Advanced-stage lung squamous-cell carcinoma (LUSC) remains a therapeutic challenge. Although immune checkpoint inhibitors (ICIs) have revolutionized LUSC treatment, only a small subset of LUSC patients can achieve durabl...Advanced-stage lung squamous-cell carcinoma (LUSC) remains a therapeutic challenge. Although immune checkpoint inhibitors (ICIs) have revolutionized LUSC treatment, only a small subset of LUSC patients can achieve durable clinical benefits, underscoring the need for novel strategies. Emerging immunotherapy strategies have demonstrated early evidence of promise for LUSC patients, particularly multi-specific antibodies and fusion proteins, antibody-drug conjugates, adoptive cell therapies, and cancer vaccines. Additionally, advances in multi-omics and artificial intelligence offer potential for precise immunotherapy by deciphering the complex tumor-immune microenvironment and predicting therapeutic responses. The future of LUSC treatment lies in rational multi-target and biological therapies to boost immune cytotoxicity, as well as innovative technologies to refine patient selection. This review highlights the evolving landscape and outlines a roadmap for next-generation immunotherapies in LUSC.
The impressive but incomplete clinical success of immunotherapy with immune checkpoint inhibitors makes it of paramount importance to understand and overcome immunotherapy resistance. The phenomenon of resistance to immu...The impressive but incomplete clinical success of immunotherapy with immune checkpoint inhibitors makes it of paramount importance to understand and overcome immunotherapy resistance. The phenomenon of resistance to immunotherapy has been largely categorized as innate or acquired; however, many cellular and molecular mechanisms of resistance are remarkably common to both. This notion raises the possibility that resistance mechanisms develop during the coevolution of the tumor and the immune response, reflecting the multiple interactions between malignant cells and cells of the tumor immune microenvironment. This tumor-editing interaction selects for often preexisting adapted genetic or epigenetic variants, and results in intratumoral heterogeneity (ITH) within tumors and among metastatic lesions. Variants encompass both tumor-intrinsic genetically driven ('hardware') and tumor-extrinsic ('software') resistance mechanisms that dynamically coevolve under strong immune selection pressures in a Darwinian fashion. The level of ITH, which is shaped by the evolution of tumors in their immune microenvironment, may dictate the ability of tumors to adapt and evade attacks by the immune system. Standardized methods and metrics for measuring and addressing ITH and making use of this information in human cancer management remain limited, partly due to the lack of suitable models, technologies, and bioinformatic tools. Opportunities exist to design therapeutic approaches to overcome immunotherapy resistance, with an emphasis on interventions targeting intrinsic versus extrinsic resistance mechanisms in the context of ITH. These therapeutic approaches can be tailored according to the nature of the specific ongoing or predicted resistance mechanisms, as observed on a per-case basis, and may include a range of options, such as biomarker-driven rational immunotherapy combinations, novel immunoregulatory targets, and the suitable incorporation of cell-based adoptive therapies. In this review, we discuss the evidence for ITH driving immunotherapy resistance and provide a perspective on integrating ITH as a biomarker and when designing more efficacious therapeutic strategies.
