McGregor, Bradley A.

PURPOSE COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non–clear cell (ncc) renal cell carcinoma (RCC). METHODS This phase Ib study ( NCT03170960 ) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety. RESULTS A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs. CONCLUSION The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes.

Objectives To evaluate outcomes of patients achieving a post‐treatment pathological stage of <ypT2N0 at radical cystectomy (RC) following neoadjuvant chemotherapy (NAC) for muscle‐invasive bladder cancer (MIBC) to identify an optimal definition of pathological response. Patients and Methods Patients from 10 international centres who underwent NAC for cT2–4aN0–1 MIBC and achieved <ypT2N0 disease at RC were included. The primary outcome was time to recurrence, either local or distant. Kaplan–Meier and Cox proportional hazards regression were used to evaluate associations between clinicopathological variables and outcomes. Results A total of 625 patients were included. The median age was 66 years and 80% were male. Gemcitabine and cisplatin (GC, 56%) and methotrexate, vinblastine, doxorubicin and cisplatin (MVAC)/dose‐dense (dd)MVAC (32%) were the most common NAC regimens. ypT0, pure ypTis, ypTa ±ypTis and ypT1 ± ypTis were attained in 58.1%, 20.0%, 7.6% and 14.2% of patients, respectively. The cumulative incidence of recurrence at 5 years was 9%, 16%, 29% and 30%, respectively. Pathological stage was prognostic for recurrence, with ypTa ± Tis (hazard ratio [HR] 3.20, 95% confidence interval [CI] 1.40–7.30) and ypT1 ± Tis disease (HR 4.03, 95% CI 2.13–7.63) associated with a significantly higher recurrence risk. Pure ypTis (HR 1.66, 95% CI 0.82–3.38) and the type of NAC regimen (ddMVAC: HR 1.59, 95% CI 0.55–4.56; MVAC: HR 1.18, 9%% CI 0.25–5.54; reference: GC) were not associated with recurrence. Conclusion We propose that optimal pathological response after NAC be defined as attainment of ypT0N0/ypTisN0 at RC. Patients with ypTaN0 or ypT1N0 disease (with or without Tis) at RC displayed a significantly higher risk of recurrence and may be candidates for trials investigating adjuvant therapy.

5564 Background: Cabozantinib (C) may enhance response to immune checkpoint inhibitors (ICIs) by promoting an immune-permissive microenvironment and has shown encouraging activity in combination with ICIs in tumor types including RCC and HCC. C and atezolizumab (A) have shown low objective response rates as monotherapy in metastatic castration-resistant prostate cancer (mCRPC) (Smith JCO 2012; Kim JCO 2018). COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating the combination of C + A in various solid tumors. We report results for Cohort 6 in mCRPC. Methods: Eligible patients (pts) were required to have radiographic progression in soft tissue after enzalutamide and/or abiraterone, measurable disease, and an ECOG PS of 0 or 1. Prior chemotherapy for mCSPC was permitted. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for the first year and Q12W thereafter. The primary endpoint is ORR per RECIST 1.1. Other endpoints include safety, ORR per irRECIST, duration of response (DOR), PFS, and OS. Results are presented for the first 44 pts enrolled. Results: Median follow-up as of Dec 20, 2019 was 12.6 mo (range 5, 20) for the 44 mCRPC pts. Median age was 70 y (range 49, 90), 50% had ECOG PS 1, 34% had visceral metastases, and 61% had extrapelvic lymph node metastases. 27% had prior docetaxel and 52% had 2 prior novel hormonal therapies. The most common any grade treatment-related adverse events (TRAEs) were fatigue (50%), nausea (43%), decreased appetite (39%), diarrhea (39%), dysgeusia (34%), and PPE (32%). One grade 5 TRAE of dehydration was reported in a 90 y/o. Median duration of treatment was 6.3 mo. ORR per RECIST 1.1 among all 44 pts was 32% (2 CRs [4.5%] and 12 PRs [27%]); 21 (48%) pts had SD resulting in a disease control rate of 80% in all pts. One pt with PD per RECIST 1.1 had an irPR per irRECIST. ORR per RECIST 1.1 was 33% in 36 pts with high-risk disease (visceral and/or extrapelvic lymph node metastases). Median DOR for all pts with response per RECIST 1.1 was 8.3 mo (range 2.8, 9.8+). 17 (50%) of 34 pts with post-baseline PSA evaluation had a decrease in PSA. In 12 responders with post-baseline PSA evaluation, 8 (67%) had a PSA decrease ≥50%. Tumor PD-L1 expression will also be reported. Conclusions: The combination of C + A had a tolerable safety profile and demonstrated clinically meaningful activity with durable responses in men with mCRPC. Given the encouraging activity in these pts, especially in those with high-risk disease, further evaluation of C + A in men with mCRPC is being pursued. Clinical trial information: NCT03170960 .

