC after BC treatment with radiotherapy (RT). RESULTS: From 98 patients who developed subsequent LC after primary BC treated with post-operative RT, 38% of patients (n = 37) received an additional RT boost, and 46% (n = 45) received hormonal treatment post radiation. A total of 61% (n = 60) were smokers. With regards to LC characteristics, adenocarcinoma was the most frequent histology (68%, n = 66); 36% (n = 35) harbored at least 1 molecular alteration, 57% (n = 20) of them being amenable to targeted therapy. Median time to first diagnosis of LC was 6 years [1.7-28.4 yrs] in the whole cohort. In the subgroup of patients treated with boost this time was reduced to 4 years [1.8-20.8 years] compared to 8 years for patients without boost [1.7-28.4 yrs] (p = 0.007). Boost, smoking usage, endocrine therapy, and age <50 yrs old at BC radiation remained independent factors associated with shorter time to first diagnosis of LC after BC treatment. DISCUSSION: We report for the first time the potential impact of boost -part of BC radiation treatment- for BC on the risk of subsequent LC. The impact of low dose radiation on lung parenchyma could explain this phenomenon, but the underlying physiopathology is still under investigation. This work highlights the need for clinicians to identify patients at risk of developing faster subsequent thoracic malignancy after BC radiation, for implementing personalized surveillance.

Outcome of adrenocortical carcinoma patients included in early phase clinical trials: Results from the French network ENDOCAN-COMETE.

BACKGROUND: At metastatic stage, treatment of adrenocortical carcinoma (ACC) relies in first line on mitotane therapy, combination of mitotane with locoregional therapies or cisplatin-based chemotherapy according to initial presentation. In second line, ESMO-EURACAN recommendations favour enrolment of patients in clinical trials investigating experimental therapies. However, the benefit of this approach remains unknown. METHODS: The aim of our retrospective study was to analyse the inclusion and outcomes of all patients of the French cohort ENDOCAN-COMETE included in early clinical trials between 2009 and 2019. RESULTS: Of the 141 patients for whom a local or national multidisciplinary tumour board recommended, as first choice, to look for clinical trial, 27 patients (19%) were enroled in 30 early clinical trials. Median progression-free survival (PFS) was 3.02 months (95% confidence interval [95% CI]; 2.3-4.6) and median overall survival (OS) was 10.2 months (95% CI; 7.13-16.3) while the best response, evaluable in 28 of 30 trial participants according to RECIST 1.1 criteria, was partial response for 3 patients (11%) stable disease for 14 patients (50%) and progressive disease for 11 patients (39%), resulting in a disease control rate of 61%. Median growth modulation index (GMI) in our cohort was 1.32, with a significantly prolonged PFS in 52% of the patients compared to the previous line. The Royal Marsden Hospital (RMH) prognostic score was not associated with OS in this cohort. CONCLUSION: Our study suggests that patients with metastatic ACC benefit from inclusion in early clinical trials in second line. As recommended, if a clinical trial is available, it should be the first choice for suitable patients.

Drug Development in Tissue-Agnostic Indications.

A better understanding of cancer biology has led to the development of targeted therapies specifically designed to modulate an altered molecular pathway in the cancer cells or their microenvironment. Despite the identification of molecular targets across cancer types, most of targeted therapies were developed per cancer type. In this ancestral paradigm, randomization was the gold-standard approach for market access. Randomization of large patient populations was feasible for drugs developed in common cancer types but more challenging in rare cancer types. The traditional paradigm of drug development in oncology was further challenged by the ever-expanding molecular segmentation of cancer with ever-smaller subgroups of patients who might benefit from specific targeted therapies or immunotherapies and the identification of molecular alterations against which drugs may be effective across cancer types. In this novel drug development paradigm, novel ways of evaluating the efficacy of drugs are highly needed in these small patient populations. One approach is to use each patient as his/her own control by comparing the efficacy of a drug to the efficacy of prior treatments received. This approach allows to overcome patient heterogeneity, especially in a tissue-agnostic drug development paradigm.