Rawson RV, Maher NG, Menzies AM
… +28 more, Lo SN, Mesbah Ardakani N, Jackett LA, Vergara IA, Pennington TE, Shannon KF, Ch'ng S, Gonzalez M, Burton EM, Lucas MW, Reijers ILM, Rozeman EA, Gyorki DE, Sandhu S, Carlino MS, Howle J, Khattak M, Van der Westhuizen A, Andrews MC, Atkinson V, van Akkooi ACJ, Spillane AJ, Saw RPM, van de Wiel BA, Blank CU, Long GV, Tetzlaff MT, Scolyer RA
BACKGROUND: Neoadjuvant immunotherapy produces event-free survival advantage over adjuvant therapy for patients with surgically resectable macroscopic stage IIIB/C/D melanoma. Pathological response, determined as percent...BACKGROUND: Neoadjuvant immunotherapy produces event-free survival advantage over adjuvant therapy for patients with surgically resectable macroscopic stage IIIB/C/D melanoma. Pathological response, determined as percentage residual viable tumor (% RVT), provides critical prognostic information and informs management decisions. Here, we assessed accuracy of %RVT calculation when reduced tumor bed (TB) was examined and leverage these results proposing streamlined protocols for pathological examination. PATIENTS AND METHODS: Comprehensive histopathological examination was carried out on 134 patient specimens after neoadjuvant immunotherapy with ipilimumab and nivolumab. Impact on %RVT when evaluating less TB than recommended by the initial International Neoadjuvant Melanoma Consortium (INMC) protocol was assessed. Firstly, % RVT of each case was recalculated using seven modified protocols and compared with % RVT obtained under INMC protocol. Next, a simulation study was carried out recalculating % RVT by random sampling 50%, 33%, and 25% of TB slides per specimen. RESULTS: There was excellent accuracy in %RVT (R > 0.97) for all the modified protocols and >90% accuracy in five protocols. Accuracy of major pathological response (MPR)/non-MPR and pathological response category classification was ≥96% in six protocols. The decrease in average slides examined per specimen ranged from 9% to 58%. In total, 85%, 79%, and 74% of simulations recalculating %RVT were within 5% of the INMC calculation when 50%, 33%, and 25% of TB slides were examined, respectively. If TB slide examination is capped at 20, %RVT calculation remains 93% accurate. CONCLUSIONS: TB embedded for histopathological examination in neoadjuvant stage IIIB/C/D melanoma specimens can be reduced without significantly compromising accuracy of %RVT calculation. We recommend an updated pathological assessment protocol: lymph nodes ≤3 cm examined in entirety; macroscopically involved lymph nodes >3 cm should have a modified examination protocol of at least a full cross-sectional transverse slice. Capping TB slides examined at 20 appears reasonable. This refined approach results in high accuracy and significant reduction in the slides examined.
Virtanen T, Kwan EM, Parekh K
… +54 more, Bacon JVW, Huang CF, Yu IPL, Ryyppö L, Bernales CQ, Donnellan G, Tam C, Sipola J, Nikkola J, Vandekerkhove G, Tolmeijer SH, Kukkonen K, Adelia, Eigl BJ, Finch D, Gagnon R, Takieldeen Y, Hardy E, Khalaf D, Kollmannsberger C, Lavoie JM, Maurice-Dror C, Miller S, Nappi L, Noonan K, Parimi S, Riminchan A, Sartori-Mueller E, Soleimani M, Vergidis J, Zulfiqar M, Hansen A, Hotte S, Jafri M, Kolinsky M, Mukherjee SD, Ong M, Rose AAN, Tu W, Winquist E, Bergman AM, van der Zande K, Zwart W, Mehra N, van Erp NP, Zhao JL, Rathkopf D, Barbieri CE, Quigley DA, Nykter M, Lack NA, Chi KN, Annala M, Wyatt AW
BACKGROUND: Somatic alterations to the androgen receptor (AR) gene are pivotal drivers of treatment resistance in metastatic castration-resistant prostate cancer (mCRPC), but their prevalence, clinical impact, and etiolo...BACKGROUND: Somatic alterations to the androgen receptor (AR) gene are pivotal drivers of treatment resistance in metastatic castration-resistant prostate cancer (mCRPC), but their prevalence, clinical impact, and etiology remain incompletely understood. PATIENTS AND METHODS: We assembled a meta-cohort of 3048 plasma cell-free DNA and matched leukocyte DNA samples from 1751 mCRPC patients, accrued from eight clinical trials and a regional biobank. Samples were sequenced with successive generations of a custom targeted hybridization capture panel with extensive coverage of the AR locus and 71 prostate cancer genes, enabling comprehensive characterization of AR genotypes including enhancer and gene copy number amplification, and mutations or structural rearrangements. RESULTS: Somatic AR alterations, detected in 84% of mCRPC, were shaped by underlying genomics, including TP53 and DNA repair defects. Wnt-mutant tumors showed unique AR amplification structures characterized by preferential incorporation of an alternative downstream enhancer and low copy number. AR mutations were present in 19.7% of mCRPC, often subclonal, and enriched in tumors with AR enhancer-only gain. We establish a functional hierarchy of AR genotypes based on treatment responses and identify a specific class of AR rearrangements truncating the ligand-binding domain within intron 4 or exon 4 (ALTR4) that are under robust positive selection and strongly impact AR pathway inhibitor outcomes, distinct from other rearrangements arising as byproducts of AR amplification. We provide evidence that a subset of AR amplifications arise through breakage-fusion-bridge cycles with associated Xq loss. Some 16% of mCRPC lacked detectable AR alterations and had reduced frequency of ETS gene fusions, with many demonstrating robust responses to AR pathway inhibitors. CONCLUSIONS: This study provides the most comprehensive resource to date characterizing somatic alterations at the AR locus. Our clinicogenomic analysis establishes the repertoire and clinical relevance of AR genotypes in mCRPC, informing efforts to target renewed AR dependency.
