Ross A. Soo, Urania Dafni, Ji-Youn Han, Byoung Chul Cho, Ernest Nadal, Chong Ming Yeo, Enric Carcereny, Javier de Castro, Maria Angeles Sala, Linda Coate, Mariano Provencio, Christian Britschgi, Patrick Vagenknecht, Georgia Dimopoulou, Roswitha Kammler, Stephen P. Finn, Solange Peters, Rolf A. Stahel
{"title":"ctDNA dynamics and mechanisms of acquired resistance in patients treated with osimertinib with or without bevacizumab from the randomised phase II ETOP-BOOSTER trial","authors":"Ross A. Soo, Urania Dafni, Ji-Youn Han, Byoung Chul Cho, Ernest Nadal, Chong Ming Yeo, Enric Carcereny, Javier de Castro, Maria Angeles Sala, Linda Coate, Mariano Provencio, Christian Britschgi, Patrick Vagenknecht, Georgia Dimopoulou, Roswitha Kammler, Stephen P. Finn, Solange Peters, Rolf A. Stahel","doi":"10.1158/1078-0432.ccr-24-0932","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0932","url":null,"abstract":"Background: ETOP 10-16 BOOSTER study was a randomised phase II trial of osimertinib and bevacizumab versus osimertinib in patients with an acquired EGFR T790M mutation. The mechanisms of acquired resistance to osimertinib and bevacizumab have not been described previously. Methods: Next generation sequencing (Guardant360®) was conducted in serial plasma samples. The association between ctDNA and efficacy outcomes was explored and molecular alterations at progression were described. Results: 136 patients (88% of 155 randomised) had plasma samples at baseline (68 per arm), 110 (71%) at week 9 and 65 (42%) at progression. In a multivariable model for progression-free survival (PFS), the treatment effect was found different by smoking status (interaction p=0.046), with the effect of smoking also different by baseline EGFR T790M (interaction p=0.033), while both TP53 at baseline and tissue EGFR Exon 21 L858R mutation were significantly associated with worse PFS outcome. Smokers (current/former) without baseline EGFR T790M showed a significant improvement in PFS under combination treatment, albeit with small numbers (p=0.015). Week-9 EGFR T790M clearance was associated with improved PFS in the osimertinib arm (p=0.0097). Acquired EGFR C797S mutations were detected in 22% and 13% of patients in the combination and osimertinib arm, respectively. Conclusions: The differential effect of treatment by smoking was not explained by TP53 mutation or other molecular alterations examined. Molecular mechanisms of acquired resistance were detected but no novel molecular alterations were identified in the combination arm.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sarina Piha-Paul, Shane A Olwill, Erika Hamilton, Anthony Tolcher, Paula Pohlmann, Stephen V Liu, Cornelia Wurzenberger, Laura-Carolin Hasenkamp, Eva-Maria Hansbauer, Rachna Shroff, Sara Hurvitz, Anuradha Krishnamurthy, Amita Patnaik, Noah Hahn, Raman Kumar, Manuela Duerr, Markus Zettl, Kayti Aviano, Louis Matis, Ingmar Bruns, Geoffrey Ku
{"title":"A First-in-Human Study of cinrebafusp alfa, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-Positive Advanced Solid Malignancies.","authors":"Sarina Piha-Paul, Shane A Olwill, Erika Hamilton, Anthony Tolcher, Paula Pohlmann, Stephen V Liu, Cornelia Wurzenberger, Laura-Carolin Hasenkamp, Eva-Maria Hansbauer, Rachna Shroff, Sara Hurvitz, Anuradha Krishnamurthy, Amita Patnaik, Noah Hahn, Raman Kumar, Manuela Duerr, Markus Zettl, Kayti Aviano, Louis Matis, Ingmar Bruns, Geoffrey Ku","doi":"10.1158/1078-0432.CCR-24-1552","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1552","url":null,"abstract":"<p><strong>Purpose: </strong>4-1BB (CD137) is a costimulatory immune receptor expressed on activated T cells, activated B cells, natural killer cells and tumor-infiltrating lymphocytes, making it a promising target for cancer immunotherapy. Cinrebafusp alfa, a monoclonal antibody-like bispecific protein targeting HER2 and 4-1BB, aims to localize 4-1BB activation to HER2-positive tumors. This study evaluated the safety, tolerability, and preliminary efficacy of cinrebafusp alfa in patients with previously treated HER2-positive malignancies.