• Angiokines associated with targeted therapy outcomes in patients with non-clear cell renal cell carcinoma

      Armstrong, A. J.; Nixon, A. B.; Carmack, A.; Yang, Q.; Eisen, T.; Stadler, W. M.; Jones, R. J.; Garcia, J. A.; Vaishampayan, U. N.; Picus, J.; et al. (2021)
      Purpose: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. Patients and methods: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS). Results: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib. Conclusions: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.
    • KEYNOTE-199 cohorts (C) 4 and 5: Phase II study of pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC)

      Hoimes, C. J.; Graff, J. N.; Tagawa, S. T.; Hwang, C.; Kilari, D.; Ten Tije, A. J.; Omlin, A.; McDermott, R. S.; Vaishampayan, U. N.; Elliott, Tony; et al. (2020)
      Background: Initial evidence suggests activity of pembro + enza in patients (pts) resistant to enza. We present results from the multicohort phase II study KEYNOTE-199 (NCT02787005) in chemotherapy-naive pts with mCRPC treated with pembro + enza after progression with enza and who had RECIST-measurable (C4) or bone-predominant (C5) disease. Methods: Pts who did or did previously receive abiraterone and for whom enza treatment failed after clinically meaningful response received pembro 200 mg Q3W, with continuation of enza for up to 2 y or until progression, toxicity, or withdrawal. End point was ORR per RECIST v1.1 (C4) by blinded independent central review (primary); DOR (C4), time to PSA progression, rPFS, OS, and safety. Results: A total of126 pts (C4, 81; C5, 45) were treated. Median (range) PSA was 31 ng/mL (0.4-1667) in C4 and 19 ng/mL (1-1750) in C5.Median (range) time from enrollment to data cut off was 15 mo (7-21) in C4 and 19 mo (7-21) in C5. In C4, ORR (95% CI) was 12% (6-22; 2 CRs, 8 PRs) and median (range) DOR was 6 mo (3+ to 13); 60% of pts had DOR ?6 mo. DCR (CR + PR + SD) was 51% in C4 and C5. Median (95% CI) time to PSA progression was 4 mo (4-4) in C4 and 4 mo (4-4) in C5. Median (95% CI) rPFS was 4 mo (3-6) for C4 and 4 mo (3-6) for C5; 12-mo rPFS rate was 17% in C4 and 23% in C5. Median (95% CI) OS was NR (16-NR) in C4 and 19 (14-NR) mo in C5; 12-mo OS rate was 70% in C4 and 75% in C5. Shorter median OS was more associated with prior enza treatment <6 mo than with prior enza treatment ?6 mo. Liver metastasis was associated with shorter median OS however, median OS in visceral disease subgroups appeared longer than expected. Any-grade/grade ?3 treatment-related AEs occurred in 75%/26% of pts in C4 and 69%/24% in C5. Two pts in C5 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Any-grade/grade 3/4 rash (regardless of relatedness) was higher than that in prior reports for individual agents (33%/6%). Conclusions: Pembro + enza after enza resistance had manageable safety and showed antitumor activity for RECIST-measurable and bone-predominant mCRPC. This combination is being evaluated in an ongoing phase III combination trial.
    • KEYNOTE-199 phase II study of pembrolizumab plus enzalutamide for enzalutamide-resistant metastatic castration-resistant prostate cancer (mCRPC): Cohorts (C) 4 and 5 update