Harbeck N, Modi S, Pusztai L
… +23 more, Ohno S, Wu J, Kim SB, Yoshida A, Fabi A, Cao X, Joseph R, Li R, Żurawski B, Escrivá-de-Romaní S, Meneguetti R, Supavavej A, Chen SC, Liu Z, Kelly C, Curigliano G, Symmans WF, Gufran M, Ke J, Konpa A, Herbolsheimer P, Boileau JF, DESTINY-Breast11 Trial Investigators
BACKGROUND: Neoadjuvant standard-of-care for HER2-positive early-stage breast cancer is trastuzumab + pertuzumab with polychemotherapy; however, existing regimens have high toxicity burdens and suboptimal outcomes. DESTI...BACKGROUND: Neoadjuvant standard-of-care for HER2-positive early-stage breast cancer is trastuzumab + pertuzumab with polychemotherapy; however, existing regimens have high toxicity burdens and suboptimal outcomes. DESTINY-Breast11 assessed efficacy and safety of neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) versus dose-dense doxorubicin + cyclophosphamide (ddAC) followed by THP for high-risk (≥cT3cN0 or cT0-4cN1-3) HER2-positive disease. PATIENTS AND METHODS: This open-label, phase III trial (147 sites, 18 countries) randomised adults 1 : 1 : 1 to T-DXd (×8 cycles), T-DXd-THP (4 + 4 cycles), or ddAC-THP (4 + 4 cycles). T-DXd-alone arm enrolment closed early following the Independent Data Monitoring Committee recommendation. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0; intent-to-treat population). Secondary endpoints included event-free survival (EFS; intent-to-treat population) and safety (safety analysis set). RESULTS: Between 25 October 2021 and 12 March 2025, 286 (T-DXd), 321 (T-DXd-THP), and 320 (ddAC-THP) female patients were randomised. pCR rates were 43.0% (T-DXd, n = 123), 67.3% (T-DXd-THP, n = 216), and 56.3% (ddAC-THP, n = 180). T-DXd-THP versus ddAC-THP absolute pCR rate difference was 11.2% [95% confidence interval (CI), 4.0% to 18.3%, P = 0.003], with benefit in hormone receptor (HR)-positive [61.4% (n/N = 145/236) versus 52.3% (n/N = 123/235); difference in pCR (ΔpCR) 9.1% (95% CI 0.2% to 17.9%)] and HR-negative [83.1% (n/N = 69/83) versus 67.1% (n/N = 57/85); ΔpCR 16.1% (95% CI 3.0% to 28.8%)] subgroups. Median EFS (T-DXd-THP versus ddAC-THP, maturity 4.5%) hazard ratio was 0.56 (95% CI 0.26 to 1.17). Grade ≥3 adverse events (AE; T-DXd, 22.6% (n = 64); T-DXd-THP, 37.5% (n = 120); ddAC-THP, 55.8% (n = 174)], serious AE [T-DXd, 10.2% (n = 29); T-DXd-THP, 10.6% (n = 34); ddAC-THP, 20.2% (n = 63)], and all-grade left-ventricular dysfunction [T-DXd, 0.7% (n = 2); T-DXd-THP, 1.3% (n = 4); ddAC-THP, 6.1% (n = 19)] rates were lower for T-DXd and T-DXd-THP than ddAC-THP. All-grade adjudicated drug-related interstitial lung disease/pneumonitis rates were low and similar across arms [T-DXd, 4.9% (n = 14); T-DXd-THP, 4.4% (n = 14); ddAC-THP, 5.1% (n = 16)]. Three treatment-related deaths occurred [T-DXd-THP, 0.3% (n = 1); ddAC-THP, 0.6% (n = 2)]. CONCLUSIONS: Neoadjuvant T-DXd-THP demonstrated statistically significant and clinically meaningful pCR benefit and improved safety versus ddAC-THP.
