Exploring the Efficacy of Pembrolizumab in Combination with Carboplatin and Weekly Paclitaxel for Frail Patients with Advanced Non-Small-Cell Lung Cancer: A Key Investigative Study.

INTRODUCTION: Immune checkpoint blockers have revolutionized the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Pembrolizumab, an anti-PD-1 monoclonal antibody, is a standard therapy either alone or in combination with chemotherapy (chemo-IO). The current study explores the efficacy and safety of pembrolizumab with carboplatin and weekly paclitaxel in a cohort of frail patients. METHODS: A monocentric retrospective study was conducted between 22 September 2020 and 19 January 2023 regarding patients with stage IV NSCLC treated with chemo-IO combination: carboplatin (AUC 5 mg/mL/min; Q4W), weekly paclitaxel (90 mg/m2 on days 1, 8, and 15), and pembrolizumab (200 mg Q4W). The primary objective was real-world progression-free survival (rwPFS). Secondary objectives were overall survival (OS), toxicity profile, and outcomes based on histological subtype. RESULTS: A total of 34 patients (20 squamous and 14 non-squamous NSCLC) benefited from the chemo-IO regimen for frail patients; 41.9% had an ECOG-PS = 2. The median age was 75.5 years. We observed an overall response rate (ORR) of 55.9%. Notably, squamous NSCLC exhibited a significantly higher ORR (80%) than non-squamous NSCLC (21.4%); p = 0.001. The median rw-PFS was 10.6 months (95% CI [6.0, NA]), with 6- and 12-month rw-PFS rates of 69% and 45.8%, respectively. The median OS was not reached, with 12- and 18-month OS rates of 75.6% and 61.4%, respectively. The median number of maintenance cycles of pembrolizumab was 5 (0; 27). Nine patients (26.5%) experienced a toxicity related to chemotherapy leading to a reduction of the dose administered and, in five patients (14.7%), to the permanent discontinuation of chemotherapy. Six patients (17.6%) had an immune-related adverse event leading to the discontinuation of immunotherapy. DISCUSSION: Pembrolizumab plus carboplatin and weekly paclitaxel demonstrates promising efficacy and safety in frail patients with metastatic NSCLC, especially for ORR in sq-NSCLC. Prospective studies focusing on frail populations are warranted in order to validate these findings and optimize therapeutic strategies in the first-line setting.

Circulating tumour cells and PD-L1-positive small extracellular vesicles: the liquid biopsy combination for prognostic information in patients with metastatic non-small cell lung cancer.

BACKGROUND: Circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), and extracellular vesicles (EVs) are minimally invasive liquid biopsy biomarkers. This study investigated whether they predict prognosis, alone or in combination, in heterogenous unbiased non-small cell lung cancer (NSCLC) patients. METHODS: Plasma samples of 54 advanced NSCLC patients from a prospective clinical trial. CtDNA mutations were identified using the UltraSEEK™ Lung Panel (MassARRAY® technology). PD-L1 expression was assessed in small EVs (sEVs) using an enzyme-linked immunosorbent assay. RESULTS: At least one ctDNA mutation was detected in 37% of patients. Mutations were not correlated with overall survival (OS) (HR = 1.1, 95% CI = 0.55; 1.83, P = 0.980) and progression-free survival (PFS) (HR = 1.00, 95% CI = 0.57-1.76, P = 0.991). High PD-L1+ sEV concentration was correlated with OS (HR = 1.14, 95% CI = 1.03-1.26, P = 0.016), but not with PFS (HR = 1.08, 95% CI = 0.99-1.18, P = 0.095). The interaction analysis suggested that PD-L1+ sEV correlation with PFS changed in function of CTC presence/absence (P interaction = 0.036). The combination analysis highlighted worse prognosis for patients with CTCs and high PD-L1+ sEV concentration (HR = 7.65, 95% CI = 3.11-18.83, P < 0.001). The mutational statuses of ctDNA and tumour tissue were significantly correlated (P = 0.0001). CONCLUSION: CTCs and high PD-L1+ sEV concentration correlated with PFS and OS, but not ctDNA mutations. Their combined analysis may help to identify patients with worse OS. TRIAL REGISTRATION: NCT02866149, Registered 01 June 2015, https://clinicaltrials.gov/ct2/show/study/NCT02866149 .

