Targeted Therapy for Older Patients with Non-Small Cell Lung Cancer: Systematic Review and Guidelines from the French Society of Geriatric Oncology (SoFOG) and the French-Language Society of Pulmonology (SPLF)/ French-Language Oncology Group (GOLF)

Systematic molecular profiling and targeted therapy (TKI) have changed the face of Non-Small Cell Lung Cancer (NSCLC) treatment. However, there are no specific recommendations to address the prescription of TKI for older patients. A multidisciplinary task force from the French Society of Geriatric Oncology (SoFOG) and the French Society of Pulmonology/Oncology Group (SPLF/GOLF) conducted a systematic review from May 2010 to May 2021. Protocol registered in Prospero under number CRD42021224103. Three key questions were selected for older patients with NSCLC: (1) to whom TKI can be proposed, (2) for whom monotherapy should be favored, and (3) to whom a combination of TKI can be proposed. Among the 534 references isolated, 52 were included for the guidelines. The expert panel analysis concluded: (1) osimertinib 80 mg/day is recommended as a first-line treatment for older patients with the EGFR mutation; (2) full-dose first generation TKI, such as erlotinib or gefitinib, is feasible; (3) ALK and ROS1 rearrangement studies including older patients were too scarce to conclude on any definitive recommendations; and (4) given the actual data, TKI should be prescribed as monotherapy. Malnutrition, functional decline, and the number of comorbidities should be assessed primarily before TKI initiation. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Optimisation of EGFR TKI efficiency in the therapeutic scheme of EGFR wild-type lung cancer.

e18532 Background: EGFR tyrosine kinase inhibitors (EGFR TKI) have improved the therapeutic care of lung cancer patients but only a small sub-population of patients, namely those harboring EGFR-mutated tumors, benefit from this therapy. The observation that EGFR TKI enhance prognosis and quality of life in all patients when used as second line or maintenance treatment impelled us into the search of potential markers of the optimal introduction kinetics of EGFR TKI in the therapeutic scheme. Methods: We used lung cancer cell lines harboring either wild-type or mutated EGFR (NCI-H1650, NCI-H1975) to study the consequences of cisplatin treatment in vitro on the consecutive sensitivity to erlotinib. Results: Sub-lethal cisplatin pretreatment (3µM) enhances erlotinib toxicity in EGFR wild-type, but not EGFR mutated cells (A549 IC50 drops from 28 to 15µM for short-term or 12µM for long-term exposure). This correlates with EGFR activation following short-term or prolonged cisplatin treatment through the secretion of EGFR ligands. This activation of EGFR is concomitant to the decrease in other receptor tyrosine kinases phosphorylation including Met. Conclusions: The sensitivity of EGFR wild-type lung cancer cells to erlotinib in vitro is enhanced by cisplatin pretreatment. We identified potential markers of this sensitization, namely EGFR ligands, which serum level might be predicitive of the optimal efficiency of EGFR TKI. In vivo validation of these markers is under investigation. The concomitant decrease in other receptor tyrosine kinases phosphorylation suggests that the targeting of other receptor tyrosine kinases might potentiate EGFR TKI efficiency. </jats:p

