Predictive and prognostic value of HER2 gene expression and HER2 amplification in patients with metastatic colorectal cancer (mCRC) enrolled in CALGB/SWOG 80405 (Alliance).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4086-4086
Author(s):  
Francesca Battaglin ◽  
Fang-Shu Ou ◽  
Xueping Qu ◽  
Monica M. Bertagnolli ◽  
Howard S. Hochster ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prognostic Value ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Her2 Expression ◽  
Her2 Amplification ◽  
Her2 Gene ◽  
Molecular Features ◽  
Predictive And Prognostic Value

4086 Background: The randomized phase III CALGB/SWOG 80405 trial found no difference in overall survival (OS) in first-line mCRC pts treated with either bevacizumab (Bev) or cetuximab (Cet) combined with the same chemotherapy. We investigated the potential prognostic and predictive value of HER2 amplification and HER2 gene expression using NGS and Nanostring data. Methods: Primary tumor DNA from 559 patients (pts) was profiled for HER2 amplification by NGS (Foundation One). Tumor tissue from 925 pts was tested for Nanostring gene expression using an 800 gene panel. OS and progression free survival (PFS) were the endpoints as time-to-event variables. Cox proportional hazard models with gene expression fitted with linear spline (one internal knot at median) were used, adjusting for pts baseline characteristics, treatment assignment, and molecular features (microsatellite instability, BRAF, all RAS). Results: Of 505 tumors with both NGS and Nanostring data, 16 harbored HER2 amplification (copy number variation > 6), limited to microsatellite stable tumors and significantly associated with HER2 expression ( P < 0.001) and wild-type RAS ( P = 0.036). HER2 amplification was neither prognostic nor predictive for OS or PFS. Conversely, HER2 expression higher than median was associated with longer PFS ( P = 0.018) but not OS ( P = 0.13). Among pts with HER2 not amplified, higher HER2 expression was associated with better OS (hazard ratio [HR], 0.83; 95%CI, 0.72-0.97; P = 0.016) and PFS (HR, 0.85; 95%CI, 0.74-0.98; P = 0.027) when the expression was less than median. Additionally, in pts with no HER2 amplification and HER2 expression lower than median, treatment with Cet was associated with worse PFS compared to Bev (HR, 1.46; 95%CI, 1.12-1.90; P = 0.005). This effect was not observed with expression higher than median regardless of HER2 amplification status. Conclusions: To our knowledge, this is the largest analysis of HER2 amplification and gene expression in mCRC pts treated with standard therapy. Our results provide novel insight on the predictive and prognostic value of HER2 gene expression in pts treated with Cet- and Bev-based regimens. Upon validation, these findings could inform pts selection and the design of more effective treatment options for pts with low HER2 expression. Clinical trial information: NCT00265850.

scholarly journals Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance)

2019 ◽  
Vol 37 (22) ◽  
pp. 1876-1885 ◽  
Author(s):  
Heinz-Josef Lenz ◽  
Fang-Shu Ou ◽  
Alan P. Venook ◽  
Howard S. Hochster ◽  
Donna Niedzwiecki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Molecular Subtype ◽  
Progression Free Survival ◽  
Classification Systems ◽  
Phase Iii ◽  
Primary Tumors ◽  
Phase Iii Trial ◽  
Consensus Molecular Subtype ◽  
Predictive And Prognostic Value

PURPOSE To determine the predictive and prognostic value of the consensus molecular subtypes (CMSs) of colorectal cancer (CRC) that represent a merging of gene expression–based features largely in primary tumors from six independent classification systems and provide a framework for capturing the intrinsic heterogeneity of CRC in patients enrolled in CALGB/SWOG 80405. PATIENTS AND METHODS CALGB/SWOG 80405 is a phase III trial that compared the addition of bevacizumab or cetuximab to infusional fluorouracil, leucovorin, and oxaliplatin or fluorouracil, leucovorin, and irinotecan as first-line treatment of advanced CRC. We characterized the CMS classification using a novel NanoString gene expression panel on primary CRCs from 581 patients enrolled in this study to assess the prognostic and predictive value of CMSs in these patients. RESULTS The CMSs are highly prognostic for overall survival (OS; P < .001) and progression-free survival (PFS; P < .001). Furthermore, CMSs were predictive for both OS ( P for interaction < .001) and PFS ( P for interaction = .0032). In the CMS1 cohort, patients treated with bevacizumab had a significantly longer OS than those treated with cetuximab ( P < .001). In the CMS2 cohort, patients treated with cetuximab had a significantly longer OS than patients treated with bevacizumab ( P = .0046). CONCLUSION These findings highlight the possible clinical utility of CMSs and suggests that refinement of the CMS classification may provide a path toward identifying patients with metastatic CRC who are most likely to benefit from specific targeted therapy as part of the initial treatment.

