Jason Harris

Findings from the phase 3 CLEAR trial (NCT02811861) shared during the 2022 International Kidney Cancer Symposium showed that patients with advanced renal cell carcinoma (RCC) treated upfront with the immunotherapy pembrolizumab (Keytruda) plus the TKI lenvatinib (Lenvima) were far less likely to need second-line therapy vs patients receiving first-line sunitinib (Sutent).

The results showed that 33.0% of patients assigned to the combination (n = 355) received subsequent systemic therapy compared with 57.7% of the sunitinib group (n = 357). Among those who progressed to subsequent systemic therapy, the median time from randomization to next line of therapy was 12.68 months (range, 1.45-37.36) in the combination arm vs 6.62 months (range, 0.39-28.52) in the sunitinib arm. The median duration of first subsequent anticancer therapy was 5.16 months (range, 0.10-30.23) in the combination arm and 6.82 months (range, 0.03-30.72) in the sunitinib arm.

Furthermore, patients in the combination arm received fewer subsequent PD-L1/PD-1 checkpoint inhibitor therapies than patients in the control arm (8.2% vs 43.1%, respectively). Patients in the combination group were also less likely to receive mTOR inhibitors (1.7% vs 4.8%) and CTLA-4 inhibitors (1.7% vs 5.0%). Patients received anti-VEGF (30.4% vs 33.6%) and other (3.4% vs 5.6%) therapies at similar rates.

The most common subsequent systemic therapy in combination arm was cabozantinib (Cabometyx; 14.9%). The most common subsequent therapy in the sunitinib arm was nivolumab (Opdivo; 39.8%).

In the open-label, randomized study, investigators assigned treatment-naïve patients to 20 mg once-daily oral Lenvatinib plus 200 mg IV pembrolizumab once every 3 weeks or 50 mg once-daily oral sunitinib in a 4-weeks-on/2-weeks-off cycle. Eligible patients had untreated, histologically or cytologically confirmed RCC with a clear-cell component and proof of advanced disease. Patients were also required to have a Karnofsky performance score of 70 or better.

The combination conferred a benefit in progression on first subsequent systemic cancer therapy or death (PFS2), irrespective of International Metastatic RCC Database (IMDC) or Memorial Sloan Kettering Cancer Center (MSKCC) risk group. The median PFS2 was not reached [NR] in the experimental arm vs 28.7 months in the experimental arm (HR, 0.50; 95% CI 0.39-0.65; nominal P < .0001). PFS2 rates at 12 months (87.6% vs 72.5%) and 24 months (72.7% vs 54.2%) also favored the combination arm.

When investigators analyzed median PFS2 by MSCKCC risk group, the median PFS2 was not reached (NR) for the combination was (95% CI, not evaluable [NE]–NE) compared with 34.7 (95% CI, 28.7-NE) in the favorable-risk group (HR, 0.47; 95% CI, 0.26-0.87). Similarly, outcomes favored the combination in the intermediate- (NR vs 23.7 months; HR, 0.53; 95% CI, 0.39-0.71), and poor- (NR vs 10.2 months; HR, 0.42; 95% CI, 0.20-0.88) risk groups.

Assessing by IMDC risk group, investigators found that the median PFS2 was again NR (95% CI, NE-NE) in the favorable-risk group with the combination compared with 34.7 months (95% CI, 28.8-NE) with sunitinib (HR, 0.57; 95% CI, 0.32-1.00). PFS2 was also NR (95% CI, 31.9-NE) in the intermediate-risk group with the combination vs 23.0 months (95% CI, 17.7-NE) with sunitinib (HR, 0.53; 95% CI, 0.38-0.73). In the poor-risk group, PFS2 was NR (95% CI, 11.8-NE) with the combination compared with 10.2 months (95% CI, 4.2-12.2) with sunitinib (HR, 0.37; 95% CI, 0.19-0.74).

Data from CLEAR previously presented at the 2022 ESMO Congress in September showed that the combination demonstrated continued improvement in overall survival (OS) and PFS compared with sunitinib with an additional 7 months of follow-up.