</p><p><strong>Experimental design: </strong>This was a multi-center dose escalation study involving patients with HER2-positive malignancies who had received prior treatment. The study assessed the safety and efficacy of cinrebafusp alfa across various dose levels. Patients were assigned to different cohorts, and antitumor responses were evaluated. The study aimed to determine the maximum tolerated dose (MTD) and to observe any clinical activity at different dose levels.</p><p><strong>Results: </strong>Out of 40 evaluable patients in the 'active dose' efficacy cohorts, 5 showed an antitumor response, resulting in an overall response rate (ORR) of 12.5% and a disease control rate of 52.5%. Clinical activity was observed at the 8 mg/kg and 18 mg/kg dose levels, with confirmed objective response rates of 28.6% and 25.0%, respectively. Cinrebafusp alfa was safe and tolerable, with Grade ≤2 infusion-related reactions being the most frequent treatment-related adverse event. MTD was not reached during the study.</p><p><strong>Conclusion: </strong>Cinrebafusp alfa demonstrates promising activity in patients with HER2-positive malignancies who have progressed on prior HER2-targeting regimens. Its acceptable safety profile suggests it could be a treatment option for patients not responding to existing HER2-directed therapies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael H Brave, William F Maguire, Chana Weinstock, Hui Zhang, Xin Gao, Fang Li, Jingyu Yu, Wentao Fu, Hong Zhao, William F Pierce, Elaine Chang, Jeannette Dinin, Mallorie H Fiero, Nam Atiqur Rahman, Shenghui Tang, Richard Pazdur, Paul G Kluetz, Laleh Amiri-Kordestani, Daniel L Suzman
{"title":"FDA Approval Summary: Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma.","authors":"Michael H Brave, William F Maguire, Chana Weinstock, Hui Zhang, Xin Gao, Fang Li, Jingyu Yu, Wentao Fu, Hong Zhao, William F Pierce, Elaine Chang, Jeannette Dinin, Mallorie H Fiero, Nam Atiqur Rahman, Shenghui Tang, Richard Pazdur, Paul G Kluetz, Laleh Amiri-Kordestani, Daniel L Suzman","doi":"10.1158/1078-0432.CCR-24-1393","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1393","url":null,"abstract":"<p><p>On December 15, 2023, the FDA granted traditional approval to enfortumab vedotin-ejfv plus pembrolizumab (EV + Pembro) for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Substantial evidence of effectiveness was obtained from EV-302/KEYNOTE-A39 (NCT04223856), an open-label, randomized, trial evaluating EV + Pembro versus cisplatin or carboplatin plus gemcitabine (Plat + Gem) in patients with previously untreated la/mUC. A total of 886 patients were randomized (1:1) to receive EV 1.25 mg/kg intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle for up to 35 cycles, or Plat + Gem for up to 6 cycles. Dual primary endpoints were progression-free survival (PFS) determined by blinded independent central review and overall survival (OS). Median PFS was 12.5 months (95% CI: 10.4, 16.6) in the EV + Pembro arm and 6.3 months (95% CI: 6.2, 6.5) in the Plat + Gem arm (HR 0.450 [95% CI: 0.377, 0.538]; p-value < 0.0001). Median OS was 31.5 months (95% CI: 25.4, NE) in the EV + Pembro arm and 16.1 months (95% CI: 13.9, 18.3) in the Plat + Gem arm (HR 0.468 [95% CI: 0.376, 0.582]; p-value < 0.0001). The safety profile of EV + pembrolizumab was similar to that observed in EV-103/KEYNOTE-869 in cisplatin-ineligible patients with la/mUC. This article summarizes the data and the FDA thought process supporting traditional approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by FDA.