scholarly journals Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Francesco Schettini ◽  
Nuria Chic ◽  
Fara Brasó-Maristany ◽  
Laia Paré ◽  
Tomás Pascual ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Overall Survival ◽  
High Activity ◽  
Triple Negative ◽  
Her2 Expression ◽  
Drug Conjugates ◽  
Molecular Features ◽  
Biological Heterogeneity ◽  
Antibody Drug

AbstractNovel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression.

Effect of JAK2 SNP rs2274472 on outcome for mCRC patients treated with first-line FOLFIRI and bevacizumab: Data from FIRE-3 trial.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 595-595
Author(s):  
Martin D. Berger ◽  
Sebastian Stintzing ◽  
Volker Heinemann ◽  
Dongyun Yang ◽  
Shu Cao ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Negative Control ◽  
Janus Kinase ◽  
Phase Iii ◽  
First Line ◽  
Angiogenic Therapy ◽  
Line Setting

595 Background: The Jak2 (Janus kinase 2) / Stat5a (signal transduction and activators of transcription 5a) pathway plays a key role in regulating cell survival, proliferation and immune function. JAK2 is a non-receptor tyrosine kinase which is stimulated by a variety of cytokines. Moreover the JAK2 / STAT5 axis is activated by hypoxia and involved in regulating angiogenesis. We therefore hypothesize that variations in the JAK2 gene may predict outcome in patients with metastatic colorectal cancer (mCRC) treated with first-line FOLFIRI and bevacizumab (bev). Methods: Theimpact of 2 functional SNPs within the JAK2 and STAT5a genes on outcome was evaluated in 295 pts with mCRC treated with first-line FOLFIRI / bev in the randomized phase III FIRE-3 trial. 227 pts receiving FOLFIRI and cetuximab (FIRE-3) served as a negative control. Genomic DNA was extracted from formalin fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics in the FOLFIRI / bev arm were as follows: female:male ratio = 1/3:2/3; median age = 65y (31-76) andmedian PFS/OS = 10.1/24.2 months. The JAK2 rs2274472 SNP showed significant association with progression-free survival (PFS). C allele carriers had a shorter median PFS compared to those with a T/T genotype (9.9 vs 11.7 months) in both univariate (HR 1.30, 95% CI 1.00-1.69, p = 0.045) and multivariate analysis (HR 1.39, 95% CI 1.06-1.83, p = 0.018). However, this association could not be observed in patients treated with FOLFIRI and cetuximab. Here, patients harboring any C allele and T/T genotype carriers showed an equal median PFS (10.0 vs 9.9 months, HR 1.00, 95% CI 0.75-1.33, p = 1.00). Conclusions: Our results provide the first evidence that the JAK2 polymorphism rs2274472 might serve as a predictive marker in pts with mCRC treated with FOLFIRI and bev in the first line setting. Targeting the JAK2 / STAT5A axis might be a promising approach to further enlarge our treatment options against mCRC and to overcome resistance to anti-angiogenic therapy.

Exploratory analysis of the effect of FTD/TPI in patients treated in RECOURSE by prognostic factors.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 677-677 ◽  
Author(s):  
Josep Tabernero ◽  
Alberto F. Sobrero ◽  
Christophe Borg ◽  
Atsushi Ohtsu ◽  
Robert J. Mayer ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Good Prognosis ◽  
Tumor Burden ◽  
Phase Iii ◽  
Kras Status ◽  
Indolent Disease ◽  
Metastatic Sites ◽  
Ecog Ps

