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Cutaneous melanoma incidence is rising. Early diagnosis and treatment administration are key for increasing the chances of survival. For patients with locoregional advanced melanoma that can be treated with complete resection, adjuvant-and more recently neoadjuvant-with targeted therapy-BRAF and MEK inhibitors-and immunotherapy-anti-PD-1-based therapies-offer opportunities to reduce the risk of relapse and distant metastases. For patients with advanced disease not amenable to radical treatment, these treatments offer an unprecedented increase in overall survival. A group of medical oncologists from the Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines, based on a thorough review of the best evidence available. The following guidelines try to cover all the aspects from the diagnosis-clinical, pathological, and molecular-staging, risk stratification, adjuvant therapy, advanced disease therapy, and survivor follow-up, including special situations, such as brain metastases, refractory disease, and treatment sequencing. We aim help clinicians in the decision-making process., (© 2024. The Author(s).)

Background and Purpose: Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions., Patients and Methods: We evaluated the association between AR expression, assessed through NanoString ® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis., Results: Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC., Conclusions: AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non-small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1-6). Lifileucel was successfully manufactured using tumor tissue from different anatomic sites, predominantly lung. The objective response rate was 21.4% (6/28). Responses occurred in tumors with profiles typically resistant to immunotherapy, such as PD-L1-negative, low tumor mutational burden, and STK11 mutation. Two responses were ongoing at the time of data cutoff, including one complete metabolic response in a PD-L1-negative tumor. Adverse events were generally as expected and manageable. Two patients died of treatment-emergent adverse events: cardiac failure and multiple organ failure. Lifileucel is a potential treatment option for patients with mNSCLC refractory to prior therapy. Significance: Autologous tumor-infiltrating lymphocyte therapy lifileucel was administered to 28 patients with heavily pretreated metastatic non-small cell lung cancer (mNSCLC). Responses were observed in patients with driver mutations, and various tumor mutational burdens and PD-L1 expression, potentially addressing an unmet medical need in patients with mNSCLC refractory to prior therapy. See related commentary by Lotze et al., p. 1366., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Cancer is a risk factor for developing severe COVID19. Additionally, SARS-CoV2 has a special tropism for renal cells and complications like thrombosis or cytokine storm could be enhanced by standard treatments in kidney cancer (i.e., antiangiogenics or immunotherapy). Thus, understanding the impact of COVID19 in patients with this tumor is key for their correct management., Methods: We designed a retrospective case-control study comparing the outcome of three groups of advanced kidney cancer patients on systemic treatment: cohort A (developed COVID19 while on antiangiogenics), cohort B (developed COVID19 while on immunotherapy) and cohort C (non-infected). Matching factors were age, gender, and treatment., Results: 95 patients were recruited in 16 centers in Spain from September 2020 to May 2021. Finally, 85 were deemed as eligible (23 cohort A, 21 cohort B, 41 cohort C). Patients with COVID required more dose interruptions (25 vs. six) and hospitalizations (10 vs. none) than those without COVID (both p = 0.001). No difference between cohorts A and B was observed regarding hospitalization or length of stay. No ICU admission was registered and one patient in cohort B died due to COVID19. Regarding cancer evolution, three patients in cohort A presented progressive disease after COVID19 compared to two in cohort B. One case in cohort B, initially deemed as stable disease, achieved a partial response after COVID19., Conclusions: Kidney cancer patients who developed COVID19 while on systemic therapy required more treatment interruptions and hospitalizations than those non-infected. However, no significant impact on cancer outcome was observed. Also, no difference was seen between cases on antiangiogenics or immunotherapy., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Purpose: The identification of subpopulations harboring druggable targets has become a major step forward in the subclassification of solid tumors into small groups suitable for specific therapies. BRAF fusions represent a paradigm of uncommon and targetable oncogenic events and have been widely correlated to the development of specific malignancies. However, they are only present in a limited frequency across most common tumor types. At this regard, we performed a genomic screening aimed to identifying rare variants associated to advanced prostate cancer development., Methods: Tumoral tissue genomic screening of 41 patients developing advanced prostate cancer was performed at our center as part of the GETHI XX study. The project, sponsored by the Spanish Collaborative Group in Rare Cancers (GETHI), aims to analyze the molecular background of rare tumors and to discover unfrequent molecular variants in common tumors., Results: Here we present the clinical outcome and an in-deep molecular analysis performed in a case harboring a SND1-BRAF fusion gene. The identification of such rearrangement in a patient refractory to standard therapies led to the administration of trametinib (MEK inhibitor). Despite unsensitive to standard therapies, the patient achieved a dramatic response to trametinib. A comprehensive study of the tumor demonstrated this event to be a trunk alteration with higher expression of MEK in areas of tumor invasion., Conclusions: Our study describes the patient-driven discovery of the first BRAF fusion-driven prostate cancer effectively treated with trametinib. Consequently, MAPK pathway activation could define a new subtype of prostate cancer susceptible to a tailored management., (© 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background: The aim of this study was to evaluate the impact of certain single-nucleotide polymorphisms (SNPs) in cabazitaxel activity and toxicity in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: 56 SNPs in five genes ( CYP3A4 , CYP3A5 , ABCB1 , TUBB1 and CYP2C8 ) were genotyped in 67 mCRPC patients and their correlation with outcomes analyzed. Results: TUBB1 -rs151352 (hazard ratio: 0.52) and CYP2C8 -rs1341164 (hazard ratio: 0.53) were associated with better overall survival, and CYP2C8 -rs1058932 with biochemical progression (odds ratio: 6.60) in multivariate analysis. ABCB1 -rs17327624 correlated with severe toxicity ≥grade 3 (odds ratio: 8.56) and CYP2C8 -rs11572093 with asthenia (odds ratio: 8.12). Conclusion: Genetic variants in mCRPC patients could explain different outcomes with cabazitaxel. Nonetheless, the small sample size and the high number of SNPs analyzed mean that the results are only hypothesis-generating and require further validation.