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Novel Therapies in Cancer: Trials and Tribulations.","authors":"Saiama N Waqar, Ramaswamy Govindan","doi":"10.1158/1078-0432.CCR-24-1127","DOIUrl":"10.1158/1078-0432.CCR-24-1127","url":null,"abstract":"<p><p>Clinical trials are the backbone for advancing therapeutic options for patients diagnosed with cancer. Yet only 7.1% of patients with cancer participate in clinical trials in the United States. In this article, we review some of the reasons for poor accrual and discuss potential solutions. See related article by van Berge Henegouwen et al., p. 3937.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jena D French, Bryan R Haugen, Francis P Worden, Daniel W Bowles, Andrew G Gianoukakis, Bhavana Konda, Ramona Dadu, Eric J Sherman, Shaylene McCue, Nathan R Foster, Yuri E Nikiforov, Ticiana D J Farias, Paul J Norman, Lori J Wirth
{"title":"Combination Targeted Therapy with Pembrolizumab and Lenvatinib in Progressive, Radioiodine-Refractory Differentiated Thyroid Cancers.","authors":"Jena D French, Bryan R Haugen, Francis P Worden, Daniel W Bowles, Andrew G Gianoukakis, Bhavana Konda, Ramona Dadu, Eric J Sherman, Shaylene McCue, Nathan R Foster, Yuri E Nikiforov, Ticiana D J Farias, Paul J Norman, Lori J Wirth","doi":"10.1158/1078-0432.CCR-23-3417","DOIUrl":"10.1158/1078-0432.CCR-23-3417","url":null,"abstract":"<p><strong>Purpose: </strong>Lenvatinib, a potent multikinase inhibitor, improves progression-free survival (PFS) in patients with radioiodine (RAI)-refractory differentiated thyroid cancer; however, most patients experience disease progression, warranting further therapy. We evaluated the efficacy and safety of lenvatinib plus pembrolizumab in these patients.</p><p><strong>Patients and methods: </strong>We enrolled patients with progressive, RAI-refractory differentiated thyroid cancer who were either naïve to multikinase inhibitors (cohort 1) or who had progressed on lenvatinib (cohort 2). Patients received oral lenvatinib daily (cohort 1, 20 mg; cohort 2, dose at progression) and intravenous pembrolizumab (200 mg) every 21 days.</p><p><strong>Results: </strong>In cohorts 1 and 2, 30 and 27 patients were enrolled, respectively. Adverse events were consistent with those observed in other cancers. In cohort 1, the confirmed overall response rate was 65.5%. There were no complete responses (primary endpoint). The 12- and 18-month PFS were 72.0% and 58.0%, respectively, and the median PFS was 26.8 months. In cohort 2, the confirmed overall response rate was 16% (primary endpoint), and the median PFS was 10.0 months (95% confidence interval, 7.0-17.9 months). Tumor histology, driver mutations, and immune-related biomarkers, including PD-L1 expression, thyroid-specific antibody levels, and CD8+ T-cell tumor infiltrate, did not correlate with response to therapy. Increased baseline peripheral blood monocytes and neutrophil to lymphocyte ratio were associated with a worse PFS in cohort 1.</p><p><strong>Conclusions: </strong>Lenvatinib plus pembrolizumab may enhance the durability of lenvatinib monotherapy in lenvatinib-naïve patients. Furthermore, the addition of pembrolizumab may be a viable salvage therapy for patients who have progressed on lenvatinib.