677 Background: The Phase III RECOURSE trial, in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard therapies, demonstrated that trifluridine/tipiracil (FTD/TPI) significantly extended overall survival (OS) and progression-free survival (PFS) versus placebo in all subgroups, regardless of age, geographical origin, or KRAS status, with acceptable safety. Literature reports have shown optimal benefit for pts with low tumor burden (< 3 metastatic sites), indolent disease (≥ 18 mo since diagnosis of first metastasis), ECOG PS 0-1, and no liver metastasis when treated in late line mCRC. Methods: This exploratory post hoc analysis of RECOURSE (all ECOG 0-1) compared pts on FTD/TPI or placebo with good prognostic characteristics (GPC; low tumor burden and indolent disease) and poor prognostic characteristics (PPC; high tumor burden and/or aggressive disease). These subgroups were then analyzed by liver metastasis at baseline, ECOG PS, KRAS status and age. Results: Baseline characteristics were generally similar between the two groups. GPC placebo pts performed better than the PPC placebo pts, but worse than the GPC pts treated with FTD/TPI. GPC pts treated with FTD/TPI showed median OS of 9.3 mo versus 5.3 mo in PPC pts (HR 0.46; 95% CI: 0.37, 0.57; p < 0.0001); there was a similar effect for PFS. GPC pts had significantly better mOS and mPFS regardless of age (≥ 65 vs. < 65 y), ECOG PS (0–1), KRAS status (mutant vs. wildtype), and liver metastasis (y/n). No liver metastasis was the best prognostic factor: mOS in such pts treated with FTD/TPI was 16.4 mo and 7.6 mo in the GPC (n = 97) and PPC (n = 35) groups, respectively (HR 0.42; 95% CI: 0.24, 0.74; p < 0.0019); there was a similar effect for PFS. Pts with ECOG PS 0 at baseline remained PS 0-1 at discontinuation in 96% of the GPC group. Conclusions: Low tumor burden and indolent disease indicate good prognosis in late line mCRC. Pts with no liver metastasis have the best prognosis and are likely to have longer OS. GPCs might explain the percentage of long-term responders on FTD/TPI in RECOURSE. Maintenance of ECOG PS 0–1 during treatment is crucial in the continuum of care, allowing pts to benefit from further treatment options. Clinical trial information: NCT01607957.

scholarly journals Treatment Options in Metastatic Renal Cell Carcinoma: Focus on mTOR Inhibitors

2010 ◽  
Vol 4 ◽  
pp. CMO.S1590 ◽  
Author(s):  
Sumanta Kumar Pal ◽  
Robert A. Figlin
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Treatment Options ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Phase Iii

The agents currently approved for use in metastatic renal cell carcinoma (mRCC) can be divided broadly into two categories: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR). The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC. Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib. In contrast, temsirolimus was approved on the basis of a phase III trial in treatment-naïve patients with poor-risk mRCC, demonstrating an improvement in overall survival relative to interferon-alfa. While these pivotal trials have created unique positions for everolimus and temsirolimus in current clinical algorithms, the role of mTOR inhibitors in mRCC is being steadily revised and expanded through ongoing trials testing novel sequences and combinations. The clinical development of mTOR inhibitors is outlined herein.

Prognostic value of early objective tumor response (EOTR) to first-line systemic therapy in metastatic colorectal cancer (mCRC): Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3520-3520 ◽  
Author(s):  
Dirkje Willemien Sommeijer ◽  
Qian Shi ◽  
Jeffrey P Meyers ◽  
Katrin Marie Sjoquist ◽  
Paulo Marcelo Hoff ◽  
...  
Keyword(s):  
Targeted Therapies ◽  
Prognostic Value ◽  
Tumor Response ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Early Assessment ◽  
Phase Ii Trials ◽  
Cox Models ◽  
Individual Patient Level