At a median follow-up of approximately 33 months, investigators observed a 28% reduction in the risk of death with the combination (HR, 0.72; 95% CI, 0.55-0.93). The 24-month OS rate with the combination was 80.2% (95% CI, 75.5%-84.1%) compared with 69.7% (95% CI, 64.4%-74.3%) for sunitinib. Median OS was not estimable for either treatment. Median PFS was 23.3 months (95% CI, 20.8-27.7) with the combination vs 9.2 months (95% CI, 6.0-11.0) with sunitinib (HR, 0.42; 95% CI, 0.34-0.52).

The objective response rate was 71% with lenvatinib plus pembrolizumab (95% CI, 66.3%-75.7%) compared with 36.1% (95% CI, 31.2%-41.1%) for sunitinib (relative risk, 1.97; 95% CI, 1.69-2.29). The rate of complete responses was 17.2% with the combination compared with 4.2% for sunitinib. The median duration of response was 26.0 months (95% CI, 22.2-41.4) with lenvatinib/pembrolizumab compared with 14.7 months (95% CI, 9.4-16.8) with sunitinib.

1. Voss MH, Powles T, McGregor B, et al. Impact of subsequent therapies in patients with advanced renal cell carcinoma receiving lenvatinib plus pembrolizumab or sunitinib in the CLEAR study. Presented at: 2022 International Kidney Cancer Symposium; November 3-5, 2022; Austin, Texas. Abst 36.

2. Porta CG, Eto M, Motzer RJ, et al. Updated efficacy of lenvatinib (LEN) + pembrolizumab (PEMBRO) vs sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CLEAR study. Ann Oncol. 2022;33(suppl 7):S1205-S1206. doi:10.1016/j.annonc.2022.07.1552.

Articles

Findings shared during the 2022 International Kidney Cancer Symposium showed that patients with advanced renal cell carcinoma treated upfront with pembrolizumab plus lenvatinib were far less likely to need second-line therapy vs patients receiving first-line sunitinib.

Immunotherapy/TKI frontline combo lowers need for subsequent therapy in advanced renal cell carcinoma

Adding the PARP inhibitor talazoparib (Talzenna) to enzalutamide (Xtandi) improved radiographic progression-free survival (rPFS) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of homologous recombination repair (

) gene mutation status, according to topline results from the phase 3 TALAPRO-2 trial.

The study met its primary endpoint, as the hazard ratio for rPFS exceeded the pre-specified threshold of 0.696, meaning the combination reduced the risk of disease progression or death by at least 30.4% versus enzalutamide alone.

The talazoparib/enzalutamide combination was also shown to have benefits in key secondary end points, including prostate specific antigen (PSA) response, time to PSA progression, and overall response rate (ORR). Although overall survival (OS) data from TALAPRO-2 trial remain immature, there was a trend toward an OS improvement with the combination observed at the time of the analysis.

Overall the 2-part, 2-cohort, multicenter, double-blind TALAPRO-2 trial (NCT03395197) enrolled 1095 patients with systemic therapy­–naïve mCRPC at clinical sites in the United States, Canada, Europe, South America, and the Asia-Pacific region. The study included an all-comer cohort of 750 patients and a 

 mutation–positive cohort of 380 patients. Patients were randomized to enzalutamide at 160 mg/day plus either talazoparib at 0.5 mg/day or placebo.

 mutation–positive cohort. At the time of the analysis, there were no new safety signals with talazoparib or enzalutamide compared with those previously reported.

Pfizer, which develops both study treatments, reported in a press release that it intends to submit the TALAPRO-2 findings for presentation at an upcoming medical meeting.

“Xtandi is a global standard of care, with overall survival demonstrated in mCRPC, non-metastatic CRPC, and metastatic castration-sensitive prostate cancer (mCSPC),” Chris Boshoff, MD, PhD, chief development officer, Oncology and Rare Disease, Pfizer Global Product Development, stated in the press release. “We are very pleased with the strong findings from TALAPRO-2, and although no definitive conclusions can be made across trials, the rPFS appears to be the longest observed in a randomized trial in this setting. These data highlight the potential for Talzenna in combination with Xtandi, if approved, to become a new standard of care for mCRPC, irrespective of 

 gene mutation status. We look forward to discussing these data with global health authorities.”