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Facts and Hopes in the Systemic Therapy of Biliary Tract Carcinomas.","authors":"Angela Lamarca, Teresa Macarulla","doi":"10.1158/1078-0432.CCR-22-2438","DOIUrl":"10.1158/1078-0432.CCR-22-2438","url":null,"abstract":"<p><p>Biliary tract cancers (BTC) are a heterogeneous group of cancers that continue to present a particularly poor prognosis. BTC treatment is rapidly evolving yet facing many challenges to improve patient outcomes and maximize benefit from treatment. Only a minority of patients are diagnosed with early-stage disease and are suitable for curative resection. Current surgical strategies are limited by a high relapse rate, and despite extensive efforts focused on adjuvant strategies, the development of more effective adjuvant strategies remains a challenge. In addition, the role of locoregional strategies, liver transplant, and neoadjuvant treatment remains unclear. Systemic treatment in the advanced setting is based on three main pillars: first, cytotoxic chemotherapy options; second, the addition of immunotherapy to chemotherapy; and third, targeted therapies. The role of targeted therapies is oriented by many promising targets, including IDH1 mutations, FGFR2 fusions, BRAF-V600E mutations, and HER2 amplifications. The aim of this review is to provide an overview of current facts and future hopes in the management of BTC, including an overview of the unmet need, and particularly focus on systemic therapies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141455634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antonio Giordano, Priya U Kumthekar, Qingchun Jin, Busem Binboga Kurt, Siyang Ren, Tianyu Li, Jose Pablo Leone, Elizabeth A Mittendorf, Alyssa M Pereslete, Laura Sharp, Raechel Davis, Molly DiLullo, Nabihah Tayob, Erica L Mayer, Eric P Winer, Sara M Tolaney, Nancy U Lin
{"title":"A phase II study of atezolizumab, pertuzumab, and high-dose trastuzumab for central nervous system metastases in patients with HER2-positive breast cancer.","authors":"Antonio Giordano, Priya U Kumthekar, Qingchun Jin, Busem Binboga Kurt, Siyang Ren, Tianyu Li, Jose Pablo Leone, Elizabeth A Mittendorf, Alyssa M Pereslete, Laura Sharp, Raechel Davis, Molly DiLullo, Nabihah Tayob, Erica L Mayer, Eric P Winer, Sara M Tolaney, Nancy U Lin","doi":"10.1158/1078-0432.CCR-24-1161","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1161","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with HER2-positive breast cancer brain metastases have few effective systemic therapy options. In a prior study, pertuzumab with high-dose trastuzumab demonstrated a high clinical benefit rate (CBR) in the central nervous system (CNS) in patients with brain metastases. The current trial evaluated whether the addition of atezolizumab to this regimen would produce further improvements in CNS response.</p><p><strong>Patients and methods: </strong>This was a single-arm, multi-center, phase II trial of atezolizumab, pertuzumab, and high-dose trastuzumab for patients with HER2-positive breast cancer brain metastases. Participants received atezolizumab 1200 mg IV every 3 weeks (q3w), pertuzumab (loading dose 840 mg IV, then 420 mg IV q3w), and high-dose trastuzumab (6 mg/kg IV weekly for 24 weeks, then 6 mg/kg IV q3w). The primary endpoint was CNS overall response rate (ORR) per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Key secondary endpoints included CBR, overall survival (OS), and safety and tolerability of the combination.</p><p><strong>Results: </strong>Among 19 enrolled participants, two had a confirmed intracranial partial response for a CNS-ORR of 10.5% (90% CI: 1.9%-29.6%). The study did not meet the prespecified efficacy threshold and was terminated early. The CBR was 42.1% at 18 weeks and 31.6% at 24 weeks. Seven patients (36.8%) required a dose delay or hold, and the most frequent any-grade adverse events were diarrhea (26.3%) and fatigue (26.3%).</p><p><strong>Conclusions: </strong>The addition of atezolizumab to pertuzumab plus high-dose trastuzumab does not result in improved CNS responses in patients with HER2-positive breast cancer brain metastases.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maryam Pourmaleki, Caitlin J Jones, Sabrina D Mellinghoff, Brian D Greenstein, Priyadarshini Kumar, Miguel Foronda, Daniel A Navarrete, Carl Campos, Mikhail Roshal, Nikolaus Schultz, Sohrab P Shah, Andrea Schietinger, Nicholas D Socci, Travis J Hollmann, Ahmet Dogan, Ingo K Mellinghoff
