Phase 3 of CheckMate 214 trial was conducted to study the long-term efficacy and suitability of NIVO+IPI as a 1L treatment for patients with Untreated Advanced or Metastatic Renal Cell Carcinoma with Sarcomatoid features.
139 patients were randomized in an open-label trial to compare the NIVO+IPI combination with SUN monotherapy, where NIVO+IPI proved superior in terms of OS, PFS, and ORR.
The minimum follow-up of Phase 3 was 5 years, in which the efficacy benefits of NIVO+IPI were maintained irrespective of the tumor PD-L1 expression. However, the magnitude of benefits was greater among tumor PD-L1 ≥ 1% of patients. No new safety signals were discovered in the longer follow-up.

In the CheckMate 214 study, Nivolumab plus Ipilimumab (NIVO+IPI) was explored as a first-line treatment and therapeutic option for patients with advanced RCC (renal cell carcinoma) with Sarcomatoid features (sRCC) with no prior treatments as an alternative to Sunitinib (SUN) treatment. Phase 3 of the study was an exploratory analysis with a minimum follow-up of 5 years to report the long-term efficacy of NIVO+IPI.

In this trial, 139 patients were identified with intermediate/poor-risk sRCC by reviewing the tumor tissue or as per the classification in the local pathology report. They were randomized into the two arms of the study, with the NIVO+IPI arm (n=74) receiving four doses of 3mg/kg NIVO with 1mg/kr IPI every 3 weeks, followed by 3mg/kg NIVO every 2 weeks. And the SUN arm (n=65) received a daily dose of 50mg SUN for 4 weeks in 6-week cycles.

The primary endpoints of the trial were the Overall Survival (OS), Progression-Free Survival (PFS), and Objective Response Rate (ORR) measured using the Response Evaluation Criteria in Solid Tumors V.1.1. The safety outcomes were reported based on the evaluation of these results.

The median OS of NIVO+IPI versus SUN was 48.6 vs 14.2 months (HR 0.46) at 5 years minimum follow-up. The median PFS and ORR were 26.5 vs 5.5 months (HR 0.50) and 60.8% vs 23.1%, respectively. 12% of the NIVO+IPI patients chose to remain on treatment at the 5 years data cutoff, while none of the SUN patients did so. The median DOR was longer with NIVO+IPI patients (not reached vs 25.1 months), with more patients completing responses (23.0% vs 6.2%). The OS, PFS, and ORR benefits of the NIVO+IPI treatment were greater among sRCC patients with tumor PD-L1 expression of ≥1%. However, NIVO+IPI remained superior irrespective of the tumor PD-L1 expression.
The primary results were supported in this 5 years follow-up data, demonstrating the superior long-term efficacy, durability, and tolerability of the NIVO+IPI combination over SUN as the preferred first-line therapy for previously untreated patients with intermediate/poor-risk sRCC.

Source Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9791431/

Trial Link: https://clinicaltrials.gov/ct2/show/NCT02231749

Citation: Rini, B. I., Signoretti, S., Choueiri, T. K., McDermott, D. F., Motzer, R. J., George, S., Powles, T., Donskov, F., Tykodi, S. S., Pal, S. K., Gupta, S., Lee, C. W., Jiang, R., & Tannir, N. M. (2022). Long-term outcomes with nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Journal for immunotherapy of cancer, 10(12), e005445. https://doi.org/10.1136/jitc-2022-005445

ctDNA Testing in mCRPC Patients with HRR Gene Alterations

KEY TAKEAWAYS

The phase 3 PROfound study included patients with mCRPC whose plasma samples were retrospectively sequenced using circulating tumor DNA (ctDNA) Next-Generation Sequencing (NGS) to test for BRCA/ATM alterations.
The efficacy of Olaparib was consistent, irrespective of the method used to identify the BRCA/ATM alterations.
The study demonstrated that ctDNA NGS might be used to identify mCRPC patients with BRAC/ATM alterations as an alternative to tissue-based NGS testing.

The Phase III PROfound study was conducted to demonstrate the clinical utility of identifying patients with metastatic Castration-Resistant Prostate Cancer (mCRPC) and BRCA1, BCRA2, and ATM (BRCA/ATM) alterations who may be eligible for Olaparib treatment, using the circulating tumor DNA (ctDNA) Next-Generation Sequencing (NGS) testing instead of tumor-based NGS testing. Additionally, the efficacy of Olaparib was evaluated as compared to Abiraterone or Enzalutamide (control) in treating patients with mCRPC with tumor Homologous Recombination Repair (HRR) gene alterations.

During the screening of the study, plasma samples were collected and later retrospectively sequenced to test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA with the help of the FoundationOne®Liquid CDx test. The patients who tested positive for BRCA/ATM alterations in the tissue testing were grouped in Cohort A (n=245), and only these patients were evaluated.