Previously reported data from the phase 2 TALAPRO-1 trial showed antitumor activity with single-agent in patients with heavily pretreated mCRPC that harbored DNA damage response 

In the study, patients received at least 1 dose of 1 mg daily of oral talazoparib at 43 medical facilities around the globe. Patients were previously treated with at least 1 taxane-based chemotherapy, as well as abiraterone acetate (Zytiga)/prednisone, enzalutamide, or both hormonal agents.

All patients had at least 1 HHR gene alteration from a panel of 11 genes likely to sensitize their tumor to PARP inhibition: 

ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C

At a median follow-up of 16.4 months (interquartile range, 11.1-22.1), the ORR was 29.8% (95% CI, 21.2%-39.6%) among 104 evaluable patients. Antitumor effects were most notable in patients with BRCA1/2 mutations, with a confirmed ORR of 45.9% and a median rPFS of 11.2 months.

In the safety analysis of 127 patients, the most common grade 3/4 treatment-emergent adverse events (TEAEs) were anemia (31%), thrombocytopenia (9%), and neutropenia (8%). Investigators observed serious TEAEs in 34% of patients. There were no treatment-related deaths.

Other study from the TALAPRO program,the 

 (NCT04821622), is evaluating the combination of talazoparib and enzalutamide in patients with 

1. Pfizer Announces Positive Topline Results from Phase 3 TALAPRO-2 Trial. Published online and accessed October 4, 2022. https://bit.ly/3SQBHn2

2. de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250-1264. doi:10.1016/S1470-2045(21)00376-4

The talazoparib/enzalutamide combination was also shown to have benefits in key secondary end points, including prostate specific antigen (PSA) response, time to PSA progression, and overall response rate.

Talazoparib/enzalutamide improves rPFS in mCRPC, regardless of HRR gene mutation status

Findings presented at the 2022 AUA Annual Meeting showed that TROP-2 and Nectin-4, surface cell targets of sacituzumab govitecan (Trodelvy) and enfortumab vedotin (Padcev), respectively, are highly expressed in urothelial cancer (UC) and variant histology bladder cancer.

However, investigators found that those transmembranes are not highly expressed in patients with neuroendocrine histology. Investigators, including lead author Fady Ghali, MD, an acting instructor and Society of Urologic Oncology fellow at the University of Washington Department of Urology in Seattle, say they are launching clinical trials to assess the implications of these findings on treatment response for variant histology bladder cancer.

Nectin-4 localized primarily in the cytoplasm rather than the membrane in plasmacytoid UC and squamous cell carcinoma (SCC) in primary, lymph node, and metastatic sites. Investigators found that Nectin-4 distribution was relatively even between membrane and cytoplasm.

TROP-2 was expressed at equal levels in both membrane and cytoplasm for both plasmacytoid UC and SCC. Investigators added the high expression was conserved from primary to metastases.

In July 2021, the FDA approved enfortumab vedotin for adults with locally advanced or metastatic UC who are ineligible for cisplatin-containing chemotherapy and who have received 1 or more prior lines of therapy. The agent was previously indicated for patients with locally advanced or metastatic UC who have received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy.

The agency granted accelerated approval to sacituzumab govitecan for patients with locally advanced or metastatic UC who previously received a platinum-containing chemotherapy and either a PD-1 or a PD-L1 inhibitor in April 2021.

Fady et al noted that the role of these novel humanized monoclonal antibody-drug conjugates (ADCs) in the treatment of variant histology bladder cancer is unknown. They designed this study to better understand how these agents affect the disease at both primary and metastatic sites.