Risks and benefits of anticancer drugs in advanced cancer patients: A systematic review and meta-analysis.

Background: Randomized clinical trials (RCTs) of anticancer drugs without active comparators in patients who have exhausted standard of care treatment options are debated. We aimed to quantify the safety and the efficacy of anticancer drugs in advanced cancer patients who have exhausted standard of care treatments from RCTs without active comparators.Methods: This systematic review and meta-analysis was conducted according to preferred reporting Items for systematic review and Meta-Analyses (PRISMA) guidelines (CRD42021243968). A systematic literature search of English language publications from January 1, 2000, to January 7, 2021, was performed using MEDLINE (PubMed). Eligible trials included all RCTs evaluating anticancer drugs in adult patients with advanced solid tumors with a control arm without any anticancer drug consisting of best supportive care with or without a placebo. RCTs performed in the adjuvant, neoadjuvant or maintenance settings were excluded, as were clinical trials evaluating anticancer drugs in combination with radiotherapy. Two authors (C.M.B. and E.C.) independently reviewed the studies for inclusion. Data from published reports were extracted by investigators, and random-effects meta-analysis was performed to estimate the overall hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS). Correlations between severe toxicity and efficacy was assessed using R2 measures.Findings: Of 3551 studies screened, 128 eligible trials were found involving 47,432 patients. The HRs for PFS and OS were 0·58 [95%CI: 0·53-0·63] and 0·82 [95%CI: 0·78-0·85]. The absolute benefits however were limited with PFS and OS gains of 2·1 and 0·5 months. The absolute excesses in all grade, severe grade III, IV and V (death) adverse events between the two arms were +13·9%, 10·2%, and +0·5%. A weak correlation was measured between the excess of severe toxicity and efficacy (all R² < 0·2).Interpretation: Anticancer drugs evaluated in RCTs against no active treatment benefited trial participants. Severe toxicity did not significantly correlate with efficacy. FUNDING: None.

Genomic Alterations in Head and Neck Squamous Cell Carcinoma: Level of Evidence According to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT).

Development of high-throughput technologies helped to decipher tumor genomic landscapes revealing actionable molecular alterations. We aimed to rank the level of evidence of recurrent actionable molecular alterations in head and neck squamous cell carcinoma (HNSCC) on the basis of the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) to help the clinicians prioritize treatment. We identified actionable alterations in 33 genes. HRAS-activating mutations were ranked in tier IB because of the efficacy of tipifarnib (farnesyltransferase inhibitor) in HRAS-mutated patients with HNSCC (nonrandomized clinical trial). Microsatellite instability (MSI), high tumor mutational burden (TMB), and NTRK fusions were ranked in tier IC because of PD-1 and TRK tyrosine kinase inhibitors tissue-agnostic approvals. CDKN2A-inactivating alterations and EGFR amplification were ranked in tier IIA because of the efficacy of palbociclib (CDK4/6 inhibitor) and afatinib (tyrosine kinase inhibitor) in these respective molecular subgroups in retrospective analyses of clinical trials. Molecular alterations in several genes, including PIK3CA gene, were ranked in tier IIIA because of clinical benefit in other tumor types, whereas molecular alterations in IGF1R and TP53 genes were ranked in tier IVA and tier V, respectively. The most compelling actionable molecular alterations in HNSCC according to ESCAT include HRAS-activating mutations, MSI, high TMB, NTRK fusions, CDKN2A-inactivating alterations, and EGFR amplification.

A computational method for prioritizing targeted therapies in precision oncology: performance analysis in the SHIVA01 trial.

