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Introduction: The phase 3 KEYNOTE-361 trial of first-line pembrolizumab with or without chemotherapy versus chemotherapy alone in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) completed enrollment before the approval of postchemotherapy maintenance avelumab for patients without progressive disease. This post hoc analysis evaluated the outcomes of patients who received chemotherapy alone in KEYNOTE-361 by retrospective eligibility for subsequent maintenance therapy., Patients and Methods: Patients in the chemotherapy alone arm were retrospectively categorized as maintenance eligible (received ≥4 cycles of chemotherapy and did not die or experience disease progression within 10 weeks of chemotherapy completion), maintenance ineligible (received <4 cycles of chemotherapy or had progressive disease or died within 0-10 weeks after completion of ≥4 cycles of chemotherapy), and indeterminate eligibility for maintenance therapy (if neither maintenance eligible or ineligible). End points included progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review and overall survival from randomization (start of chemotherapy)., Results: Median follow-up was 31.7 months (range, 22.0-42.3). Among 342 patients who received chemotherapy alone, 172 (50.3%) were maintenance eligible, 108 (31.6%) were maintenance ineligible, and 62 (18.1%) had indeterminate eligibility for maintenance therapy. The median progression-free survival was 9.0 months (95% CI 8.4-10.4) in maintenance-eligible patients, 5.1 months (4.2-6.0) in maintenance-ineligible patients, and 2.3 months (1.9-3.8) in the indeterminate group; median overall survival was 23.3 months (95% CI 19.4-26.1), 10.2 months (9.1-11.6), and 5.5 months (3.7-8.5), respectively., Conclusion: This post hoc analysis suggests that a majority of patients with untreated la/mUC who initiated chemotherapy in a clinical trial may have been considered eligible for maintenance therapy and had favorable survival outcomes compared with those considered maintenance ineligible., Competing Interests: Disclosure R. Mamtani reports research grants or contracts to his institution from Astellas and MSD and consulting fees from Astellas, Bristol Myers Squibb, Merck & Co, Inc, and Seagen outside the submitted work. N. Matsubara reports research grants or contracts to his institution from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Chugai, Eisai, Eli Lilly, Janssen, MSD, Pfizer, PRA Health Science, Roche, Taiho, Takeda, and Seagen; personal payment or honoraria from Sanofi; and support for attending meetings and/or travel from Pfizer outside the submitted work. A. Montesa Pino reports consulting fees from Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck & Co, Inc, MSD, Novartis, and Pfizer; support for attending meetings and/or travel from Bayer, Ipsen, Merck & Co, Inc, and Pfizer; and participation on a data safety monitoring board or advisory board of Advanced Accelerator Applications, Ipsen, and Merck & Co, Inc outside the submitted work. U. Anido Herranz reports payments for lectures from Ipsen and Merck & Co, Inc outside the submitted work. M. A. N. Şendur reports consulting fees and payments or honoraria from Astellas, AstraZeneca, Bristol Myers Squibb, Gilead, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda. G. Gravis reports research grants or contracts to his institution from Bristol Myers Squibb and Janssen; payments or honoraria to his institution for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Advanced Accelerator Applications, Alliance Merck-Pfizer, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, MSD, Pfizer, and Sanofi; support for attending meetings and/or travel from AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, and Pfizer; and participation on a data safety monitoring board or advisory board of Advanced Accelerator Applications, Alliance Merck-Pfizer, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, and Pfizer outside the submitted work. O. Huillard reports payments or honoraria to his institution for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Advanced Accelerator Applications, Bristol Myers Squibb, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, and Sanofi; and support for attending meetings and/or travel from Advanced Accelerator Applications and Ipsen outside the submitted work. R. Gafanov reports funding for the present manuscript from MSD; research grants or contracts to him and his institution from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche; payments or honoraria to him and his institution for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche; support for attending meetings and/or travel from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche; and participation on a data safety monitoring board or advisory board of Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche outside the submitted work. F. Joly reports grants or contracts to her institution for ISS protocol from Ipsen; consulting fees paid to her for membership of scientific board of Esai Co, Ltd., Ipsen, and Pfizer; payment for lectures from Ipsen and Pfizer; and support for congress attendance from Esai Co, Ltd. and Ipsen. J. Bedke reports receiving medical writing support and local principal investigator payments to his institution for the present manuscript from MSD; local principal investigator payments to his institution from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, MSD, Nektar, Novartis, Pfizer, Roche, and Seagen; consulting fees from Apogepha, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Merck Serono, MSD, Pfizer, and Roche; payment or honoraria to him and his institution for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Astellas, Bristol