Mayer EL, Bidard FC, Park YH
… +22 more, Janni W, Ma C, Cristofanilli M, Iwata H, Bianchini G, Kalinsky K, Chia S, Brufsky A, Fasching PA, Nowecki Z, Chen SC, Pascual J, Moreau L, Ruiz-Borrego M, Shai A, Karadurmus N, Sohn JH, Zhu Y, Leddin I, Miralles MS, Bartlett CH, Turner N
BACKGROUND: In SERENA-6, switching from aromatase inhibitor (AI) to camizestrant with continuation of CDK4/6 inhibitor (CDK4/6i) guided by emergence of ESR1 mutations (ESR1-mut) during first-line AI-CDK4/6i in patients w...BACKGROUND: In SERENA-6, switching from aromatase inhibitor (AI) to camizestrant with continuation of CDK4/6 inhibitor (CDK4/6i) guided by emergence of ESR1 mutations (ESR1-mut) during first-line AI-CDK4/6i in patients with hormone receptor (HR)-positive advanced breast cancer (ABC) resulted in statistically significant and clinically meaningful improvement in progression-free survival compared with AI-CDK4/6i and reduction in the risk of deterioration in global health status (GHS)/quality of life (QoL) (hazard ratio 0.54). Here we report additional data from patient-reported outcomes (PROs). PATIENTS AND METHODS: Patients completed PRO questionnaires at pre-specified timepoints, including the European Organisation for Research and Treatment of Cancer (EORTC) oncology-specific EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and breast cancer-specific (QLQ-BR23) and Patient Global Impression of Treatment Tolerability (PGI-TT). All PRO endpoints and analyses were pre-defined, including secondary endpoints of time to deterioration (TTD) in pain, physical functioning, breast symptoms and arm symptoms. RESULTS: EORTC QLQ-C30 and EORTC QLQ-BR23 baseline scores were similar between treatment arms. Switching to camizestrant-CDK4/6i delayed TTD and reduced the risk of deterioration in patient-reported cancer symptoms [pain (hazard ratio 0.57, 95% confidence interval 0.37-0.86), fatigue (0.75, 0.46-1.24), shortness of breath/dyspnoea (0.52, 0.28-0.93), breast symptoms (0.59, 0.28-1.24) and arm symptoms (0.69, 0.34-1.39)] and functioning [physical (0.74, 0.44-1.24), role (0.73, 0.48-1.10) and emotional (0.51, 0.29-0.87)] compared with AI-CDK4/6i. Most patients reported they were 'not at all' or 'a little bit' bothered by the side effects of cancer therapy across timepoints (e.g. week 2: 86% camizestrant-CDK4/6i versus 82% AI-CDK4/6i). CONCLUSIONS: Together with the clinical efficacy and manageable safety profile of camizestrant-CDK4/6i, and reduced risk of GHS/QoL deterioration, the PROs from the SERENA-6 trial support switching to this combination as a potential new treatment strategy to optimise and improve outcomes in patients with HR-positive/HER2-negative ABC and ESR1-mut emergence, ahead of disease progression, during first-line AI-CDK4/6i.