3520 Background: EOTR has been suggested as a potential surrogate for overall survival (OS) in patients (pts) with mCRC and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at the individual patient level, the correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in pts with mCRC treated with 1stline chemotherapy with or without a targeted agent as a first step in a surrogacy demonstration. Methods: IPD from 13,949 pts enrolled on 15 randomized Phase III trials in 1st line mCRC were used; 8 trials included targeted (anti-angiogenic and anti-EGFR) agents. EOTR prognostic value was assessed by landmark analyses using Cox models stratified by treatment assignment. P-values <0.01 were considered statistically significant to account for multiple comparisons. Results: Of 13,949 pts, 11,987 had sufficient response data to be included in the analysis. Median OS was 21.7 months (mo) in pts with an EOTR vs. 16.5 mo without EOTR at 6 wk (p<.0001, Hazard Ratio [HR] 0.64, 95% confidence interval [CI] 0.58-0.70, c statistic [c] 0.55). HRs were similar whether pts were treated with targeted therapies (p<.0001, HR 0.68, 95% CI 0.58-0.80, x 0.54) or non-targeted therapies (p<.0001, HR 0.61, 95% CI 0.55-0.69, x 0.55). Median PFS was 8.4 mo in pts with EOTR at 6 wk vs. 7.0 mo in pts without EOTR (p<.0001, HR 0.79, 95% CI 0.73-0.85). EOTR at 8 and 12 wks were also significantly associated with longer OS and PFS. The prognostic value of EOTR at 6, 8 and 12 wks remained significant (p<0.0001) after adjusting for age, gender, performance statusand location of metastatic disease (lung or liver). Overall tumor response (to 26 wk) however provided superior OS prediction (p<.0001, HR 0.51, 95% CI, 0.47-0.56, CS 0.61) vs. EOTR. Conclusions: Early response measured at 6, 8 or 12 wk after starting 1st line treatment was a strong and independent predictor of both OS and PFS in patient with mCRC and warrants further consideration as a potential endpoint for future trials, particularly randomized phase II trials.

Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial.

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA7008-LBA7008 ◽  
Author(s):  
John C. Byrd ◽  
Jennifer R. Brown ◽  
Susan Mary O'Brien ◽  
Jacqueline Claudia Barrientos ◽  
Neil E. Kay ◽  
...  
Keyword(s):  
Treatment Options ◽  
Randomized Study ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Drug Discontinuation ◽  
Purine Analog ◽  
Independent Review ◽  
Secondary Endpoints

LBA7008 Background: Treatment options for CLL/ SLL patients (pts) who fail chemoimmunotherapy are limited. We report interim results from a phase III randomized study of ibrutinib (ibr), a first in class covalent BTK inhibitor, vs ofatumumab (ofa) in R/R CLL/SLL. The Data Monitoring Committee recommended this analysis be considered final, based on meeting the primary and a key secondary endpoint. Methods: R/R CLL/SLL pts who failed ≥1 therapy received 420 mg oral ibr daily until progression or IV ofa 300/2000mg for 12 doses. Primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). Secondary endpoints included overall survival (OS), IRC assessed overall response rate (ORR) and safety. Results: Of 391 pts enrolled (median age 67 years; 40% ≥70 years; 57% Rai stage III/IV disease; 30% del 17p), 195 were randomized to ibr and 196 to ofa. Ibr pts had median 3 prior therapies vs 2 for ofa. Median follow-up was 9.4 months (m). Ibr significantly lengthened PFS (median not reached vs 8.1 m; HR 0.215, CI 0.146–0.317, p<0.0001; 78.5% risk reduction), and significantly improved OS (median not reached; HR 0.434, CI 0.238–0.789, p=0.0049) compared with ofa. ORR was 42.6 vs 4.1% (p<0.0001) and ORR+PR with lymphocytosis was 62.6 vs 4.1% for ibr vs ofa. Similar effects were seen in del17p and purine analog refractory subsets. In each arm 2 pts had confirmed Richter’s transformation. Most frequent adverse events (AE) for ibr vs ofa were diarrhea (47.7 vs 17.8%) fatigue (27.7 vs 29.8%), and nausea (26.2 vs 18.3%). Atrial fibrillation was more frequent with ibr (5.1 vs 0.5%). Major hemorrhages were reported in 1.0 vs 1.6% for ibr vs ofa. Drug discontinuation due to AE was 4.1 vs 3.6% for ibr vs ofa. 86% of ibr pts were continuing treatment. 57 pts randomized to ofa with confirmed PD had initiated ibr at cross-over. Conclusions: Compared with ofa, ibr significantly improved PFS, OS and ORR in pts with R/R CLL/SLL. The safety profile was comparable with that previously reported (Byrd NEJM 2013). These results support ibr as a beneficial therapy for R/R CLL patients irrespective of del 17p or purine analog refractory disease. Clinical trial information: NCT01578707.