Investigators collected 68 metastatic bladder cancer tissue samples from 20 total patients. Twenty-seven samples were UC, 19 were SCC, 17 were plasmacytoid, and 5 were neuroendocrine. They then performed immunohistochemistry for Nectin-4 and TROP-2 on matched primary and metastatic tumors. Staining was scored by intensity (0-3) and multiplied by percent of positive cells resulting in a range of 0 to 300 H-score; H-score greater than or equal to 30% was considered positive for Nectin-4 and greater than or equal to 100 was considered positive for TROP-2. Investigators separately evaluated membranous and cytoplasmic staining for each sample.

Investigators collected 11 samples from primary tumor sites, 20 from the lymph nodes, and 37 from various metastatic sites. Seventeen (85%) patients previously received systemic chemotherapy and 35% had received immunotherapy. No patient had received enfortumab vedotin or sacituzumab govitecan.

For Nectin-4, investigators found that positive H scores were higher in cytoplasmic localization for primary tumors (60.0% vs 30.0%), lymph node tumors (80.0% vs 26.7%), and metastatic tumors (66.7% vs 23.8%) compared with membranous localization. When assessed by histology, positive H scores were higher in cytoplasmic localization vs membranous localization for UC (57.7% vs 30.8%), plasmacytoid UC (94.1% vs 5.9%), and SCC (78.9% vs 42.1%). Nectin-4 was not expressed in neuroendocrine tumors in either membranous (0%) or cytoplasmic (0%) localization.

For TROP-2, investigators found that positive H scores were 90.9% for both localizations for primary tumors and 90.2% in both localizations for metastatic tumors. However, positive H score was significantly higher for cytoplasmic lymph node tumors (93.8% vs 43.8%).

When assessed by histology, positive H scores favored cytoplasmic localization for UC (100% vs 96.2%) and plasmacytoid UC (100% vs 55.6%) but favored membranous localization in SCC (100% vs 89.5%). Again, the transmembrane was not highly expressed in neuroendocrine tumors at either the membranous (0%) or cytoplasmic localizations (20.0%).

Investigators added that it is not clear whether differences in membranous vs cytoplasmic localization affects response to treatment with ADCs.

Ghali, F, Roudier M, Vakar-Lopez F, et al. Antibody drug conjugates and variant histology muscle-invasive bladder cancer: are the targets present in primary and/or metastatic tumors? 

2022;207(suppl 5):e913. doi:10.1097/JU.0000000000002630.09

FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. News release. July 9, 2021. Accessed May 16, 2022. https://bit.ly/3lfWa5Y

FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. News release. April 13, 2021. Accessed May 16, 2022. https://bit.ly/38AQaSq

TROP-2 and Nectin-4, surface cell targets of sacituzumab govitecan and enfortumab vedotin, respectively, are highly expressed in variant histology bladder cancer.

Study provides clues on potential of antibody-drug conjugates in variant histology bladder cancer

Findings presented at the 2022 AACR Annual Meeting indicated that high genomic loss of heterozygosity (gLOH) may predict response to the PARP inhibitor talazoparib (Talzenna) in patients with metastatic castration-resistant prostate cancer (mCRPC).

In a post-hoc exploratory analysis of the phase 2 TALAPRO-1 trial (NCT03148795), 2 thresholds were used to evaluate gLOH-high and gLOH-low status: 8.8%, based on literature showing this cutoff was optimally distinguished from prostate cancers bearing 

 wild-type, and 9.2%, based on the median gLOH score in TALAPRO-1 in the gLOH-evaluable population. A total of 55 patients were included in this study.

The objective response rate with talazoparib among 30 patients with gLOH-high status at the 8.8% cutoff was 53.3% (95% CI, 34.3%-71.7%) vs 12.0% (95% CI, 2.5%-31.2%) for those with gLOH-low status (n = 25; odds ratio [OR], 8.38; 95% CI, 1.83-51.0; 2-sided 

 = .0017). The complete response (CR) rate was 10% vs 4%, respectively, and the partial response (PR) rate was 43.3% vs 8.0%, respectively.