Zheng MM, Xia Y, Pan K
… +33 more, Sun F, Tan AC, Dong XR, Tu HY, Tang LB, Li YS, Yin K, Borgeaud M, Singhal S, Zhu E, Zhang J, Nilsson M, Wu J, Gibbons DL, Wakelee H, Neal JW, Lee J, Vaporciyan AA, Ringsurongkawong W, Tran HT, Zhang RZ, Zhang T, Zhou Q, Zhong WZ, Li W, Zhang YC, Riess JW, Addeo A, Heymach JV, Myall N, Tan D, Wu YL, Le X
BACKGROUND: Leptomeningeal metastatic disease (LMD) represents a devastating complication of non-small-cell lung cancer (NSCLC) with a poor prognosis. Our understanding of LMD is limited in the era of molecular testing a...BACKGROUND: Leptomeningeal metastatic disease (LMD) represents a devastating complication of non-small-cell lung cancer (NSCLC) with a poor prognosis. Our understanding of LMD is limited in the era of molecular testing and emerging therapeutic options for lung cancer. PATIENTS AND METHODS: We conducted an international, multicenter, retrospective study involving eight institutions across Asia, United States, and Europe. Patients diagnosed with LMD from advanced NSCLC were identified (2007-2024). Clinicopathological characteristics, treatment patterns, and outcomes were analyzed. The primary endpoint was overall survival from the LMD diagnosis (LMOS). RESULTS: A total of 2052 patients with NSCLC and LMD were included and analyzed by molecular subtypes: epidermal growth factor receptor (EGFR) (n = 1610), ALK (n = 141), other actionable genomic alterations (other AGA; n = 137), and non-AGA (n = 164). The cumulative prevalence of LMD by molecular subgroups was EGFR, 11.1%; ALK, 11.2%; ROS1, 16%; ERBB2, 12.3%, non-AGA, 3.6%. A higher proportion of LMD was diagnosed >3 years after initial metastatic diagnosis. By the European Association of Neuro-Oncology (EANO)-European Society for Medical Oncology (ESMO) diagnostic criteria, type I (cerebrospinal fluid cytology positive) had significantly shorter LMOS than type II (magnetic resonance imaging and/or symptom positive). Median LMOS was 10.9 months [95% confidence interval (CI) 10.0-11.8 months] in all patients. Compared with historical cohorts, patients demonstrated improved LMOS in contemporary cohorts (7.3 versus 11.5 months, P < 0.0001), across all molecular subtypes. In AGA NSCLC, tyrosine kinase inhibitors (TKIs) were associated with improved LMOS [hazard ratio (HR) 0.39, 95% CI 0.31-0.48, P < 0.0001]. Immune checkpoint inhibitors (ICIs) conferred survival benefit in non-AGA patients (HR 0.45, 95% CI 0.25-0.84, P = 0.012). For the EGFR-mutated cohort, central nervous system (CNS)-penetrant TKI usage delayed LMD onset (P < 0.0001). Continued CNS-penetrant TKIs after LMD diagnosis were associated with longer LMOS (12.4 versus 6.0 months, P < 0.0001). CONCLUSIONS: The prevalence of LMD is rising, largely due to prolonged survival in advanced NSCLC. Contemporary systemic treatments, including TKIs and ICIs, were the main contributors to delayed LMD onset and improved LMD survival.