5077 Background: Several ICIs are used in first and subsequent lines of therapy for mRCC, either alone or in combination with another ICI or targeted therapy (TT). There are no data on the efficacy and safety of using an ICI in patients who have already received an ICI in a prior line of therapy. Methods: We reviewed patients with mRCC at 8 institutions who received 2 separate lines of ICI therapy (ICI-1, ICI-2), including as a single-agent and/or combination with other agents. The primary outcomes were overall response rate (ORR) and time to progression (TTP) with ICI-1 and ICI-2. Immune-related adverse events (irAEs) were graded using CTCAEv5.0. Results: 65 patients were included. Median age at diagnosis of mRCC was 60 years (range 30-86) and the majority had clear cell RCC (n=56, 86%). Median follow-up was 3.5 years (95% CI 2.9-4.4). Median lines at which ICI-1 and ICI-2 were received were 1 (1-6) and 3 (2-8) respectively. Reasons for discontinuing ICI-1 were disease progression (n=47, 72%), toxicity (n=15, 23%) or other (n=3, 5%). Therapies received at ICI-2 were single-agent ICI (n=26, 40%), or combinations of ICI with another ICI (n=20, 31%), TT (n=11, 17%) or other agent (n=8, 12%). Responses to ICI-1 and ICI-2 are shown in the Table; ORR to ICI-2 was significantly lower than to ICI-1 (23% vs. 36%, p=0.044). Amongst those who responded to ICI-2 (n=14), 7 (50%) received single-agent ICI, and the remainder received ICI in combination with another ICI (n=4, 29%) or TT (n=3, 21%); 7 patients (50%) had previously responded to ICI-1. The ORR to ICI-2 was higher in responders to ICI-1 (32%) compared to those with SD (17%) or PD (15%) to ICI-1. Median TTP (mTTP) at ICI-2 was shorter compared to ICI-1 (5.3 months vs. 8.5 months, Wilcoxon p=0.024). 29 patients (45%) experienced an irAE with ICI-2; 8 (12%) and 3 (5%) had a grade 3 or 4 irAE respectively, with 3 (30%) of these patients having previously had ≥grade 3 irAE to ICI-1. There were no treatment-related deaths. Conclusions: The ORR to ICI-2 was 23%, which is comparable to that seen with ICI after prior TT. Responses were seen even amongst those receiving single-agent ICI at ICI-2 and the likelihood of response to ICI-2 was higher if a patient had previously responded to ICI-1. No increase in toxicity with ICI-2 was apparent. Additional data from prospective studies are needed to determine whether sequential ICI has a role in treatment of mRCC. [Table: see text]

5061 Background: The phase 3 JAVELIN Renal 101 trial (NCT02684006) in treatment-naive patients with advanced renal cell carcinoma (aRCC) demonstrated significantly improved progression-free survival (PFS; hazard ratio [HR], 0.69; 95% CI, 0.56, 0.84; P < 0.001) and higher objective response rate (ORR; 51.4% vs 25.7%) with avelumab + axitinib vs sunitinib (Motzer RJ, et al. N Engl J Med. 2019;380:1103-15). NLR has emerged as a potential prognostic biomarker in aRCC; elevated NLR is associated with poorer prognosis. Here, we describe the association of NLR with the efficacy of avelumab + axitinib from JAVELIN Renal 101. Methods: We examined baseline NLR and its association with efficacy outcomes. PFS, best overall response (per blinded independent central review using RECIST 1.1), and overall survival (OS) data from the avelumab + axitinib arm from the first interim analysis of JAVELIN Renal 101 were analyzed (data cutoff, June 20, 2018). Multivariate Cox regression analyses of PFS and OS were also conducted. Results: In the avelumab + axitinib arm, patients with < median NLR (N = 217) had longer observed PFS (stratified HR, 0.85; 95% CI, 0.634, 1.153) and longer observed OS (stratified HR, 0.51; 95% CI, 0.300, 0.871) than patients with ≥ median NLR (N = 217). The ORR was 57.1% in patients with < median NLR vs 47.5% in patients with ≥ median NLR, with complete response in 5.5% vs 1.4%. Multivariate analysis showed that low NLR was associated with longer PFS and OS by treating baseline NLR as either a continuous variable or a binary variable (dichotomized by median). Conclusions: Low NLR was associated with better observed treatment outcomes in patients with aRCC who received avelumab + axitinib. Clinical trial information: NCT02684006 .