Optimal First-Line Medico-Surgical Strategy in Ovarian Cancers: Are We There Yet?

In spite of tremendous advances in advanced ovarian cancer management through the past decade, notably owing to surgical expertise and novel combination molecules (including bevacizumab and PARP inhibitors), the optimal initial sequential strategy remains a major concern. Indeed, following seminal clinical trials, primary cytoreductive surgery (PCS) followed by adjuvant systemic therapy and interval cytoreductive surgery (ICS) following neoadjuvant chemotherapy (NACT) have been positioned as validated alternatives with distinct pros and cons, although a definite response is still unassessed. In clinical practice, decisions between PCS and ICS rely on multilayer parameters: the tumor itself, the patient, and the health structure. In this state-of-the-art review, we will discuss the current evidence based on clinical trials and real-world data and highlight the remaining questions, including the fittest positioning of PCS vs. ICS and the optimal number of NACT cycles; subsequently, we will discuss current axes of research such as dedicated clinical trials and more global perspectives. These ongoing strategies and perspectives could contribute to improving the patient journey through personalized medicine.

Comedications with Immune Checkpoint Inhibitors: Involvement of the Microbiota, Impact on Efficacy and Practical Implications.

Immune checkpoint inhibitors (ICIs) have been a major breakthrough in solid oncology over the past decade. The immune system and the gut microbiota are involved in their complex mechanisms of action. However, drug interactions have been suspected of disrupting the fine equilibrium necessary for optimal ICI efficacy. Thus, clinicians are facing a great deal of sometimes contradictory information on comedications with ICIs and must at times oppose conflicting objectives between oncological response and comorbidities or complications. We compiled in this review published data on the role of the microbiota in ICI efficacy and the impact of comedications. We found mostly concordant results on detrimental action of concurrent corticosteroids, antibiotics, and proton pump inhibitors. The timeframe seems to be an important variable each time to preserve an initial immune priming at ICIs initiation. Other molecules have been associated with improved or impaired ICIs outcomes in pre-clinical models with discordant conclusions in retrospective clinical studies. We gathered the results of the main studies concerning metformin, aspirin, and non-steroidal anti-inflammatory drugs, beta blockers, renin-angiotensin-aldosterone system inhibitors, opioids, and statins. In conclusion, one should always assess the necessity of concomitant treatment according to evidence-based recommendations and discuss the possibility of postponing ICI initiation or switching strategies to preserve the critical window.

[Combination strategies for checkpoint inhibition: Current practices and perspectives]. / Combinaisons d'inhibiteurs de points de contrôle immunitaires en oncologie : état de l'art et perspectives.

T-cell checkpoint blockade therapies have revolutionized treatment protocols and prognosis in patients with cancer. Pointed out by the success of PD-1 (programmed cell death-1) plus CTLA-4 (cytotoxic-T-lymphocyte associated antigen 4) blockade in patients with melanoma, the perspective of new synergistic immunotherapy combinations seems to be an important opportunity to improve outcomes for patients. In this article, we first focus on immunotherapy combinations that have shown their efficiency and that are currently approved in solid tumors. Then, we present a summary of emerging targets with reported pre-clinical efficacy and currently evaluated through ongoing clinical trials and other immunomodulatory molecules in the tumor microenvironment.

Combining Three Tyrosine Kinase Inhibitors: Drug Monitoring Is the Key.