Myers Squibb, Ipsen, Merck Serono, MSD, Pfizer, Roche, and Seagen; support for attending meetings and/or travel from Ipsen and Merck & Co, Inc; payments to his institution for participation on a steering committee of Bristol Myers Squibb, MSD, and Seagen and participation on a data safety monitoring board or advisory board of MSD and Pfizer, outside the submitted work. K. Imai, B. Homet Moreno, and J. Z. Xu are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and have stock in Merck & Co, Inc, Rahway, NJ, USA. A. Alva reports funding to his institution for the present manuscript from MSD and research grants or contracts to his institution from MSD. T. Powles reports grants or contracts from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Gilead, Ipsen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Seattle Genetics, and Roche; consulting fees from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Mashup, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Mashup, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; support for attending meetings and/or travel from Astellas, AstraZeneca, Gilead, Ipsen, MSD, Pfizer, and Roche; participation on a data safety monitoring board or advisory board of Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and other financial or nonfinancial interests as principal investigator for AstraZeneca, Eisai, MSD, Novartis, Pfizer, and Roche/Genentech, outside the submitted work. H. J. Lee, A. Sella, and Y.-H. Chang declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Thyroid cancer is the most frequent endocrine tumor. However, in locally advanced or metastatic disease we have only two types of treatment at our disposal: radioactive iodine (RAI) when the disease is RAI-sensitive and multikinase inhibitors (MKIs), lenvatinib and sorafenib, when the disease becomes RAI-refractory (RR). This review revisits the published data on the potential combination of MKIs/lenvatinib with RAI in RR-differentiated thyroid cancer and evaluates some special situations where this combination may be of particular interest. The combination of MKIs/lenvatinib with RAI could, at least hypothetically, improve the efficacy seen in both treatments alone via a synergistic effect and with a lower rate of toxicity rates. Early preclinical data support this notion, while its generalized use awaits the results of ongoing clinical trials., (© 2022 The Author. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC)., Objective: To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and circulating tumor DNA (ctDNA) in the ABACUS trial., Design, Setting, and Participants: ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy., Intervention: Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected., Outcome Measurements and Statistical Analysis: The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements., Results and Limitations: The median follow-up time was 25 mo (95% confidence interval [CI] 25-26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21-41). Two-year DFS and OS were 68% (95% CI 58-76) and 77% (95% CI 68-85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65-94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio [HR] 0.60 [95% CI 0.24-1.5], p = 0.26, and 0.72 [95% CI 0.31-1.7], p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 [95% CI 0.09-0.68], p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 [95% CI 1.3-13], p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work., Conclusions: Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future., Patient Summary: We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC)., Objective: To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial., Design, Setting, and Participants: ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy., Intervention: Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC., Outcome Measurements and Statistical Analysis: Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed., Results and Limitations: Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue [20%], decreased appetite [6%], and transaminases increased [6%]). Treatment-related grade 3-5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1-2) and major (grade 3-5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non-treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available., Conclusions: Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention., Patient Summary: Here, we report a comprehensive dataset of patients receiving neoadjuvant immune checkpoint inhibitors before radical cystectomy. Treatment with neoadjuvant atezolizumab is safe and does not seem to complicate surgery significantly., (Copyright © 2020. Published by Elsevier B.V.)

Background: Adjuvant treatment for both small-cell and non-small-cell lung cancer is a controversial topic. There are no published results from prospective studies that either confirm or reject the benefit of adjuvant radiotherapy, although the presentation of recent studies at a number of conferences questions whether there should be a change in the paradigm of adjuvant RT for lung cancer., Aim: The main goal of this study is to review the most relevant publications on the topic, updating the state of the matter regarding adjuvant radiotherapy following lung surgery, and analyzing the role of chemotherapy in the process., Relevance for Patients: This review aims to assess the potential benefit of PORT in NSCLC and SCLC patients by looking at recent research. In doing so, it will be possible to determine which patients might benefit from it as adjuvant treatment after pulmonary resection., Competing Interests: The authors declare no conflict of interest related to the submitted work in accordance with the ICMJE guidelines., (Copyright: © Whioce Publishing Pte. Ltd.)