5043 Background: Pathologic complete response (pCR) after NAC for MIBC is strongly correlated with long-term overall survival. However, there are sparse data on the risk of recurrence based on depth of pathologic response (pT0, pTa, pTis, pT1), and the differential impact of clinicopathologic factors and NAC regimen on recurrence. Methods: Baseline data on all pts with cT2-4N0-1 MIBC receiving NAC and who achieved < ypT2N0 disease at radical cystectomy (RC) from 9 international centers were obtained. The key outcome was time to recurrence (TTR) – defined as the time to any recurrence in the urinary tract or regional/distant metastasis, with death (in the absence of recurrence) considered a competing risk. Cox regression analysis was used to analyze the impact of clinical factors on recurrence. Results: A total of 506 pts were available. Median age was 66 years (range 33-86) and 78% (n = 396) were male; median follow-up after RC was 2.6 years. The majority of patients had pure urothelial histology (n = 371, 73%), and baseline stage was cT2N0 (n = 368, 73%), cT3-4N0 (n = 95, 19%) and TanyN1 (n = 43, 9%). NAC regimens were gemcitabine-cisplatin (GC, n = 296, 59%), dose-dense methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC, n = 141, 28%), split-dose GC (n = 29, 6%), MVAC (n = 29, 6%) and non-cisplatin based regimens (n = 11, 2%). At RC, 304 patients (60%) had ypT0N0 disease, 32 (6%) had ypTaN0, 107 (21%) had ypTisN0 and 63 (13%) had ypT1N0. Overall, 43 patients (8%) recurred with a median TTR of 56 weeks (range 7-251); 5-year freedom from recurrence was 87% (95% CI 83-91). The majority (n = 38) recurred outside the urinary tract. On multivariable analysis, ypTa (HR = 3.36 [1.24-9.11]) and ypT1 (HR = 2.88 [1.33-6.22], p = 0.013) disease at RC were predictors of shorter TTR, while female sex was associated with longer TTR (HR = 0.52 [0.27-0.98], p = 0.043). The type of NAC was not predictive of TTR (GC vs. other, HR = 1.49 [0.75-2.97], p = 0.26). Conclusions: To our knowledge, this is the largest study to quantify the risk of recurrence in pts achieving pathologic response after NAC and RC for MIBC. 8% of patients undergoing NAC and achieving < ypT2N0 at RC recurred. Residual ypTa and ypT1 disease conferred a significantly higher risk of recurrence, while ypTis did not; female sex was associated with a lower risk of recurrence. Importantly, the type of cisplatin-based NAC regimen used was not an independent predictor of recurrence.

CRA1008 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

139 Background: C may enhance response to immune checkpoint inhibitors by promoting an immune-permissive microenvironment. COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating the combination of C with A in various solid tumors. We report interim results from Cohort 6 in mCRPC. Methods: Eligible pts were required to have radiographic progression in soft tissue after enzalutamide and/or abiraterone, measurable disease, and an ECOG PS of 0 or 1. Prior chemotherapy for mCSPC was permitted. Pts received C 40 mg PO qd and A 1200 mg IV q3w. CT/MRI scans were performed q6w for 52w and q12w thereafter. Bone scans were performed q12w. The primary endpoint is ORR per RECIST 1.1. Other endpoints include safety, ORR per irRECIST, duration of response (DOR), PFS, and OS. Results: As of Oct 2019, 44 mCRPC pts were enrolled with a median follow-up of 10.6 mo (range 3.4+, 17.9). Median age was 70 y (range 49, 90), 50% had ECOG PS 1, 34% had visceral metastases, and 61% had extrapelvic lymph node metastases. 27% of pts had prior docetaxel and 52% had ≥2 prior novel hormonal therapies. The most common any grade TEAEs were fatigue (57%), nausea (48%), decreased appetite (45%), diarrhea (39%), PPE (32%), and vomiting (32%). One Grade 5 TRAE of dehydration was reported in a 90 y/o. Median duration of treatment was 5.3 mo. The ORR per RECIST 1.1 among all pts was 32% (2 CRs [4.5%] and 12 PRs [27%]); 21 (48%) pts had SD giving a disease control rate of 80% in all pts. One pt with initial PD per RECIST 1.1 had an irPR per irRECIST. ORR per RECIST 1.1 was 33% in 36 pts with high-risk clinical features (visceral and/or extrapelvic lymph node metastases). Median DOR for all pts with response per RECIST 1.1 was 8.3 mo (range 1.38+, 9.76+). In 12 responders with at least 1 post-baseline PSA evaluation, 8 (67%) had a PSA decline ≥50%. Conclusions: The combination of C+A had a tolerable safety profile and demonstrated clinically meaningful activity with durable responses in men with mCRPC. Given the encouraging activity in these pts, especially in those with visceral and/or extra pelvic lymph node metastases, further evaluation of C+A in men with mCRPC is being pursued. Clinical trial information: NCT03170960.

Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.