Abstract 2559: Optimisation of EGFR TKI efficiency wild-type EGFR lung cancer

Abstract Background : Lung cancer is the first cause of cancer death worldwide. EGFR tyrosine kinase inhibitors (EGFR-TKI) have improved the survival of patient harboring EGFR activating mutations. Besides, EGFR-TKIs have shown clinical activity for patients with wild type EGFR (wtEGFR) tumors as maintenance treatment and for a fraction of them as second line treatment. These observations impel us to objective and document the mechanisms implicated in order to optimize the use of EGFR-TKI in the treatment of wtEGFR lung cancer. Methods : In vitro experiments rely on lung cancer cell lines expressing either wtEGFR or mutated EGFR. Their sensitivity to erlotinib in control conditions or short after a sublethal cisplatin treatment was studied. In vitro results were validated on lung patients-derived xenografts (PDX) with four wtEGFR human adenocarcinomas. Results : Cisplatin pretreatment enhances erlotinib toxicity in wtEGFR cells (providing its robust expression) but not in EGFR-mutated cells. Cisplatin priming increases erlotinib toxicity either through apoptosis or autophagy depending on the cell line. This sensitization correlates with an increase in EGFR expression and phosphorylation and a raise in AKT and Erk phosphorylation. The sensitization is also observed during long-term cisplatin treatment in a cisplatin-resistant subpopulation, together with concomitant EGFR pathway activation. The in vivo experiments conducted in PDX confirm that cisplatin pretreatment potentiates erlotinib in three of the four wtEGFR lung tumors models. Of note, the sensitization to erlotinib occured independently from KRas status. Conclusion : The sensitivity of the wtEGFR lung cancer cells and lung cancer xenografts to erlotinib is enhanced by cisplatin pretreatment, whatever the type of induced cell death. Cisplatin induces activation of EGFR and his downstream kinases AKT and Erk. This sensitization is independent from the tumor K-Ras status. EGFR phosphorylation could be a potential marker of this sensitization and might be predicitive of the optimal efficiency of EGFR TKI. In vivo validation of this marker is still ongoing. This study was supported by Roche laboratory and by the foundation for medical research. Citation Format: Judith Raimbourg, Mathilde Cabart, Marie-Pierre Joalland, Didier Decaudin, Ludmilla Deplater, Didier Lanoe, Jean-Yves Douillard, Jaafar Bennouna, François Vallette, Lisenn Lalier. Optimisation of EGFR TKI efficiency wild-type EGFR lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2559. doi:10.1158/1538-7445.AM2015-2559</jats:p

Prostate cancer and PARP inhibitors: progress and challenges

AbstractDespite survival improvements achieved over the last two decades, prostate cancer remains lethal at the metastatic castration-resistant stage (mCRPC) and new therapeutic approaches are needed. Germinal and/or somatic alterations of DNA-damage response pathway genes are found in a substantial number of patients with advanced prostate cancers, mainly of poor prognosis. Such alterations induce a dependency for single strand break reparation through the poly(adenosine diphosphate-ribose) polymerase (PARP) system, providing the rationale to develop PARP inhibitors. In solid tumors, the first demonstration of an improvement in overall survival was provided by olaparib in patients with mCRPC harboring homologous recombination repair deficiencies. Although this represents a major milestone, a number of issues relating to PARP inhibitors remain. This timely review synthesizes and discusses the rationale and development of PARP inhibitors, biomarker-based approaches associated and the future challenges related to their prescription as well as patient pathways.</jats:p

Impact of 18FDG-PET CT in the management of invasive bladder cancer.

444 Background: Guidelines do not recommend FDG-Positron Emission Tomography (PET) Computed Tomography (CT) for the staging of Muscle Invasive Bladder Cancer (MIBC), but rather CT scan for lymph node (LN) and metastatic staging, despite its low accuracy. We performed a retrospective analysis of patients (pts) with MIBC who had a FDG-PET CT for staging, indicated by multidisciplinary team, in two centers, and analyzed its utility in this setting. Methods: All pts who had a FDG-PET CT performed at the time of diagnosis of MIBC from 01/2005 to 12/2017 in Bordeaux (Bergonie Institute and University Hospital) were retrospectively reviewed. Nodal and metastatic staging on CT and FDG-PET CT were done independently according to the 8th TNM classification. The aims of the study were to evaluate the accuracy of the FDG-PET CT for LN staging and to determine the rate of treatment modification (neoadjuvant chemotherapy for curative intent, no surgery for metastatic disease), according to FDG-PET CT results. Results: Among the 130 pts included, with a median age of 65 years, 74% were considered free from nodal metastasis (N0) by CT whereas only 44% were N0 from FDG-PET CT. Based on CT results, 88% of pts were free from distant metastasis (M0) but only 75% were classified M0, on FDG-PET CT. Accuracy of LN staging for CT and FDG-PET CT at initial diagnosis were analyzed for 85 pts (including 70 pts treated with neoadjuvant chemotherapy) and compared to pathological examination of resected LN. Sensitivity of FDG-PET CT was better than CT (respectively 80.8% versus 26.9%) but the specificity was low (respectively 54.2% versus 83.1%). Youden index was better for FDG-PET CT (0.35; 0.1 for CT), being more accurate for determining LN staging of MIBC. FDG-PET CT findings allowed a treatment decision modification in 34/130 pts (26.1%): therapeutic intensification in 12 pts (9.2%), including surgery not previously indicated, modified radiotherapy; or de-escalation in 22 pts (16.9%), mostly avoiding surgery. Conclusions: FDG-PET CT is more sensitive to detect LN involvement at initial diagnosis of MIBC than standard CT scan. Moreover, in the present study, treatment decisions were modified, according to FDG-PET CT results, in a quarter of pts according to LN and distant metastatic staging. </jats:p