Precision oncology is currently based on pairing molecularly targeted agents (MTA) to predefined single driver genes or biomarkers. Each tumor harbors a combination of a large number of potential genetic alterations of multiple driver genes in a complex system that limits the potential of this approach. We have developed an artificial intelligence (AI)-assisted computational method, the digital drug-assignment (DDA) system, to prioritize potential MTAs for each cancer patient based on the complex individual molecular profile of their tumor. We analyzed the clinical benefit of the DDA system on the molecular and clinical outcome data of patients treated in the SHIVA01 precision oncology clinical trial with MTAs matched to individual genetic alterations or biomarkers of their tumor. We found that the DDA score assigned to MTAs was significantly higher in patients experiencing disease control than in patients with progressive disease (1523 versus 580, P = 0.037). The median PFS was also significantly longer in patients receiving MTAs with high (1000+ <) than with low (<0) DDA scores (3.95 versus 1.95 months, P = 0.044). Our results indicate that AI-based systems, like DDA, are promising new tools for oncologists to improve the clinical benefit of precision oncology.

Fine-needle aspiration as an alternative to core needle biopsy for tumour molecular profiling in precision oncology: prospective comparative study of next-generation sequencing in cancer patients included in the SHIVA02 trial.

High-throughput molecular profiling of solid tumours using core needle biopsies (CNB) allows the identification of actionable molecular alterations, with around 70% success rate. Although several studies have demonstrated the utility of small biopsy specimens for molecular testing, there remains debate as to the sensitivity of the less invasive fine-needle aspiration (FNA) compared to CNB to detect molecular alterations. We aimed to prospectively evaluate the potential of FNA to detect such alterations in various tumour types as compared to CNB in cancer patients included in the SHIVA02 trial. An in-house amplicon-based targeted sequencing panel (Illumina TSCA 99.3 kb panel covering 87 genes) was used to identify pathogenic variants and gene copy number variations (CNV) in concomitant CNB and FNA samples obtained from 61 patients enrolled in the SHIVA02 trial (NCT03084757). The main tumour types analysed were breast (38%), colon (15%), pancreas (11%), followed by cervix and stomach (7% each). We report 123 molecular alterations (85 variants, 23 amplifications and 15 homozygous deletions) among which 98 (80%) were concordant between CNB and FNA. The remaining discordances were mainly related to deletions status, yet undetected alterations were not exclusively specific to FNA. Comparative analysis of molecular alterations in CNB and FNA showed high concordance in terms of variants as well as CNVs identified. We conclude FNA could therefore be used in routine diagnostics workflow and clinical trials for tumour molecular profiling with the advantages of being minimally invasive and preserve tissue material needed for diagnostic, prognostic or theranostic purposes.

Current Clinical Evidence and Potential Solutions to Increase Benefit of CAR T-Cell Therapy for Patients with Solid Tumors.

Immunotherapy by chimeric antigen receptor (CAR)-modified T-cells has shown unprecedented clinical efficacy for hematological malignancies. Recently two CAR T-cell based therapeutics, Kymriah (Tisagenlecleucel) and Yescarta (Axicabtagene ciloleucel) were approved by the US Food and Drug Administration and by the European Medicines Agency. Despite the progress in treating hematological malignancies, challenges remain for the use of CAR T-cell therapy in patients with solid tumors. Barriers yet to overcome for achieving effective CAR T-cell therapy include antigenic heterogeneity of solid tumors, an immune-suppressive microenvironment, and organ-specific properties that limit T-cell entry. This review will summarize available clinical data for CAR T-cell therapy in solid tumors, including present obstacles and promising strategies to advancement.

Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer.

Recently many therapeutic classes have emerged in advanced hormone receptor-positive breast cancer, which is the leading cause of cancer death in women. In absence of visceral crisis, treatment relies on endocrine therapy combined with cyclin dependent kinase 4 and 6 inhibitor. Many mechanisms lead to resistance to endocrine therapy, including the activation of intracellular signaling pathways critical for cell survival. Approximately 70% of breast tumors harbor an alteration in the phosphoinositide 3 kinase (PI3K)/Akt pathway, leading to its hyper activation. This pathway is involved in the regulation of growth, proliferation and cell survival as well as in angiogenesis and is consequently a major target in the oncogenesis. An aberrant PIK3CA mutation is a common phenomenon in breast cancer and found in approximately 40% of patients with advanced hormone receptor-positive breast cancer. For the moment, the only positive trials showing a progression free survival benefit in this population are BOLERO-2 (2012), SOLAR-1 (2019), which tested everolimus, a mammalian target of rapamycin inhibitor, and alpelisib, a PI3K inhibitor, and led to their marketing authorization. However, many other inhibitors of this pathway are promising; nevertheless their development is actually limited by toxicity, mainly cutaneous (rash), digestive (diarrhea) and endocrine (diabetes).