{"title":"Multiplexed Spatial Profiling of Hodgkin Reed-Sternberg Cell Neighborhoods in Classic Hodgkin Lymphoma.","authors":"Maryam Pourmaleki, Caitlin J Jones, Sabrina D Mellinghoff, Brian D Greenstein, Priyadarshini Kumar, Miguel Foronda, Daniel A Navarrete, Carl Campos, Mikhail Roshal, Nikolaus Schultz, Sohrab P Shah, Andrea Schietinger, Nicholas D Socci, Travis J Hollmann, Ahmet Dogan, Ingo K Mellinghoff","doi":"10.1158/1078-0432.CCR-24-0942","DOIUrl":"10.1158/1078-0432.CCR-24-0942","url":null,"abstract":"<p><strong>Purpose: </strong>Classic Hodgkin lymphoma (cHL) is a B-cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1%-5%) of the malignant Hodgkin Reed-Sternberg (HRS) cells within a network of nonmalignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown.</p><p><strong>Experimental design: </strong>We performed spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein-Barr virus (EBV)-positive and EBV-negative cHL tumors.</p><p><strong>Results: </strong>We show that MHC-I expression on HRS cells is associated with immune-inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD1 and VISTA). We identified spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T-cell-excluded neighborhoods in a subset of EBV-negative tumors. Finally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T-cell-high neighborhoods harboring HRS cells with augmented proliferative capacity.</p><p><strong>Conclusions: </strong>Our study links HRS cell properties with distinct immunophenotypes and potential immune escape mechanisms in cHL.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paul Jank, Thomas Karn, Marion van Mackelenbergh, Judith Lindner, Denise Treue, Jens Huober, Knut Engels, Christine Solbach, Kurt Diebold, Frederik Marmé, Volkmar Müller, Andreas Schneeweiss, Hans-Peter Sinn, Tanja Fehm, Christian Schem, Elmar Stickeler, Peter Fasching, Jan Budczies, Bärbel Felder, Valentina Nekljudova, Johannes Holtschmidt, Michael Untch, Carsten Denkert, Sibylle Loibl
{"title":"An Analysis of PIK3CA Hotspot Mutations and Response to Neoadjuvant Therapy in Patients with Breast Cancer from Four Prospective Clinical Trials.","authors":"Paul Jank, Thomas Karn, Marion van Mackelenbergh, Judith Lindner, Denise Treue, Jens Huober, Knut Engels, Christine Solbach, Kurt Diebold, Frederik Marmé, Volkmar Müller, Andreas Schneeweiss, Hans-Peter Sinn, Tanja Fehm, Christian Schem, Elmar Stickeler, Peter Fasching, Jan Budczies, Bärbel Felder, Valentina Nekljudova, Johannes Holtschmidt, Michael Untch, Carsten Denkert, Sibylle Loibl","doi":"10.1158/1078-0432.CCR-24-0459","DOIUrl":"10.1158/1078-0432.CCR-24-0459","url":null,"abstract":"<p><strong>Purpose: </strong>The PI3K signaling pathway is frequently dysregulated in breast cancer, and mutations in PIK3CA are relevant for therapy resistance in HER2-positive (HER2pos) breast cancer. Mutations in exons 9 or 20 may have different impacts on response to neoadjuvant chemotherapy-based treatment regimens.</p><p><strong>Experimental design: </strong>We investigated PIK3CA mutations in 1,691 patients with early breast cancer who were randomized into four neoadjuvant multicenter trials: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880), and GeparSepto (NCT01583426). The role of different PIK3CA exons and hotspots for pathologic complete response (pCR) following neoadjuvant chemotherapy (NACT) and patient survival were evaluated for distinct molecular subgroups and anti-HER2 treatment procedures.