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.
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.
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 (
)-mutated NSCLC developing a
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.
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.
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.
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 (
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
mutation, a
and
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
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.
Bone metastases (BM) in renal cell carcinoma (RCC) are associated with a poor prognosis based on retrospective studies evaluating antiangiogenic agents. Few data are available regarding immune ...checkpoint inhibitors (ICI) in patients with bone metastatic RCC. NIVOREN is a multicentre prospective study in which patients were treated with nivolumab after the failure of antiangiogenic agents. We aim to assess the impact of BM on prognosis, and the efficacy and safety of nivolumab in patients enrolled in the NIVOREN trial.
All patients with BM at inclusion were included in our study. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), safety, and skeletal-related events (SRE).
Among 720 patients treated with nivolumab, 194 presented BM at inclusion. The median follow-up was 23.9 months. Median OS was 17.9 months in patients with BM versus 26.1 months in patients without BM (p = 0.0023). The difference was not statistically significant after adjustment (p = 0.0707). The median PFS was shorter in patients with BM even after adjustment (2.8 versus 4.6 months, p = 0.0045), as well as the ORR (14.8% versus 23.3%). SRE occurred for 36% of patients with BM. A post-hoc analysis evaluating the impact of bone-targeting agents (BTA) on SRE incidence showed a significant benefit of BTA on the incidence of SRE (OR = 0.367, CI95% 0.151–0.895).
Nivolumab is associated with shorter PFS, and lower ORR in RCC patients with BM. Our study suggests that BTA in association with immunotherapy decreases the incidence of SRE.
•Lower efficacy of nivolumab if bone metastases (BM) in renal cell carcinoma (RCC).•Negative impact of BM, known with antiangiogenic agents, still present with nivolumab.•First study evaluating bone-targeting agents (BTA) with immunotherapy in RCC with BM.•Benefit of BTA on skeletal-related events incidence without an increase of BTA toxicity.•The use of BTA with immunotherapy alone should be considered.
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.
The administration of systemic corticosteroid therapy for a prolonged period in patients undergoing treatment with immune checkpoint inhibitors for metastatic lung cancer can have a direct impact on the tumor response and may be reversible.
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.
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.
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.
Most thoracic oncologists in France are using teleconsultation, mostly as an additional tool that should not replace the doctor-patient in-person relationship.
Supportive care has become a new pilar of modern oncology, and a great deal of research is being conducted in that area, especially on immune checkpoint inhibitors (ICIs), to help fine-tune ...immunotherapy. Four major areas of supportive care can enhance responsiveness to cancer immunotherapy whilst minimizing adverse effects: diet (indirectly, by modulating the microbiota or directly, by modulating the immune system), physical activity (by modulating the immune system), electronic patient-reported outcomes (ePRO) (by detecting and treating immune-related adverse events early on), and co-medication management (to possibly suppress those drugs that negatively affect the efficacy of ICIs). Therefore, patients treated with ICIs could receive a systematic multimodal supportive care program encompassing regular nutritional counseling, regular physical activity under the supervision of a physical activity professional, ePRO follow-up, and regular pharmaceutical counseling. This type of approach needs to be evaluated in well-conducted randomized clinical trials.
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