73.9% of the Cohort A patients (n=181) consented to plasma sample ctDNA testing. 76.8% of them (139 patients) yielded a result with 111 patients (79.9%) identified with BRCA/ATM alterations. These patients were then grouped into the ctDNA group (n=73) and received Olaparib. The remaining 38 patients received the control drug. Notably, the characteristics and baseline demographics of the patients, along with the prevalence of the HRR alterations, were at par with the Cohort A ITT (intention-to-treat) population.

Clinical outcomes of Cohort A and ctDNA subgroup were compared. The Radiological Progression Free Survival (rPFS) was the primary outcome measure and was longer in the Olaparib group at a median of 7.4 versus 3.5 months in the control group and hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001. The results of the Cohort A ITT population were consistent at HR, 0.34; 95% CI, 0.25–0.47.

The Phase III PROfound study was concluded with the observation that ctDNA NGS testing proved to be a reliable alternative to testing the BRAC/ATM alterations in mCRPC patients that are eligible for Olaparib treatments when Tumor Tissue Testing has failed or is not feasible. The testing method does not affect the efficacy of the Olaparib treatment.

Source: https://aacrjournals.org/clincancerres/article/29/1/92/711958/Olaparib-Efficacy-in-Patients-with-Metastatic

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02987543

Citation: Matsubara, N., de Bono, J., Olmos, D., Procopio, G., Kawakami, S., Ürün, Y., van Alphen, R., Flechon, A., Carducci, M. A., Choi, Y. D., Hotte, S. J., Korbenfeld, E., Kramer, G., Agarwal, N., Chi, K. N., Dearden, S., Gresty, C., Kang, J., Poehlein, C., Harrington, E. A., … Hussain, M. (2023). Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA. Clinical cancer research : an official journal of the American Association for Cancer Research, 29(1), 92–99. https://doi.org/10.1158/1078-0432.CCR-21-3577

Comparing HRQOL in R/R Large B-cell Lymphoma: Liso-cel vs SOC

KEY TAKEAWAYS

A phase 3 clinical trial (TRANSFORM) was conducted to evaluate the efficacy of liso-cel compared to SOC as second-line therapy for relapsed/refractory LBCL.
HRQOL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – 30 items and the Functional Assessment of Cancer Therapy-Lymphoma subscale.
Results revealed a significant improvement in global health status/quality of life (QOL) for the liso-cel arm compared to the SOC arm from day 126 to month 6.
Mean scores for other domains were maintained or improved in both arms.
The study indicated that HRQOL was either improved or maintained from baseline in patients with relapsed/refractory LBCL in the liso-cel arm versus SOC arm as second-line treatment.

Lisocabtagene maraleucel (liso-cel) has demonstrated encouraging efficacy in clinical trials for individuals with relapsed or refractory large B-cell lymphoma (LBCL). The health-related quality of life (HRQOL) results presented here are from the TRANSFORM study, the first to directly compare liso-cel to SOC as second-line therapy for this group of patients.

Patients who had LBCL that had been resistant to or had relapsed ≤ 12 months after first-line therapy and were candidates for autologous stem cell transplantation were randomly assigned to receive either liso-cel or SOC at a 1:1 ratio (3 cycles of immunochemotherapy in which responders proceeded to high-dose chemotherapy and autologous stem cell transplantation). Human health quality of life was evaluated using the Functional Assessment of Cancer Therapy–Lymphoma subscale and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (30-item version).

Patients with ≥ 1 examination postbaseline were considered (liso-cel, n = 47; SOC, n = 43). Significantly more patients in the liso-cel arm than in the SOC arm experienced notable improvement in global health status/quality of life (QOL) from day 126 to month 6, while fewer patients in the SOC arm experienced deterioration. When compared between the two groups, significant declines in global health status/QOL at month 6, fatigue at day 29 and month 6, and pain at month 6 with SOC were observed, while scores for all other domains were either stable or better.

Time to confirm deterioration in global health status/QOL was longer in the liso-cel arm than in the SOC arm (median: not reached vs. 19.0 weeks, respectively; hazard ratio, 0.47; 95% confidence range, 0.24-0.94). Patients with relapsed or resistant LBCL treated with liso-cel as second-line therapy had better HRQOL than those treated with SOC.