Fizazi K, Clarke NW, De Santis M
… +19 more, Uemura H, Fay AP, Karadurmus N, Kwiatkowski M, Alvarez-Fernandez C, Jiang S, Sotelo M, Parslow D, Oliveira N, Kwon TG, Ye D, Boudewijns S, Danchaivijitr P, Rooney C, Gresty C, Yeste-Velasco M, Logan J, George DJ, CAPItello-281 Study Group
BACKGROUND: In metastatic hormone-sensitive prostate cancer (mHSPC), phosphatase and tensin homolog (PTEN) deficiency results in phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway activation, providing an in...BACKGROUND: In metastatic hormone-sensitive prostate cancer (mHSPC), phosphatase and tensin homolog (PTEN) deficiency results in phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway activation, providing an independent proliferative drive, which cannot be suppressed by androgen receptor pathway inhibitors (ARPIs), resulting in worse outcomes. Dual inhibition of PI3K/AKT and AR pathways with capivasertib and abiraterone may delay progression and improve disease outcomes. PATIENTS AND METHODS: In CAPItello-281 (NCT04493853), patients with PTEN-deficient mHSPC (diagnostic cut-off: ≥90% viable malignant cells with no specific cytoplasmic PTEN immunohistochemistry staining) received capivasertib or placebo (1 : 1) plus abiraterone, prednisone/prednisolone, and androgen deprivation therapy (ADT). The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS); overall survival (OS) was a key secondary endpoint. Post hoc exploratory subgroups at increasing PTEN cut-off thresholds were also assessed. RESULTS: 25.3% (1519/6003) of patients with valid tumor test results had PTEN-deficient tumors. In the randomized PTEN-deficient population, a statistically significant improvement in rPFS was observed with capivasertib plus abiraterone (n = 507, median 33.2 months) versus placebo plus abiraterone [n = 505, 25.7 months; hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.66-0.98, P = 0.034]. Post hoc rPFS analyses for loss of PTEN cut-offs of ≥95%, ≥99%, and 100% showed that the capivasertib plus abiraterone arm performed consistently across cut-offs, but the placebo plus abiraterone arm performed progressively worse as the cut-off for the degree of PTEN loss was increased, resulting in a numerically improved treatment effect. In the overall population studied, the HR for OS (26.4% maturity) was 0.90, 95% CI 0.71-1.15, P = 0.401. The most common adverse events (AEs) for capivasertib plus abiraterone were diarrhea (51.9%; 8.0% placebo plus abiraterone), hyperglycemia (38.0%; 12.9%), and rash (35.4%; 7.0%). Deaths associated with an AE were reported in 36 (7.2%) and 26 (5.2%) patients in the capivasertib plus abiraterone and placebo plus abiraterone arms, respectively. CONCLUSIONS: Capivasertib plus abiraterone improves rPFS versus placebo plus abiraterone in PTEN-deficient mHSPC, on a background of ADT, with a 7.5-month improvement in median rPFS. AE profile was consistent with that of the individual agents. Patients with PTEN-deficient mHSPC benefit from dual blockade of the PI3K/AKT and AR pathways with capivasertib plus abiraterone.
BACKGROUND: We report the long-term efficacy and safety from the multicenter, randomized, double-blind, placebo-controlled, phase III ATHENA-MONO/GOG-3020/ENGOT-ov45 (NCT03522246) study of first-line rucaparib maintenanc...BACKGROUND: We report the long-term efficacy and safety from the multicenter, randomized, double-blind, placebo-controlled, phase III ATHENA-MONO/GOG-3020/ENGOT-ov45 (NCT03522246) study of first-line rucaparib maintenance for advanced ovarian cancer. PATIENTS AND METHODS: Patients were randomized 4 : 1 to oral rucaparib + intravenous (i.v.) placebo or oral + i.v. placebo. Stratification factors were homologous recombination deficiency (HRD; BRCA mutation and loss of heterozygosity status) classification, residual disease post-chemotherapy, and surgical timing. The primary endpoint was investigator-assessed progression-free survival (invPFS) in HRD and intent-to-treat (ITT) populations. Overall survival (OS) and safety were secondary endpoints. Second event of progression (PFS2) and time to first subsequent treatment (TFST) were exploratory. Interim OS and final safety analyses data cut-off was 9 March 2023. Updated invPFS, PFS2, and TFST analyses data cut-off was 5 May 2025. RESULTS: Median invPFS follow-up was ∼59 months for both rucaparib (HRD, n = 185; ITT, n = 427) and placebo (HRD, n = 49; ITT, n = 111). invPFS was significantly longer with rucaparib versus placebo in the HRD [31.4 versus 12.0 months; hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.35-0.76] and ITT (20.2 versus 9.2 months; HR 0.53, 95% CI 0.42-0.69) populations. Interim OS was immature (OS maturity: ITT 35%) with the median (95% CI) OS not reached with rucaparib and 46.2 (34.6-not reached) months with placebo for the ITT population (HR 0.83, 95% CI 0.58-1.17). ITT TFST (median 23.6 versus 12.1 months) and PFS2 (35.1 versus 26.9 months) were longer with rucaparib versus placebo. Overall, 34.6% of patients receiving rucaparib completed the 24-month treatment cap versus 17.3% receiving placebo. As of 5 May 2025, 40.0% of patients on rucaparib were still on study and in long-term follow-up. Safety remained consistent with the primary analysis. CONCLUSIONS: Rucaparib monotherapy provides significant and durable long-term benefit as first-line maintenance for patients with advanced ovarian cancer with and without HRD.