      Omlin, A. G.; Graff, J. N.; Hoimes, C. J.; Tagawa, S. T.; Hwang, C.; Kilari, D.; Ten Tije, A. J.; McDermott, R.; Vaishampayan, U. N.; Elliott, Tony; et al. (2020)
      Background: We present results including time to cytotoxic chemotherapy and time to new anticancer therapy from the multicohort phase 2 study KEYNOTE-199 (NCT02787005) in chemotherapy-naive patients (pts) with mCRPC treated with pembrolizumab (pembro) + enzalutamide (enza) after progression on enza and whoResults: 126 pts (C4, 81; C5, 45) were treated. Median (range) PSA was 31 ng/mL (0.4- 1667) in C4 and 19 ng/mL (1-1750) in C5. Median (range) time from enrollment to data cut off was 15 mo (7-21) in C4 and 19 mo (7-21) in C5. In C4, ORR (95% CI) was 12% (6-22; 2 CRs, 8 PRs) and median (range) DOR was 6.3 mo (2.5+ to 13.4); 4 responders (73% by Kaplan-Meier estimation) had a response 6 mo. Efficacy analyses are displayed in the table. Grade 3 treatment-related AEs occurred in 26% of pts in C4 and 24% in C5. Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any grade/grade 3-4 rash (regardless of treatment relatedness) was higher than previously reported for individual agents (33%/ 6%) but manageable with standard of care treatments. Conclusions: Pembro + enza after enza resistance had manageable safety and showed antitumor activity for RECIST-measurable and bone-predominant mCRPC. This combination is being evaluated in the ongoing KEYNOTE-641 phase III trial (NCT03834493). had RECIST-measurable (C4) or bone-predominant nonmeasurable (C5) disease. Methods: Pts with or without prior abiraterone were eligible if they developed resistance to enza following prior response. Pts continued on enza and received pembro 200 mg IV Q3W for up to 2 y or until progression, toxicity, or withdrawal. End points: ORR per RECIST v1.1 (C4) by blinded independent central review (primary), DOR (C4), DCR, rPFS per PCWG3-modified RECIST, OS, time to cytotoxic chemotherapy, time to new anticancer therapy, and safety
    • Pembrolizumab plus enzalutamide for enzalutamide-resistant metastatic castration-resistant prostate cancer (mCRPC): Updated analyses after one additional year of follow-up from cohorts 4 and 5 of the KEYNOTE-199 study

      Graff, J. N.; Tagawa, S. T.; Hoimes, C. J.; Gerritsen, W. R.; Vaishampayan, U. N.; Elliott, Tony; Hwang, C.; Ten Tije, A. J.; Omlin, A.; McDermott, R. S.; et al. (2021)
      Background: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study to evaluate pembrolizumab (pembro) in mCRPC. A previous analysis of patients with RECIST-measurable (cohort 4 [C4]) or bone-predominant nonmeasurable (cohort 5 [C5]) disease who were chemotherapy-naive and had progression while on enzalutamide (enza) found that pembro + enza showed antitumor activity and manageable safety. Long-term outcomes are of interest with immunotherapy; hence, updated efficacy and safety data after an additional 1 year of follow-up are presented. Methods: Pts were eligible if they had resistance to enza after prior response. Prior treatment with abiraterone was allowed. Pts received pembro 200 mg Q3W for up to 35 cycles + enza QD until progression, unacceptable toxicity, or withdrawal. Primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR) in C4. Secondary end points were DOR (C4), and DCR, rPFS, OS and safety (both cohorts). Results: 126 pts (C4, 81; C5, 45) were treated. Median age was 72 years (range 43-92), 32.5% had visceral disease and 87.3% previously received ≥6 mo of enzalutamide; 121 pts (96.0%) discontinued, most because of progressive disease. Median (range) time from enrollment to data cutoff was 31.7 mo (23.1-37.1) in C4 and 35.5 mo (22.9-37.3) in C5. In C4, confirmed ORR was 12.3% (95% CI 6.1-21.5) (2 CRs, 8 PRs); median (range) DOR was 8.1 mo (2.5+ to 15.2), and 62.5% had a response ≥6 mo (Kaplan-Meier estimate). Additional efficacy analyses are outlined in the table. A total of 27.2% and 28.9% of pts in C4 and C5, respectively, experienced grade ≥3 treatment-related adverse events. Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any-grade (34.1%) and grade 3 or 4 (5.6%) rash, regardless of relatedness to treatment, was higher than previously reported for individual agents but manageable with standard-of-care treatments; 2 pts discontinued because of rash. Conclusions: After an additional 1 year of follow-up, pembro + enza continued to show antitumor activity and a manageable safety profile in pts with mCRPC who became resistant to enza. The treatment combination is being further evaluated in the ongoing phase 3 KEYNOTE-641 trial (NCT03834493).
    • Phase II study of pembrolizumab (pembro) plus enzalutamide for enzalutamide (enza)-resistant metastatic castration-resistant prostate cancer (mCRPC): Cohorts (C) 4 and 5 update from KEYNOTE-199