Background: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies., Patients and Methods: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate., Results: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib., Conclusion: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens., Competing Interests: Disclosure EG has received honoraria for speaker engagements, advisory roles, or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, GSK, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, Thermo Fisher Scientific. TAG has received support for the present manuscript (protocol review and manuscript review); has received research grants from Pfizer, Roche, and Ipsen; has received consulting fees from Ipsen, Pfizer, Roche, Sanofi, Bayer, Astellas, Janssen-Cilag, BMS, and EISAI; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Pfizer, Eisai, and Merck; has received support for attending meetings and/or travel from Pfizer, Sanofi, BMS, and IPSEN. OR has received personal payment from Eusapharma, BMS, Pfizer, and Ipsen; has received support for attending meetings and/or travel from Ipsen and Pfizer; has participated in the Advisory Board of BMS and Bayer. XGdM has received consulting fees from Roche, Pharmamar, BMS, Ipsen, Lilly, Eusapharma, Pfizer, Merck, and Astellas; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from BMS, Astellas, Pharma, Eisai, Pfizer, and EusaPharma; has received support for attending meetings and/or travel from Pfizer and Roche; and has received research funding from AstraZeneca. MJM has received payment or honoraria as invited speaker from Janssen-Cilag, Bayer Healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, EISAI, Norvartis, Pfizer, and MSD; has received travel support from Roche and Ipsen; has participated on Data Safety Monitoring Board or Advisory Board of Janssen-Cilag, Bayer Healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, EISAI, Novartis, Pfizer, and MSD. JGD has received grants or contracts from Eusapharma, Bristol Myers, Novartis, GSK, Merck, MSD, Sanofi, Janssen, Astellas, Astra Zeneca, and Ipsen; has received support for attending meetings and/or travel from Roche; has participated on a Data Safety Monitoring Board or Advisory Board from Pfizer and Pharmamar. MGR has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche; has received support for attending meetings and/travel from Roche, Ipsen, AstraZeneca, MSD, and Jansen. JAAA has received grants or contracts from Bristol-Myers Squibb (grant to Spanish GU Oncology Group for research in prostate cancer); has received consulting fees from Janssen, Cilag, Pfizer, MSD, and Bristol-Myers Squibb; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas, Pfizer, and MSD; has received support for attending meetings and/or travel from MSD, Bristol-Myers Squibb, and Astra Zeneca. PLC has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from MSD and Bristol; has participated on a Data Safety Monitoring Board or Advisory Board from Sanofi and Roche. JMC has received support for the present manuscript (protocol review and manuscript review); has received grants or contracts from Pfizer and Ipsen; has received consulting fees from Ipsen, Pfizer, Roche, Sanofi, Astellas, Janssen Cilag, BMS, and EISAI; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Pfizer, and BMS; and has received support for attending meetings and/or travel from Pfizer, BMS, and Ipsen. BM has received research grant/funding (self) from Jansen, Roche, Astellas, Sanofi, and Bayer; has received payment or honoraria for speaker bureau from Pfizer, Ipsen, Jansen, Roche, Astellas, Sanofi, BMS, and Bayer; has received support for travel accommodation from Pfizer, Ipsen, Janssen, and Roche; other financial or non-financial interests: advisory and speaker bureau rom Pfizer, Ipsen, Jansen, Roche, Astellas, Sanofi, BMS, and Bayer; travel accommodation from Pfizer, Ipsen, Jansen, and Roche; and research grant/funding (self) from Roche, Astellas, Sanofi Jansen, BMS, and Bayer. CAF has received consulting fees from Ipsen, Boehringer Ingelheim, and Astra Zeneca; has received support for attending meetings and/or travel from Roche, Pfizer, and Astellas. GDV has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from BMS, Pfizer, Roche, Merk, MSD, Bayer, Eusapharma, Astellas, and Ipsen; has received support for attending meetings and/or travel from Roche; has participated on a Data Safety Monitoring Board or Advisory