A combination of tyrosine kinase inhibitors (TKIs) is likely to be a therapeutic option for numerous oncological situations due to high frequency of oncogenic addiction and progress in precision oncology. Non-small cell lung cancer (NSCLC) represents a subtype of tumors for which oncogenic drivers are frequently involved. To the best of our knowledge, we report the first case of a patient treated with three different TKIs. Osimertinib and crizotinib were administered concurrently for an epidermal growth factor receptor (EGFR)-mutated NSCLC developing a MET amplification as a resistance mechanism to osimertinib. Simultaneously, imatinib was administered for a metastatic gastrointestinal stromal tumor. The progression-free survival was 7 months for both tumors with this tritherapy. The use of therapeutic drug monitoring to assess plasma concentrations of each TKI was a powerful tool to manage the toxicity profile of this combination (creatine phosphokinase elevation) while preserving an optimal exposure to each TKI and treatment efficacy. We observed an imatinib over-exposition related to crizotinib introduction, probably explained by drug-drug interaction mediated by crizotinib enzymatic inhibition on cytochrome P-450 3A4. Posology adjustment due to therapeutic drug monitoring was probably involved in the good survival outcome of the patient. This tool should be used more routinely for patients treated by TKIs to prevent co-treatment interactions and, in particular, for patients receiving TKI combinations to obtain optimal therapeutic exposure and efficacy while reducing possible side-effects.

Optimal timing of interval debulking surgery for advanced epithelial ovarian cancer: A retrospective study from the ESME national cohort.

OBJECTIVE: Interval debulking surgery is recommended after 3-4 cycles (standard IDS) of neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer (EOC) not able to received upfront complete debulking surgery. However, real world practices frequently report performing IDS after ≥5 NAC cycles (delayed IDS). The aim of this work was to evaluate the impact on survival of the number of NACT cycles before IDS. METHODS: We identified from a French national database, women with newly diagnosed EOC who underwent IDS from January 2011 to December 2016. Progression free survival (PFS) and overall survival (OS) were compared using Cox model with adjustments for confounding factors provided by two propensity score methods: inverse probability of treatment weighting (IPTW) and matched-pair analysis. RESULTS: 928 patients treated by IDS for which our propensity score could be applied were identified. After a median follow-up of 49.0 months (95% CI [46.0;52.9]); from the IPTW analysis, median PFS was 17.6 months and 11.5 months (HR = 1.42; CI 95% [1.22-1.67]; p < 0.0001); median OS was 51.2 months and 44.3 months (HR = 1.29; CI 95% [1.06-1.56]; p = 0.0095) for the standard and delayed IDS groups. From the matched-pair analysis (comparing 352 patients for each group), standard IDS was associated with better PFS (HR = 0,77; CI 95% [0.65-0.90]; p = 0.018) but not significantly associated with better OS (HR = 0,84; CI 95% [0.68-1,03]; p = 0.0947). CONCLUSIONS: Carrying IDS after ≥5 NACT cycles seems to have a negative effect on patients survival. The goal of IDS surgery is complete resection and should not be performed after >3-4 NACT cycles.

Brief Report on Teleconsultation in Lung Cancer: Toward a Semiotic Paradigm Shift?

Introduction: Telehealth is taking an increasingly important part of medicine. This practice change is being accelerated by the pandemic linked to coronavirus disease 2019. Oncology is a medical specialty for which this paradigm shift is particularly relevant. Methods: We developed a survey aiming at evaluating the use of teleconsultation by physicians managing patients with lung cancer in France. The survey was available online from December 15, 2020, to February 10, 2021. Results: Answers were obtained from 142 clinicians (73.9% pneumologists, 18.3% medical oncologists, and 7.7% with another specialty), 129 (90.8%) of whom had already performed teleconsultation. Among those, 123 (95.3%) started after the coronavirus disease 2019 pandemic. In addition, 72.9% had a moderate usage of this tool (<10 teleconsultations/mo). The frequency of clinicians never using teleconsultation was higher in private practices (p = 0.029). The two clinical situations for which teleconsultation was frequently used were visits during treatment without imaging assessment (53.5%) and post-treatment surveillance (80.3%). Depending on the type of treatment received, the frequency of teleconsultation was variable. Lung cancer subtype also affected the clinician's practice. Indeed, 47.2% never proposed this tool for SCLC. Teleconsultation was considered to be of no contribution, a moderate contribution, a significant contribution, or a revolution of the clinical practice for 14.1%, 66.2%, 10.6%, and 2.1% of the respondents, respectively. The participants expected to decrease, stabilize, or increase their teleconsultation activity in 18.3%, 52.8%, and 23.2% of the cases, respectively. Conclusions: Most thoracic oncologists in France are using teleconsultation, mostly as an additional tool that should not replace the doctor-patient in-person relationship.