      Vaishampayan, U. N.; Elliott, Tony; Omlin, A. G.; Graff, J. N.; Hoimes, C. J.; Tagawa, S. T.; Hwang, C.; Kilari, D.; Ten Tije, A. J.; McDermott, R. S.; et al. (2020)
      Background: Chemotherapy-naive patients (pts) with mCRPC who had disease progression with enza were enrolled in C4 and C5 of the multicohort phase II KEYNOTE- 199 study (NCT02787005). Methods: Pts who did or did not previously take abiraterone acetate were eligible if they developed resistance to enza after prior response. Cohorts were composed of ptswho had RECIST-measurable (C4) or bone-predominant nonmeasurable (C5) disease. Pts received pembro 200 mg Q3W for up to 35 cycles + enza QD until progression, toxicity, or withdrawal. The primary end point was ORR per RECIST v1.1 by blinded independent central reviewin C4; DORwas also analyzed. Secondary end points (both cohorts)were DCR, rPFS, OS, time to cytotoxic chemotherapy, time to new anticancer therapy, and safety. Results: A total of 126 pts (C4, 81; C5, 45) were treated. Median (range) time from enrollment to data cutoff was 15 mo (7-21) and 19 mo (7-21) in C4 and C5, respectively. In C4, ORR (95% CI) was 12% (6-22) (2 CRs, 8 PRs) and median (range) DOR was 6.3 mo (2.5+ to 13.4); 4 responders (73% by Kaplan-Meier estimation) had a response 6 mo (Table). Median time to cytotoxic chemotherapy was 11.1 and 11.3 mo in C4 and C5, and time to PSA progression was 4.2 mo in both cohorts (Table). A total of 26% and 24% of pts in C4 and C5, respectively, experienced grade 3 treatment-related adverse events (TRAEs). Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any-grade/grade 3 or 4 rash (33%/6%), regardless of treatment relatedness, was higher than previously reported for individual agents but manageable with standard-of-care treatments.
    • Targeting resistant prostate cancer, with or without DNA repair defects, using the combination of ceralasertib (ATR inhibitor) and olaparib (the TRAP trial)

      Reichert, Z. R.; Devitt, M. E.; Alumkal, J. J.; Smith, D. C.; Caram, M. V.; Palmbos, P.; Vaishampayan, U. N.; Alva, A. S.; Braun, T.; Yentz, S. E.; et al. (2022)
      Background: Men with metastatic, castration resistant prostate cancer (mCRPC) harboring DNA repair defects (̃20%) achieve a radiographic progression free survival of 7.4 months with PARP inhibitors (PARPi). Preclinical studies combining a PARPi (olaparib) and DNA damage checkpoint inhibitor (ATR inhibitor, ceralasertib) show synergy, providing the rationale to test this combination in men with mCRPC, including where single agent olaparib has been shown to be active. Methods: Two cohorts were accrued to a trial combining ceralasertib with olaparib in men a) with or b) without DNA repair defects. All patients progressed on ≥1 prior mCRPC therapy with no prior PARPi or platinum chemotherapy. The primary endpoint was disease response (confirmed PSA decline ≥50% and/or RECIST response), while disease progression was defined per Prostate Cancer Working Group 3 definition. Each cohort is analyzed independently for disease endpoints, while both groups were combined for toxicity assessments. Results: The 12 person DNA repair-deficient (DRDef) cohort allowed patients with germline BRCA2 loss (n = 4), somatic BRCA2 loss (n = 1) and ATM loss (n = 1 germline, n = 5 somatic and n = 1 somatic with unknown germline). 35 men without BRCA2/BRCA1 or ATM genomic loss were accrued to the DNA repair-proficient (DRPro) cohort. These men had next-generation sequencing (NGS) on contemporary biopsies (prior to enrolment without intervening therapy, 12), prior NGS on metastatic tissue (10), prior NGS on primary prostatic tissue (n = 3), or cell-free analyses (5). Five patients have incomplete cell-free analyses. At data cutoff (October 2021), in the DRDef cohort, the response rate by confirmed ≥50% PSA decline was 4/10 (40%) including 3 of 4 BRCA2 patients, and another is awaiting sufficient follow up; 1 of 6 ATM-deficient patients responded and another is awaiting sufficient follow up. All 4 DRDef responders remain on therapy (median of 8 months). For patients in the DRPro cohort who have completed therapy and response assessment (n = 21), 3 responded, one with a duration of 12 months, two with 6 months. An updated analysis will be presented. Conclusions: This analysis suggests potential activity of the doublet for DRDef (BRCA2 mainly) and DRPro mCRPC. Ongoing biomarker analysis (e.g. ATM IHC, contemporaneous cell-free DNA analysis rather than archived tissue) may help guide selection of patients most likely to benefit.
    • Tissue based biomarkers in non-clear cell RCC: Correlative analysis from the ASPEN clinical trial

      Halabi, S.; Yang, Q.; Carmack, A.; Zhang, S.; Foo, W. C.; Eisen, T.; Stadler, W. M.; Jones, R. J.; Garcia, J. A.; Vaishampayan, U. N.; et al. (2021)
      Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.