In an analysis of patients using the 9.2% threshold, among the 28 patients with gLOH-high status, the ORR was 53.6% (95% CI, 33.9%-72.5%) vs 14.8% (95% CI, 4.2%-33.7%) for the 27 patients with gLOH-low status (OR, 6.64; 95% CI, 1.60-32.2; 2-sided 

 = .0041). The CR rates were 7.1% vs 7.4%, respectively, and the PR rates were 46.4% vs 7.4%, respectively.

gLOH scores are relatively low in prostate cancer and do not exhibit the dynamic range seen in breast and ovarian cancers. However, study author Johann de Bono, MB, ChB, FRCP, MSc, PhD, FMedSci, who is an honorary consultant in medical oncology, a professor in experimental cancer medicine, and director of The Drug Development Unit at The Institute of Cancer Research and Royal Marsden in London, notes that these findings suggest gLOH status is worthy of study in a larger patient population as a predictive biomarker.

“Based on these retrospective ad hoc exploratory analyses, gLOH-high status seems to associate with a higher enhanced response to talazoparib…in men with heavily pretreated mCRPC,” he said.

Investigators have previously shown that biallelic alterations in DNA damage response (DDR)/homologous recombination repair (HRR) genes are associated with increased response across several solid tumors that may benefit from treatment with PARP inhibitors. High gLOH is a known marker of sensitivity to platinum-based chemotherapy and PARP inhibitors.

de Bono said it is likely that patients with 

 mutations are driving the gLOH data compared with those who have 

 mutations. Not surprisingly, patients with BRCA mutations were more likely to display a positive ORR compared with 

Specifically, using the 8.8% threshold, 17 patients had gLOH-high status and 13 patients had gLOH-low status and a 

mutation. The ORR was 70.6% (95% CI, 44.0%-89.7%) vs 23.1% (95% CI, 5.0%-53.8%), respectively (OR, 8.0; 95% CI, 1.23-61.0; 2-sided 

 = .0253). The CR and PR rates were 11.8% and 58.8% for those with gLOH-high status, and were 7.7% and 15.4% for those with gLOH-low status.

-mutant disease, 4 patients had gLOH-high status and 6 patients had gLOH status. The ORR was 50% (95% CI, 6.8%-93.2%) vs 0% (95% CI, 0%-45.9%), respectively. One patient had a CR, and 1 patient had a PR following treatment with talazoparib in the gLOH-high cohort compared with no patients experiencing a response in the gLOH cohort.

gLOH status did not translate into longer radiologic progression-free survival (rPFS). At the 8.8% threshold, the median rPFS was 10.9 months (95% CI, 7.5-not evaluable) in the gLOH-high group (n = 30) compared with 11.1 months (95% CI, 2.1-19.2) in the gLOH-low group (n = 25).

“The gLOH cut-off did not define patients who were staying on PARP inhibition [the] longest,” de Bono said. “The Kaplan Meier plot shows gLOH-high and -low [status] was not significantly different and did not separate significantly in this analysis.”

The analysis follows the published findings of the TALAPRO-1 trial, in which heavily pretreated patients with mCRPC received at least 1 dose of 1 mg daily oral talazoparib at 43 medical facilities around the globe. Patients were previously treated with at least 1 taxane-based chemotherapy, as well as abiraterone acetate (Zytiga)/prednisone, enzalutamide (Xtandi), or both hormonal agents.

1. de Bono JS, Mehra N, Laird D, et al. TALPRO-1: talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)-exploration of genomic loss of heterzygosity (gLOH) and potential association with antitumor activity. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT031. Accessed April 11, 2022. https://www.abstractsonline.com/pp8/#!/10517/presentation/20169

High genomic loss of heterozygosity may serve as a predictive marker for response to talazoparib in patients with metastatic castration-resistant prostate cancer.

Jason Harris

Articles

Immunotherapy/TKI frontline combo lowers need for subsequent therapy in advanced renal cell carcinoma

Talazoparib/enzalutamide improves rPFS in mCRPC, regardless of HRR gene mutation status

Study provides clues on potential of antibody-drug conjugates in variant histology bladder cancer

Potential response biomarker emerges for talazoparib in mCRPC