[Combining surgery and medical treatments for ovarian cancer: Is there an optimal strategy?] / Combinaison de la chirurgie et du traitement médical du cancer de l'ovaire : y a-t-il une stratégie optimale ?

The objective of this review is to evaluate the optimal positioning of cytoreduction surgery and perioperative medical treatments in the initial management and relapse of advanced-stage epithelial ovarian carcinoma. In the initial management, primary surgery should be proposed if the absence of tumor residue is feasible with reasonable surgery (extensive surgical resections to be considered and their complications, but also the general condition of the patient). Guidelines recommend 3 to 4 cycles of neoadjuvant chemotherapy before interval surgery for patients not eligible for primary surgery. Late interval surgery (i.e. after≥5-6 cycles of chemotherapy) is not a standard of care and should only be proposed in case of poor tumor response after 3-4 cycles and when complete interval surgery seems feasible. At first tumor recurrence in platinum-sensitive patients, a primary cytoreduction surgery can be considered if complete surgery can be managed. Predictive scores (AGO score; i-model score) can be used to select eligible patients. Given the lack of strong evidence, performing cytoreduction surgery at first recurrence in platinum-resistant patients or in the event of subsequent recurrence cannot be recommended. Nevertheless, obtaining a complete surgery in these clinical situations seems to provide a benefit in terms of overall survival and its application should be based on the expertise of specialized teams.

Case report: Liquid biopsy, the sooner the better?

The detection of circulating tumor DNA (ctDNA) by liquid biopsy is taking an increasing role in thoracic oncology management due to its predictive and prognostic value. For non-small cell lung cancer, it allows the detection of molecular mutations that can be targeted with tyrosine kinase inhibitors (TKIs). We report the case of a patient with life-threatening hepatocellular failure and thrombotic microangiopathy at the diagnosis. A salvage chemotherapy was attempted, resulting in a major worsening of her general condition and the decision to stop all anti-cancer treatment. The liquid biopsy performed at the time of immunohistochemical non-small cell lung cancer diagnosis revealed within 7 days the presence of an epidermal growth factor receptor (EGFR) DEL19 activating mutation with 736,400 DNA copies/ml of plasma. It was finally decided to attempt a treatment with osimertinib (third generation anti-EGFR TKI) despite the fact that the patient was in a pre-mortem situation. Osimertinib led to a significant and prompt improvement of her performance status after only one week of treatment. The tumor tissue genotyping performed by next-generation sequencing (NGS) was available 10 days after starting TKI treatment. It revealed in addition to the EGFR DEL19 mutation, a JAK3 and EGFR amplification, highlighting the complex interactions between EGFR and the JAK/STAT signaling pathways. The first CT-scan performed after 2 months under osimertinib showed a tumor morphologic partial response. The biological assay showed a major decrease in the EGFR DEL19 mutation ctDNA levels (40.0 copies/ml). The liquid biopsy allowed an early implementation of a targeted therapy without which the patient would probably be dead. Testing for ctDNA should be discussed routinely at diagnosis in addition to tumor tissue genotyping for patient with metastatic non-small cell lung cancer that raise the clinical profile of oncogenic addiction.

Enteral administration of alectinib for ALK-positive non-small cell lung cancer in an elderly patient: A case report.