</p><p><strong>Results: </strong>A total of 302 patients (17.9%) of the full cohort of 1,691 patients had a tumor with a PIK3CA mutation, with a different prevalence in molecular subgroups: luminal/HER2-negative (HER2neg) 95 of 404 (23.5%), HER2pos 170 of 819 (20.8%), and triple-negative breast cancer 37 of 468 patients (7.9%). We identified the mutations in PIK3CA exon 20 to be linked with worse response to anti-HER2 treatment (OR = 0.507; 95% confidence interval, 0.320-0.802; P = 0.004), especially in hormone receptor-positive HER2-positive breast cancer (OR = 0.445; 95% confidence interval, 0.237-0.837; P = 0.012). In contrast, exon 9 hotspot mutations p.E452K and p.E545K revealed no noteworthy differences in response therapy. Luminal/HER2neg patients show a trend to have worse treatment response when PIK3CA was mutated. Interestingly, patients with residual disease following neoadjuvant treatment had better survival rates when PIK3CA was mutated.</p><p><strong>Conclusions: </strong>The PIK3CA hotspot mutation p.H1047R is associated with worse pCR rates following NACT in HER2pos breast cancer, whereas hotspot mutations in exon 9 seem to have less impact.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Martin Forster, Irene Brana, Antonio L Pousa, Bernard Doger, Patricia Roxburgh, Pawan Bajaj, Julio Peguero, Matthew Krebs, Enric Carcereny, Grisma Patel, Christian Mueller, Chrystelle Brignone, Frederic Triebel
{"title":"Eftilagimod Alpha (Soluble LAG3 Protein) Combined with Pembrolizumab as Second-Line Therapy for Patients with Metastatic Head and Neck Squamous Cell Carcinoma.","authors":"Martin Forster, Irene Brana, Antonio L Pousa, Bernard Doger, Patricia Roxburgh, Pawan Bajaj, Julio Peguero, Matthew Krebs, Enric Carcereny, Grisma Patel, Christian Mueller, Chrystelle Brignone, Frederic Triebel","doi":"10.1158/1078-0432.CCR-24-0473","DOIUrl":"10.1158/1078-0432.CCR-24-0473","url":null,"abstract":"<p><strong>Purpose: </strong>Eftilagimod alpha (efti), a soluble LAG3 protein, activates antigen-presenting cells (APC) and downstream T cells. TACTI-002 (part C) evaluated whether combining efti with pembrolizumab led to strong antitumor responses in patients with second-line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) while demonstrating good tolerability.</p><p><strong>Patients and methods: </strong>In this multinational phase II trial using Simon's two-stage design, patients who were PD-L(1)-naïve with R/M HNSCC who had failed first-line platinum-based therapy, unselected for PD-L1, received intravenous pembrolizumab (200 mg, once every 2 weeks) combined with subcutaneous efti (30 mg once every 2 weeks for 24 weeks and once every 3 weeks thereafter). The primary endpoint was objective response rate per RECIST 1.1 modified for immune-based therapy by investigator assessment. Additional endpoints included duration of response, progression-free survival, overall survival, and tolerability. Pharmacodynamic effects (absolute lymphocyte count) and Th1 cytokine biomarkers (IFNγ/CXCL10)] were evaluated in liquid biopsies.</p><p><strong>Results: </strong>Between March 2019 and January 2021, 39 patients were enrolled; 37 were evaluated for response. All patients received prior chemotherapy, and 40.5% were pretreated with cetuximab; 53.1% of patients had PD-L1 combined positive score <20. With a median follow-up of 38.8 months, the objective response rate was 29.7%, including 13.5% complete responders. The median duration of response was not reached. Rapid and sustained absolute lymphocyte count increase was observed in patients who had an objective response. Th1 biomarkers increased sustainably after first treatment. No unexpected safety signals were observed.</p><p><strong>Conclusions: </strong>Efti plus pembrolizumab was safe and showed encouraging antitumor activity and pharmacodynamic effects in patients with second-line head and neck squamous cell carcinoma (HNSCC), thus supporting further evaluation of this combination in earlier treatment lines.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}