Suarez C, Rojas C, Shin SJ
… +17 more, Yanez Weber P, Albiges L, Motzer R, Hammers H, Peer A, Lee JL, Miller WH, Waddell T, Neiman V, Keizman D, Zwenger Kloster A, Weickhardt A, Dziadziuszko R, Suttner L, Sharma M, Burgents JE, Powles T
BACKGROUND: First-line triplet therapy may expand clinical benefit for advanced clear-cell renal cell carcinoma (ccRCC). The phase Ib/II KEYMAKER-U03 substudy 03A (NCT04626479) investigated novel pembrolizumab (pembro)-b...BACKGROUND: First-line triplet therapy may expand clinical benefit for advanced clear-cell renal cell carcinoma (ccRCC). The phase Ib/II KEYMAKER-U03 substudy 03A (NCT04626479) investigated novel pembrolizumab (pembro)-based regimens in this setting. PATIENTS AND METHODS: Participants with advanced ccRCC and no prior systemic therapy were randomized 2 : 1 to quavonlimab (qmab)/pembro plus lenvatinib (lenva), favezelimab (fave)/pembro plus lenva, pembro plus lenva plus belzutifan (bel), and vibostolimab (vibo)/pembro plus bel or a concurrent reference treatment (pembro plus lenva). A safety lead-in of ∼10 participants occurred for all investigative treatments before randomization. Primary endpoints were objective response rate (ORR) per RECIST v1.1 by blinded independent central review in all randomized participants (excluding safety lead-in), and safety in all treated participants. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: As of 31 March 2025, 393 participants were enrolled. Median follow-up for randomized participants across the five cohorts ranged between 16 and 39 months. The ORR was 80.6% [95% confidence interval (CI) 68.6% to 89.6%] with pembro plus lenva, 71.3% (95% CI 60.0% to 80.8%) with qmab/pembro plus lenva, 62.7% (95% CI 48.1% to 75.9%) with fave/pembro plus lenva, 77.5% (95% CI 66.8% to 86.1%) with pembro plus lenva plus bel, and 42.5% (95% CI 31.5% to 54.1%) with vibo/pembro plus bel. Median PFS was 26.3 months (95% CI 15.3-39.8 months) with pembro plus lenva, 18.0 months (95% CI 11.6-34.3 months) with qmab/pembro plus lenva, 26.0 months (95% CI 8.2-31.8 months) with fave/pembro plus lenva, 31.8 months [95% CI 26.3 months-not reached (NR)] with pembro plus lenva plus bel, and 15.2 months (95% CI 12.4 months-NR) with vibo/pembro plus bel. Median OS was not reached in any arm. Grade ≥3 treatment-related adverse events occurred in 71.0% (44/62) of participants treated with pembro plus lenva, 73.3% (66/90) with qmab/pembro plus lenva, 86.9% (53/61) with fave/pembro plus lenva, 70.0% (63/90) with pembro plus lenva plus bel, and 68.9% (62/90) with vibo/pembro plus bel. CONCLUSIONS: Observed efficacy and safety of pembro plus lenva were confirmatory of prior observations for this combination. ORR was similar to reference for pembro plus lenva plus bel and qmab/pembro plus lenva, but not the other investigative arms. Further investigation of pembro plus lenva plus bel and qmab/pembro plus lenva versus pembro plus lenva is ongoing in the phase III LITESPARK-012 study.