RATIONALE: Alectinib is a tyrosine kinase inhibitor (TKI) approved for use as first-line metastatic therapy for patients with anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Certain medical conditions related to the tumor lesions may not allow oral administration of TKIs. PATIENT CONCERNS: We hereby report the case of a 90-year-old patient with anaplasic lymphoma kinase-rearranged lung cancer with severely impaired general condition and swallowing disorders. DIAGNOSIS: A thoracic computerized tomography (CT)-scan confirmed the presence of a mediastinal tumor lesion explaining the swallowing disorders secondary to recurrent paralysis. INTERVENTIONS: As no oral administration was feasible, alectinib was administered by percutaneous gastrostomy. OUTCOMES: The patient had few side-effects. He presented a major clinical and radiological response. After 2 months of treatment with alectinib, his mini-mental state examination had increased from 8/30 to 23/30. He had a 60% reduction in targeted pulmonary, bone and node lesions according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). After 6 months of treatment, the patient's performance status had evolved from 3 to 1. This improvement in general condition made it possible to remove the feeding tube. LESSONS: In cases of lung cancer with oncogenic addiction, enteral administration of TKIs should be considered for elderly patients with an impaired general condition.

Generation and Characterization of a New Preclinical Mouse Model of EGFR-Driven Lung Cancer with MET-Induced Osimertinib Resistance.

Despite the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to treat advanced lung cancer harboring EGFR-activating mutations, the prognosis remains unfavorable because of intrinsic and/or acquired resistance. We generated a new state-of-the-art mouse strain harboring the human EGFRT790M/L858R oncogene and MET overexpression (EGFR/MET strain) that mimics the MET amplification occurring in one out of five patients with EGFR-mutated lung cancer that relapsed after treatment with osimertinib, a third-generation anti-EGFR TKI. We found that survival was reduced in EGFR/MET mice compared with mice harboring only EGFRT790M/L858R (EGFR strain). Moreover, EGFR/MET-driven lung tumors were resistant to osimertinib, recapitulating the phenotype observed in patients. Conversely, as also observed in patients, the crizotinib (anti-MET TKI) and osimertinib combination improved survival and reduced tumor burden in EGFR/MET mice, further validating the model's value for preclinical studies. We also found that in EGFR/MET mice, MET overexpression negatively regulated EGFR activity through MIG6 induction, a compensatory mechanism that allows the coexistence of the two onco-genic events. Our data suggest that single EGFR or MET inhibition might not be a good therapeutic option for EGFR-mutated lung cancer with MET amplification, and that inhibition of both pathways should be the best clinical choice in these patients.

Dissociated response related to corticosteroids in lung cancer treated by immunotherapy: A case report.

We report the case of a patient with a complete metastatic adrenal response on Pembrolizumab for metastatic lung cancer. Treatment with a systemic corticosteroid-induced a time-dependent progression at his metastatic site. Surprisingly, after stopping the corticosteroid, we observed a new complete response in long-term adrenal metastases.

Pembrolizumab Plus Chemotherapy in Metastatic Thymic Carcinoma: A Case Report.

Metastatic thymic carcinomas have a poor prognosis. Pembrolizumab, an anti-PD-1 antibody, has recently been evaluated for patients with metastatic thymic carcinomas progressing after at least one line of platinum-based chemotherapy. The antitumor activity of immunotherapy appears to be promising for these patients and pembrolizumab in monotherapy is actually a treatment option in second metastatic line. To the best of our knowledge, we report the first case of a patient treated for metastatic thymic adenocarcinoma with a combination of chemotherapy-immunotherapy. The patient is a 46-year-old man with metastatic thymic adenocarcinoma treated in third metastatic line with a combination of pembrolizumab plus platinum-based chemotherapy with a very good metabolic tumor response. He had a progression-free survival of 7.9 months and did not experience any severe side effects related to pembrolizumab. The association of immunotherapy and chemotherapy, as in non-small cell and small cell lung cancers, could be of interest for future therapeutic trials evaluating the survival of patients with metastatic thymic carcinoma.