In-depth gene expression analysis of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with ribociclib-containing therapy in the Phase III MONALEESA-7 trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1018-1018 ◽  
Author(s):  
Yen-Shen Lu ◽  
Sara A. Hurvitz ◽  
Fei Su ◽  
Wei He ◽  
Debu Tripathy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Large Set ◽  
Premenopausal Patients ◽  
Low Expression

1018 Background: The Phase III MONALEESA-7 study (NCT02278120) is the first dedicated trial of endocrine therapy (ET) ± a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in premenopausal patients (pts) with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) ABC. The study demonstrated that the addition of ribociclib (RIB) to a nonsteroidal aromatase inhibitor (NSAI) or tamoxifen (TAM) + goserelin (GOS) significantly extended progression-free survival (PFS; hazard ratio [HR] 0.55; Tripathy D, et al. Lancet Oncol. 2018). Here we present a gene expression analysis of baseline tumor mRNA from MONALEESA-7. Methods: Premenopausal pts with HR+/HER2− ABC were treated with RIB or placebo (PBO) + GOS with either an NSAI (letrozole or anastrozole) or TAM. Baseline archival tumor samples from 360 of 672 intent-to-treat (ITT) pts were evaluated for gene expression (RIB n = 185; PBO n = 175) using a customized NanoString nCounter® GX 800-gene panel containing relevant breast cancer, CDK, and proliferation pathway–related genes. Pt subgroups were classified as having low or high mRNA expression using median expression as the cutoff. Results: PFS benefit in the biomarker-assessed group was similar to that in the ITT population. A trend toward a more pronounced PFS benefit with RIB was observed in pts with high vs low expression of CCND1 (HR 0.38 vs 0.67, respectively), IGF1R (HR 0.33 vs 0.77), and ERBB3 (HR 0.33 vs 0.76). The PFS benefit seen with RIB also trended to be greater in pts with low vs high expression of CCNE1 (HR 0.38 vs 0.65, respectively) and MYC (HR 0.37 vs 0.69). The PFS benefit with RIB was similar in pts with high vs low expression of FGFR1 (HR 0.45 vs 0.61, respectively), ESR1 (HR 0.57 vs 0.57), and tumor proliferation genes, such as MKI67 (HR 0.50 vs 0.51). Conclusions: This is the first gene expression analysis of a large set of premenopausal pts with ABC. The benefit with RIB was generally consistent across gene expression subgroups, although the magnitude varied in certain subsets. This analysis suggests that there may be unique resistance mechanisms to ET ± CDK4/6 inhibitors in premenopausal pts with ABC. Clinical trial information: NCT02278120.

Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5087-TPS5087
Author(s):  
Kim N. Chi ◽  
Ur Metser ◽  
Johannes Czernin ◽  
Jeremie Calais ◽  
Vikas Prasad ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Alternative Hypothesis ◽  
Treatment Options ◽  
Objective Response ◽  
Hormonal Treatment ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Psma Pet ◽  
To Receive

TPS5087 Background: Treatment options with minimal toxicity and novel mechanisms of action are urgently needed to improve clinical outcomes from mCRPC. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a new treatment for patients with PSMA-avid mCRPC. 177Lu-PNT2002 (also known as [Lu-177]-PSMA-I&T) is a PSMA-targeting agent and studies have shown demonstrable promising initial data. This trial seeks to prospectively evaluate the efficacy of 177Lu-PNT2002 for men with progressive mCRPC after androgen receptor axis-targeted (ARAT) therapy. Methods: This is a multi-center, open-label, phase III study. All patients must be at least 18 years of age, have documented progressive mCRPC at time of screening, high PSMA expression by PSMA PET/CT per blinded independent central review (BICR), chemotherapy naïve for CRPC and unfit or unwilling to receive chemotherapy. The study will commence with a 25-patient dosimetry lead-in. In the dosimetry phase, patients will receive up to four cycles of 177Lu-PNT2002 at 6.8 GBq every 8 weeks. In the randomization phase, approximately 390 patients will be randomized in a 2:1 ratio to receive 177Lu-PNT2002 (Arm A) versus enzalutamide or abiraterone (with prednisone or dexamethasone) (Arm B). Patients randomized to Arm B have an option to crossover to 177Lu-PNT2002 treatment after BICR-assessed radiologic progression. The primary endpoint is Radiological progression-free survival (rPFS) assessed by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) (bone) criteria. Key secondary endpoints include objective response rate, duration of response, PSA response, and overall survival. The study is powered at 90% to test the alternative hypothesis of a hazard ratio (HR) ≤ 0.66 at an α of 0.025. ClinicalTrials.gov identifier: NCT04647526. Clinical trial information: NCT04647526.

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