BACKGROUND: First-line treatments for metastatic clear-cell renal-cell carcinoma (ccRCC) combine programmed cell death protein 1 (PD-1) immune checkpoint inhibition (ICI) with cytotoxic T-lymphocyte associated protein 4...BACKGROUND: First-line treatments for metastatic clear-cell renal-cell carcinoma (ccRCC) combine programmed cell death protein 1 (PD-1) immune checkpoint inhibition (ICI) with cytotoxic T-lymphocyte associated protein 4 ICI or angiogenesis targeted therapies (TT). Upon progression, common options include cabozantinib or lenvatinib + everolimus, although these regimens have never been directly compared. We hypothesized that lenvatinib + everolimus will improve progression-free survival (PFS) compared with cabozantinib after progression on PD-1 ICI. PATIENTS AND METHODS: This multicenter, randomized phase II trial enrolled patients with metastatic ccRCC previously treated with one to two lines including PD-1 ICI. Participants received lenvatinib 18 mg/day + everolimus 5 mg/day versus cabozantinib 60 mg/day, stratified by International Metastatic RCC Database Consortium risk group and prior TT. A Bayesian optimal phase II design was used. RESULTS: In total 90 patients were randomized; 86 patients received at least one dose of assigned lenvatinib + everolimus (n = 40) or cabozantinib (n = 46). Median time from randomization to data cut-off date (1 August 2025) was 20 months (interquartile range 14.9-22.5 months). A total of 60 PFS events were observed. Median PFS was 15.7 months with lenvatinib + everolimus and 10.2 months with cabozantinib [hazard ratio 0.51, 95% confidence interval (CI) 0.29-0.89, P = 0.02]. The objective response rate was 52.6% with lenvatinib + everolimus and 38.6% with cabozantinib. Overall survival (OS) data were immature and inconclusive due to a low number of events (n = 24/86; 1-year OS probability 87.0% versus 84.6% [95% CI 0.47% to 2.38%] with lenvatinib + everolimus versus cabozantinib, respectively. Discontinuation rates due to toxicity were 20% with lenvatinib + everolimus and 10.9% with cabozantinib. CONCLUSIONS: In this randomized phase II trial in metastatic ccRCC that progressed on prior PD-1 ICIs, lenvatinib + everolimus significantly prolonged PFS over cabozantinib. As the first head-to-head comparison of contemporary second-line or later treatments after ICI, these results are relevant to treatment sequencing and inform oncology practice.
BACKGROUND: Re-treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies offers a promising approach to extend the continuum of care of patients with RAS and BRAF wild-type (wt) metastatic colorec...BACKGROUND: Re-treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies offers a promising approach to extend the continuum of care of patients with RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) with no mutations of resistance in their circulating tumor DNA (ctDNA) at the time of treatment re-exposure. PATIENTS AND METHODS: PARERE (NCT04787341) is an open-label, multicenter, randomized phase II trial investigating the optimal sequencing of panitumumab and regorafenib in chemorefractory RAS and BRAF wt mCRC patients, who previously derived benefit from first-line anti-EGFR-containing regimens, then received at least one intervening anti-EGFR-free line of treatment, and were prospectively selected for the absence of RAS and BRAF mutations in their ctDNA. Eligible patients were randomly assigned 1 : 1 to receive anti-EGFR re-treatment with panitumumab followed by regorafenib after progression (arm A) versus the reverse sequence (arm B). The primary endpoint was overall survival (OS). RESULTS: Between December 2020 and December 2024, 428 patients underwent molecular screening, and 213 with RAS/BRAF ctDNA wt were randomized (arm A/B = 106/107). At a median follow-up of 31.9 months, no difference in terms of OS was observed between treatment arms, with a median OS of 11.7 and 11.6 months in arms B and A, respectively (hazard ratio 1.13, 85% confidence interval 0.90-1.41, P = 0.441). However, re-treatment with panitumumab was associated with higher objective response rate (ORR; first ORR: 16% versus 2%, P = 0.003; second ORR: 18% versus 0%, P = 0.013) and disease control rate (DCR; first DCR: 61% versus 36%, P < 0.001; second DCR: 62% versus 38%, P = 0.003), and longer progression-free survival (PFS; first PFS: 4.2 versus 2.4 months, P = 0.103; second PFS: 3.9 versus 2.7 months, P = 0.019) than regorafenib, regardless of the sequence of the study treatments. CONCLUSIONS: Anti-EGFR re-treatment should be regarded as an option in the continuum of care of chemorefractory mCRC patients with RAS and BRAF wt tumors, with no alterations of acquired resistance in their ctDNA.