Source: https://ashpublications.org/bloodadvances/article/6/23/5969/486699/Health-related-quality-of-life-with-lisocabtagene

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03575351

Abramson JS, Johnston PB, Kamdar M, Ibrahimi S, Izutsu K, Arnason J, Glass B, Mutsaers P, Lunning M, Braverman J, Liu FF, Crotta A, Montheard S, Previtali A, Guo S, Shi L, Solomon SR. Health-related quality of life with lisocabtagene maraleucel vs standard of care in relapsed or refractory LBCL. Blood Adv. 2022 Dec 13;6(23):5969-5979. doi: 10.1182/bloodadvances.2022008106. PMID: 36149968; PMCID: PMC9713278.

ctDNA Testing in mCRPC Patients with HRR Gene Alterations

KEY TAKEAWAYS

The phase 3 PROfound study included patients with mCRPC whose plasma samples were retrospectively sequenced using circulating tumor DNA (ctDNA) Next-Generation Sequencing (NGS) to test for BRCA/ATM alterations.
The efficacy of Olaparib was consistent, irrespective of the method used to identify the BRCA/ATM alterations.
The study demonstrated that ctDNA NGS might be used to identify mCRPC patients with BRAC/ATM alterations as an alternative to tissue-based NGS testing.

The Phase III PROfound study was conducted to demonstrate the clinical utility of identifying patients with metastatic Castration-Resistant Prostate Cancer (mCRPC) and BRCA1, BCRA2, and ATM (BRCA/ATM) alterations who may be eligible for Olaparib treatment, using the circulating tumor DNA (ctDNA) Next-Generation Sequencing (NGS) testing instead of tumor-based NGS testing. Additionally, the efficacy of Olaparib was evaluated as compared to Abiraterone or Enzalutamide (control) in treating patients with mCRPC with tumor Homologous Recombination Repair (HRR) gene alterations.

During the screening of the study, plasma samples were collected and later retrospectively sequenced to test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA with the help of the FoundationOne®Liquid CDx test. The patients who tested positive for BRCA/ATM alterations in the tissue testing were grouped in Cohort A (n=245), and only these patients were evaluated.

73.9% of the Cohort A patients (n=181) consented to plasma sample ctDNA testing. 76.8% of them (139 patients) yielded a result with 111 patients (79.9%) identified with BRCA/ATM alterations. These patients were then grouped into the ctDNA group (n=73) and received Olaparib. The remaining 38 patients received the control drug. Notably, the characteristics and baseline demographics of the patients, along with the prevalence of the HRR alterations, were at par with the Cohort A ITT (intention-to-treat) population.

Clinical outcomes of Cohort A and ctDNA subgroup were compared. The Radiological Progression Free Survival (rPFS) was the primary outcome measure and was longer in the Olaparib group at a median of 7.4 versus 3.5 months in the control group and hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001. The results of the Cohort A ITT population were consistent at HR, 0.34; 95% CI, 0.25–0.47.

The Phase III PROfound study was concluded with the observation that ctDNA NGS testing proved to be a reliable alternative to testing the BRAC/ATM alterations in mCRPC patients that are eligible for Olaparib treatments when Tumor Tissue Testing has failed or is not feasible. The testing method does not affect the efficacy of the Olaparib treatment.

Source: https://aacrjournals.org/clincancerres/article/29/1/92/711958/Olaparib-Efficacy-in-Patients-with-Metastatic

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02987543

Citation: Matsubara, N., de Bono, J., Olmos, D., Procopio, G., Kawakami, S., Ürün, Y., van Alphen, R., Flechon, A., Carducci, M. A., Choi, Y. D., Hotte, S. J., Korbenfeld, E., Kramer, G., Agarwal, N., Chi, K. N., Dearden, S., Gresty, C., Kang, J., Poehlein, C., Harrington, E. A., … Hussain, M. (2023). Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA. Clinical cancer research : an official journal of the American Association for Cancer Research, 29(1), 92–99. https://doi.org/10.1158/1078-0432.CCR-21-3577

PURE-01 Trial: Neoadjuvant Pembrolizumab and Radical Cystectomy in MIBC Patients

KEY TAKEAWAYS

The PURE-01 phase 2 clinical trial evaluated the efficacy of neoadjuvant pembrolizumab before radical cystectomy in muscle-invasive urothelial bladder carcinoma patients.
PD-L1 expression was the strongest predictor of response post-RC, with significantly better EFS observed in the high tertile.
The results of the PURE-01 trial further corroborate the sustained efficacy of preoperative pembrolizumab treatment.

Neoadjuvant immune-checkpoint inhibitor (ICI) therapy before radical cystectomy (RC) in patients with muscle-invasive urothelial bladder cancer was first implemented in the PURE-01 study (NCT02736266) (MIBC). Researchers report the survival rates after a median of three years of follow-up.

A total of 155 patients have been included in the “intention to treat” (ITT) population analysis. Time to radiographic progression precluding RC, the commencement of neoadjuvant chemotherapy, recurrence after RC, or death was considered event-free survival (EFS) once treatment with pembrolizumab was begun. Recurrence-free survival (RFS) after RC and overall survival (OS) were additional measures of success. EFS was analyzed using multivariate Cox regression. Kaplan-Meier analysis evaluated EFS outcomes based on baseline PD-L1 combined positive score (CPS) and molecular subtypes.