A randomized, non-comparative, phase II multicentric trial on short-term darolutamide (ODM-201) concomitant to radiation therapy for patients with unfavorable intermediate-risk prostate cancer: DARIUS (AFU-GETUG P15)

Background: Androgen Deprivation Therapy (ADT) with external beam radiation therapy (EBRT) is a standard of care for patients (pts) with unfavorable intermediate-risk prostate cancer (Pca). However, ADT generates side effects with 30% decrease of quality of life (QoL). Enzalutamide (E) and Darolutamide (D) combined with ADT offer an overall survival benefit in advanced Pca. Without ADT, E avoid most of the deleterious effects of ADT. In a population of pts with intermediate risk Pca, 92% achieved PSA values , 0.1 ng/ml at the end of a treatment with EBRT and E alone.1 In pre-clinical models treated with D alone, testosterone (T) level remained normal.2 Such side effects related to T loss and to peripheral aromatization of T might be decreased with D alone. We assume that a combination of D given 6 months with EBRT in the treatment of unfavorable intermediate risk Pca is efficient and safe, without consequences on QoL. Methods: DARIUS is a national, multi-center, non-comparative randomized phase II prospective study (NCT05346848). The primary objective is to assess antitumor activity of D given 6 months with EBRT in pts with unfavorable intermediate risk Pca, using a biological response defined as PSA #0.1ng/ml, 6 months after randomization. D 6 months + EBRT and ADT 6 months + EBRT are offered in experimental and standard arm respectively. Randomization is 2:1. Regarding the experimental arm, given that E used alone achieved a 49% 6-month biological response rate in a hormone-sensible Pca pts,3 the association D+ EBRT will be considered useful if it can increase this rate to at least 70%. Using a single-stage design, standard response rate (P0) is 50% and alternative hypothesis P1 is 70% (one-sided 5% type I error rate, 80% power). Following one-stage A’Hern design, 37 and 19 pts are required in the experimental and standard arm, respectively. Adding 10% of non-eligible/assessable pts, the total number is 62. Enrollment have already begun and 5 pts have been enrolled. Inclusion criteria are: PS ECOG # 2; histological diagnosis of Pca, without metastasis (on Pelvic MRI AND thoraco-abdomino-pelvic contrast-enhanced CT-Scan AND Bone Scintigraphy); with unfavorable intermediate risk Pca diagnosis (NCCN Guidelines): 1- either Gleason = 7 (4+3) OR, 2-$ 50% of the core of biopsies positive for adenocarcinoma OR, 3- two or three of the following criteria (PSA value between 10-20 ng/ml, Gleason 7 (3+4) or 6, T2b (clinical or radiological)). Pts with T3a extension on MRI can be included if Gleason score is 6 and PSA , 20. Secondary objectives are biochemical Progression Free Survival, MFS, DFS, Pca-specific survival, Time to T recovery, safety, QoL and bone mineral density. Predictive factors will be investigated using Radiomics and DECIPHER. 1. Lara Front Oncol 2022. 2. Molainen Sci Rep 2015. 3. Tombal Lancet Oncol 2014. Clinical trial information: NCT05346848. Research Sponsor: None

Sensitization of EGFR wild-type non-small cell lung cancer cells to EGFR-tyrosine kinase inhibitor erlotinib.: wtEGFR non-small cell lung cancer sensitization to erlotinib

International audienceThe benefit of EGFR-TKI in non-small cell lung cancer has been demonstrated in mutant EGFR tumors as first-line treatment but the benefit in wild-type EGFR tumors is marginal as well as restricted to maintenance therapy in pretreated patients. This work aimed at questioning the effects of cisplatin initial treatment on the EGFR pathway in non-small cell lung cancer and the functional consequences in vitro and in in vivo animal models of Patient-Derived Xenografts (PDX). We establish here that cisplatin pretreatment specifically sensitizes wild-type EGFR expressing cells to erlotinib, contrary to what happens in mutant-EGFR cells and with a blocking EGFR antibody, both in vitro and in vivo. The sensitization entails the activation of the kinase Src upstream of EGFR, thereafter transactivating EGFR through a ligand-independent activation. We propose a combination of markers which enable to discriminate between the tumors sensitized to erlotinib or not in PDX models, that should be worth testing in patients. These markers might be useful for the selection of patients who would benefit from erlotinib as a maintenance therapy