Introduction: The MAJA study compared vinflunine (VFL) plus best supportive care (BSC) maintenance therapy versus BSC alone in advanced urothelial carcinoma responsive to first-line chemotherapy. The primary end point of progression-free survival was achieved. We present the final overall survival (OS) and long-term follow-up safety analyses., Patients and Methods: Patients were enrolled, and a subsequent post hoc analysis was performed on the basis of radiologic response or stabilization to first-line cisplatin/gemcitabine (CG) chemotherapy (4-6 cycles), according to Response Evaluation Criteria in Solid Tumors (RECIST). VFL + BSC versus BSC alone were randomly assigned until disease progression., Results: At final analysis, 58 patients (66.7%) had died while 29 (33.3%) had survived; the BSC arm had higher mortality (VFL + BSC, n = 26, 59.1% vs. BSC, n = 32, 74.4%). Median follow-up of surviving patients was 38.8 months (interquartile range, 23.8-61.6). Median OS was 16.7 months (95% confidence interval, 0-34.5) in VFL and 13.2 months (95% confidence interval, 6-20.4) in the BSC groups (hazard ratio, 0.736; 95% confidence interval, 0.44-1.24, P = .182). Post hoc group division did not affect median OS in either study arm., Conclusion: Final analysis supported a benefit of VFL in maintenance therapy in patients with disease control after first-line treatment with CG, with no unexpected long-term adverse effects. The study was insufficiently powered to show a significant OS advantage., (Copyright © 2020 Elsevier Inc. All rights reserved.)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers 1,2 . Biomarkers may facilitate identification of these responding tumors 3 . Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer 4-7 . Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.

Prostate cancer is the most frequent cancer amongst men. Until recently, only two therapeutic options, initial androgen-deprivation therapy in patients without castration-resistant prostate cancer, with addition of docetaxel when the disease becomes castration-resistant, were considered as standard. In the last years, new drugs (abiraterone, enzalutamide, Ra-223, Sipuleucel) have been developed for prostate cancer treatment with important advantages in safety and efficacy. Results from the recent Chaarted study, in patients that received docetaxel for the hormone sensitive disease, have contributed to change the initial treatment approach in metastatic prostate cancer, in order to adapt the best sequence for each patient. Those results have been supported by the Stampede trial. Stampede survival data showed not only a benefit in overall survival of adding docetaxel initially, but also a prolonged time to first skeletal related event. Now it is discussed in which setting the available drugs should be administered. This review article summarizes the treatment options for patients treated with docetaxel initially for hormone sensitive prostate cancer after developing progressive disease, and offers an algorithm proposal for treatment., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Enzalutamide (MDV3100), an androgen receptor-signalling inhibitor, represents the most recent compound added to the therapeutic armamentarium for the treatment of metastatic castration-resistant prostate cancer (mCRPC) who progressed to docetaxel. The anti-tumour activity and safety of enzalutamide has been demonstrated in a phase III clinical trial, showing a benefit in overall survival, which was the primary endpoint. There are no head-to-head studies comparing the different treatment options in this subset of patients. In this article, most relevant data published in the literature have been reviewed, with special attention to the therapeutic alternatives currently available for postdocexatel mCRPC patients, emphasising the mechanisms of action of the different drugs, efficacy and quality of life-related aspects., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Renal cell carcinoma (RCC) with sarcomatoid features has an aggressive course. There is no standard treatment for this histological subtype. Some authors have previously reported the use of chemotherapy, but the activity of new agents against renal carcinoma with sarcomatoid differentiation has to be formally evaluated. Temsirolimus, an inhibitor of the mammalian target or rapamycin, is active in RCC, including those tumors with non-clear histologies. We have tested the activity of this agent in three consecutive patients. A first patient showed a rapid progression, dying 2 months after the diagnosis. The second patient showed clinical improvement and a partial response to lung metastasis that was maintained for 14 months. The third patient is still alive, evaluated as stable disease after 7 months on temsirolimus. Importantly, toxicity was not a main issue during the use of temsirolimus and only grade 2 hyperglycemia, asthenia, hyperlipidemia, and pleural effusion were detected. Temsirolimus is a valid therapy in this subset of patients, with some lasting stabilizations and with manageable toxicity.