A 36-month event-free survival (EFS) was 74.4% [95% CI, 67.8-81.7], and OS was 83.8% [95% CI, 77.8-90.2) in the ITT population after a median (interquartile range, IQR) follow-up of 39 (30-47) months. A total of 143 (92.3%) patients were treated with RC. Patients who had ypT0N0, ypT1/a/isN0, ypT2-4N0, and ypTanyN1-3 responses had a 36-month RFS of 96.3% (95% CI, 91.6-100), 74.9% (95% CI, 60.2-93), and 58.3% (95% CI, 36.2-94.1), respectively, among the group of patients who did not receive further treatment (N = 125). Lower tertile PD-L1 EFS was 59.7%, middle tertile PD-L1 EFS was 76.7%, and high tertile PD-L1 EFS was 89.8% (P = 0.0013). The basal/squamous and claudin-low subtypes showed the fewest occurrences overall.

PURE-01 results, with a median follow-up of 3 years, further show the long-term effectiveness of neoadjuvant pembrolizumab before RC. The expression of PD-L1 was found to be the most significant indicator of long-term survival after RC.

Source: https://aacrjournals.org/clincancerres/article-abstract/28/23/5107/711056/Neoadjuvant-Pembrolizumab-and-Radical-Cystectomy?redirectedFrom=fulltext

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02736266

Basile G, Bandini M, Gibb EA, Ross J, Raggi D, Marandino L, Padua T, Crupi E, Colombo R, Colecchia M, Lucianò R, Nocera L, Moschini M, Briganti A, Montorsi F, Necchi A. Neoadjuvant Pembrolizumab and Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Cancer: 3-Year Median Follow-Up Update of PURE-01 Trial. Clin Cancer Res. 2022 Dec 1;28(23):5107-5114. doi: 10.1158/1078-0432.CCR-22-2158. PMID: 36190522.

KEYNOTE-407 Study: Pembrolizumab Plus Chemo in Squamous NSCLC

KEY TAKEAWAYS

KEYNOTE-407 is a phase III clinical trial evaluating the efficacy and safety of pembrolizumab plus chemotherapy in the first-line treatment of metastatic squamous NSCLC.
The trial’s primary endpoints were overall survival (OS) and progression-free survival (PFS) as measured by BICR.
The results showed a significant improvement in OS and PFS. The 5-year OS rate was 18.4% for pembrolizumab plus chemotherapy and 9.7% for placebo plus chemotherapy.

T he phase III KEYNOTE-407 study looked at how well it worked and how safe it was for 5 years. Patients with metastatic squamous non-small-cell lung cancer (NSCLC) who had never been treated were given either pembrolizumab 200 mg or a placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3 weeks for 4 cycles. Afterward, they got pembrolizumab or a placebo for up to 35 cycles.

Overall survival (OS) and progression-free survival (PFS) according to RECIST version 1.1 by blinded independent central review (BICR) were the main goals. In the “intention-to-treat” population, 559 patients were randomly given either pembrolizumab plus chemotherapy or placebo plus chemotherapy. The median time from random assignment to the end of the data collection period was 56.9 months (range: 49.9–66.2). OS and PFS were better with pembrolizumab plus chemotherapy than with placebo plus chemotherapy (hazard ratio [95% CI], 0.71 [0.59 to 0.85] and 0.62 [0.52 to 0.74]), with 5-year OS rates of 18.4% versus 9.7%, respectively. The toxicity wasn’t too bad.

The objective response rate was 90.9% among the 55 patients who finished 35 cycles of pembrolizumab, and the 3-year OS rate after finishing 35 cycles (about 5 years after random assignment) was 69.5%. Pembrolizumab plus chemotherapy was better than placebo plus chemotherapy for OS and PFS patients with metastatic squamous NSCLC who had not been treated before. Pembrolizumab is a standard first-line treatment for metastatic squamous NSCLC, regardless of how much-programmed death ligand 1 is expressed.

Source: https://ascopubs.org/doi/10.1200/JCO.22.01990?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02775435

Novello S, Kowalski DM, Luft A, Gümüş M, Vicente D, Mazières J, Rodríguez-Cid J, Tafreshi A, Cheng Y, Lee KH, Golf A, Sugawara S, Robinson AG, Halmos B, Jensen E, Schwarzenberger P, Pietanza MC, Paz-Ares L. Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol. 2023 Feb 3:JCO2201990. doi: 10.1200/JCO.22.01990. Epub ahead of print. PMID: 36735893.

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