Board from BMS, Pfizer, Roche, Merck, MSD, Bayer, and Astellas. JFRM has received support for the present manuscript from Pfizer; has received grants or contracts from HM Hospitales; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Pfizer, BMS, Novartis, and MSD; has received support for attending meetings from Pfizer, BMS, Novartis, and MSD; has participated on a Data Safety Monitoring Board or Advisory Board from BMS and Novartis; and has participated in corporate-sponsored research in his institution from AstraZeneca, BMS, Amgen, Roche, Novartis, MSD, Janssen, Pfizer, Astellas, GSK, PharmaMar, Ipsen, Tesaro, Abbvie, Aprea Therapeutics, Eisai, Bayer, and Merck. CSR has received grants or contracts from AB Science, Aragon Pharmaceuticals, Astellas Pharma, Astra Zeneca AB, Bayer, Blueprint Medicines Corporation, Boehringer Ingelheim España SA, BMS, Clovis Oncology, Exelixix Inc F, Genentech Inc, GlaxoSmithKline SA, Hoffman-La Roche LTD, Novartis Farmaceutica SA, Pfizer SLU, and Sanofi-Aventis; has received payment or honoraria for speakers’ bureau from Astellas Pharma, BMS, Hoffmann-La Roche LTD, Ipsen, Pfizer SLU; has participated on a Data Safety Monitoring Board or Advisory Board from Astellas Pharma, Bayer, BMS, Eusapharma, Hoffmann-La Roche LTD, Ipsen, MSD, Novartis, Pfizer, and Sanofi-Aventis E. All other authors have declared no conflicts of interest. Data sharing The clinical trial data are available from the corresponding author upon reasonable request., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment. At the time of publication, the patient was disease-free 8 years after temsirolimus treatment. Multiregion whole-exome sequencing (WES) on 3 regions of the primary tumor, 1 metastasis, and blood revealed tumor mutations in driver genes in ccRCC: a missense mutation in VHL (p.W88L), a loss-of-function mutation in BAP1 (p.E454Rfs*15), and a novel missense mutation in MTOR (p.Y1974H). The MTOR mutation was present in all tumor regions, with similar allele frequency as the VHL mutation, and in vitro functional assessment of the MTOR variant demonstrated that it increased mTORC1 activity. Consistently, immunohistochemistry in the tumor samples demonstrated increased levels of phospho-S6. In conclusion, multiregion WES identified a novel MTOR mutation acquired early during tumor development as the event leading to a high sensitivity to temsirolimus treatment. This study supports tumor multiregion sequencing to detect truncal mutations in the mTOR pathway to identify patients sensitive to mTOR inhibitors., (Copyright © 2017 by the National Comprehensive Cancer Network.)

Uterine cervical cancer is the second most common gynecological malignancy. It is estimated that over 35% of tumors are diagnosed at locally advanced disease, stage IB2-IIB with an estimated 5-year overall survival of 60%. During the last decades, the initial treatment for these women has been debated and largely varies through different countries. Thus, radical concurrent chemoradiation is the standard of care in United Sated and Canada, and neoadjuvant chemotherapy followed by radical surgery is the first line of treatment in some institutions of Europe, Asia and Latin America. Until today, there is no evidence of which strategy is better over the other. This article describe the evidence as well as the advantages and disadvantages of the main strategies of treatment for women affected by uterine cervical cancer stage IB2-IIB.

Targeted therapies alone or combined with chemotherapy have improved response rates as well as the progression-free survival and overall survival in several solid tumors. Trastuzumab is a monoclonal antibody with a revolutionary effect on tumoral breast cells, but also on the myocardium, as has been identified recently, following the inherent cascade signaling shared between both cells. Instead of decreasing the use of trastuzumab, investigations based on the results of Metastatic and Adjuvant Breast Cancer Trials tend to develop monitoring schemes as well as risk factor identification and prophylactic applications in order to improve the number of patients receiving full treatment instead of restricting it. Moreover, the largely reversible trastuzumab effect (different from anthracyclines) allows its reintroduction or its later withdrawal with cardiologic directed therapy. In conclusion, every action is aiming at optimizing trastuzumab's application instead of abandoning.