Pseudoprogression and Hyperprogression as New Forms of Response to Immunotherapy.

Indications of immunotherapy in oncology are continuously expanding, and unconventional types of response have been observed with these new treatments. These include transient progressive disease followed by a partial response, described as pseudoprogression, that raises the question of treatment beyond progression; and rapid disease progression associated with clinical decline, reported as hyperprogression. However, there are currently no consensual definitions of these phenomena and their impact on daily practice remains unclear. We reviewed existing data on pseudoprogression and hyperprogression with a focus on the definitions, incidence, predictive factors, potential biological mechanisms, and methods published to help distinguish pseudoprogression from progression and hyperprogression. The incidence of pseudoprogression ranged from 0 to 15%, with some authors also including disease stabilization after a first progression. For hyperprogression, incidence ranged from 4 to 29% with various definitions, and several authors reported a correlation with worse survival. Both phenomena were observed in a large panel of cancer types. Several radiological and biological methods have been reported to help distinguish pseudoprogression from progression and hyperprogression, such as analysis of radiomics, and circulating-tumor DNA or cell-free DNA, but these need to be confirmed in larger prospective cohorts. In conclusion, pseudoprogression and hyperprogression are both frequent types of responses under immunotherapy, and there is a need to better characterize these to improve the management of cancer patients. Treatment beyond progression should always be considered with caution and necessitates close clinical monitoring. In case of suspected hyperprogression, immunotherapy should be stopped early.

Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data.

Pembrolizumab is a full-length human immunoglobulin G4 (IgG4) monoclonal antibody directed against the immune checkpoint PD-1 to remove its binding with PD-L1 and thus to restore an anti-tumor immune response of T cells. Pembrolizumab is one of the most advanced immune checkpoint inhibitors for cancer care. Apart from rare and serious adverse effects, its favorable tolerance profile enables to treat fragile patients who have often no other choice than best supportive care. The effective retained dose of pembrolizumab is a venous administration of 200 mg every 3 weeks until disease progression, intolerance or up to 24 months. Pembrolizumab has already proven its efficacy and thus obtained marketing authorization in so-called hot or hypermutated tumors or tumors expressing PD-L1 such as melanomas, non-small cell lung cancers, urothelial carcinomas, cervical cancer, etc. Pembrolizumab is also authorized in the United States in the treatment of mismatch repair-deficient tumors or with microsatellite instability. The current challenge is to expand its use in tumor types that are supposed to be less immunogenic, for example, by attempting to warm up the tumor microenvironment, or by combining pembrolizumab with other molecules. An acceptable toxicity profile of such combinations remains to explore. We review here the current indications of this drug, the main prognostic and predictive factors of its efficacy as well as the potential forthcoming indications.

Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study.

BACKGROUND: Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy. METHODS: We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively. FINDINGS: Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1. INTERPRETATION: Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.

Ipilimumab-induced autoimmune pancytopenia in a case of metastatic melanoma.

A 77-year-old patient treated with ipilimumab (anti-CTLA-4 antibody) for metastatic melanoma developed autoimmune pancytopenia (anemia, thrombocytopenia, and neutropenia) 8 days after the fourth infusion. This pancytopenia was resistant to high-dose oral corticosteroids (1 mg/kg) and to hematopoietic growth factors. It resolved after intravenous immunoglobulins injection. To date, only 1 case of autoimmune pancytopenia has been reported after this treatment. According to the case that we report, it seems essential to control the leukocyte count before any injection of ipilimumab.