Wayne Kuznar

Most patients with metastatic renal cell carcinoma (RCC) whose disease progresses after immunotherapy given either alone or in combination with other agents receive subsequent treatment with VEGF tyrosine kinase inhibitors (TKIs) or mTOR inhibitors. When administered post-immunotherapy, cabozantinib (Cabometyx) is associated with superior median progression free survival (PFS), according to retrospective data from a real-world study of patients treated at 16 Italian referral centers.

Of 162 patients with metastatic RCC who were referred to centers that were part of the Meet-Uro group, 111 (68.5%) were treated after progression on immuno-oncology drugs. Of the 79 patients (71.2%) who received subsequent cabozantinib, median PFS was 7.6 months (95% CI, 5.2-10.1 months), compared with a median of 3.2 months (95% CI, 1.8-4.5 months) in the 11 patients (9.9%) who received everolimus as subsequent therapy (

= .001 for cabozantinib vs. everolimus) and a median of 4.3 months (95% CI, 1.3-7.4 months) in the 21 who received other drugs as subsequent therapy.

Median overall survival from first-line therapy was 41.1 months (95% CI, 30.4-51.8 months).

The data were reported at the 2020 Genitourinary Cancer Symposium by investigators led by Daniele Santini, MD, co-chief and professor in the Department of Medical Oncology, Campus Bio-Medico University of Rome, Italy.

They undertook this project because little real-world data exist on safety and outcomes of metastatic RCC patients after progression on immuno-oncology drugs.

Previously, using data from 8 international cancer centers, Graham et al assessed outcomes of patients with metastatic RCC who were treated with targeted therapy after prior immuno-oncology therapy. Their study found an advantage of VEGF-TKIs over mTOR inhibitors on the end points of time to treatment discontinuation (adjusted HR, 0.46; 95% CI, 0.30-0.71;

<.01), 1-year probability of survival (65% vs 47%;

<.01), and objective response rate (29.8% vs 3.6%;

The study presented here included 104 men and 58 women. A total of 136 (83.9%) had prior nephrectomy. About two thirds (65.4%) had received sunitinib (Sutent) as first-line therapy, 29.6% received pazopanib (Votrient), and 5% other agents as first line. Metastatic sites were lymph nodes in 70.3%, visceral in 25.3%, and bone in 76.5%. At baseline, Sixty-six percent of patients had an ECOG performance status of 0-1 and 44% had an ECOG performance status of 2. Histology was clear cell in 87.6% and non-clear cell in 12.4%. Sarcomatoid histology was present in 15.5%.

The median PFS was 4 months in patients pretreated with pazopanib (95% CI, 2.4-5.5 months) versus 3.9 months in those pretreated with sunitinib (95% CI, 2.9-4.9 months).

= .004) in patients reporting adverse events of any grade (5.03 months; 95% CI, 3.8-6.1 months) compared with those not reporting adverse events (2.99 months; 95% CI, 2.4-3.5 months). Median PFS also trended longer among patients without nephrectomy (4.1 months vs. 2.9 months among those with prior nephrectomy;

Physician-assessed best response was stable disease (SD) or partial response (PR) in 55 patients (49.5%) and progressive disease in 26 (23.4%). A total of 42 patients (53.1%) who received cabozantinib as subsequent therapy had SD/PR as best response compared with 2 (18.1%) who received everolimus as treatment subsequent to immune-oncologic therapy and 6 patients (5.4%) who received other agents as subsequent treatment.

Patients with an ECOG performance status of 0 after immuno-oncologic therapy compared with ECOG performance status of 1 or 2.

All-grade adverse events were reported in 83 patients (74%), with grade 3-4 adverse events reported by 39 (35%).

Santini D, Stellato M, De Giorgi U, et al. Clinical outcomes of metastatic renal carcinoma following disease progression to programmed death (PD)-1 or PD-L1 inhibitors (I-O): a Meet-URO group real-world study (Meet-Uro 7). Presented at: GU Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 69

Graham J, Shah AY, Wells JC, et al. Outcomes of patients with metastatic renal cell carcinoma treated with targeted therapy after immuno-oncology checkpoint inhibitors.[published online ahead of print, 2019 Nov 27].

. 2019;S2588-9311(19)30160-9. doi:10.1016/j.euo.2019.1001

Articles

Most patients with metastatic renal cell carcinoma whose disease progresses after immunotherapy given either alone or in combination with other agents receive subsequent treatment with VEGF tyrosine kinase inhibitors or mTOR inhibitors. When administered post-immunotherapy, cabozantinib is associated with superior median progression free survival, according to retrospective data from a real-world study of patients treated at 16 Italian referral centers.

Patients With Metastatic RCC Receive TKIs or mTOR Inhibitors After Immunotherapy

Stereotactic body radiotherapy (SBRT) combined with nivolumab (Opdivo) was associated with &ldquo;high&rdquo; disease control and overall survival (OS) rates in a phase II study of pretreated patients with metastatic renal cell carcinoma (RCC), according to lead investigator Cristina Masini, MD, who presented the data at the 2020 Genitourinary Cancers Symposium.

In the single-arm, multicenter NIVES study, the objective response rate (ORR) to the SRBT/nivolumab combination was 17.4% in the intent-to-treat (ITT) analysis and 19.0% in the per protocol analysis,

which fell short of the hypothesized rate of 40% on ITT analysis. Among the 69 patients enrolled, there was 1 complete response and 11 partial responses. Stable disease was the best response in 28 patients, for a disease control rate of 58.0% (40 of 69) on ITT analysis.

The median duration of response was 9.7 months, with 9 of the 12 responses ongoing. Six patients have ongoing stable disease.

The median progression-free survival (PFS) was 4.1 months (95% CI, 2.8-7.1), with a 12-month PFS rate of 32.6% (95% CI, 21.0%-44.6%). Median OS was 22.07 months (95% CI, 18.1-not reached), with a 12-month OS rate of 73.4% (95% CI, 60.6%-82.6%).

The investigators were looking to improve upon the dismal prognosis of metastatic RCC, which carries a 5-year survival rate of only about 10%. SBRT is a focused radiation therapy thought to effectively kill tumor cells while minimizing damage to adjacent healthy tissue and enhancing antitumor immune responses, said Masini, from the Medical Oncology unit, Clinical Cancer Centre, Azienda Unit Sanitaria Locale di Reggio EmiliaInstituto di Ricovero e Cura Carattere Scientifico, Reggio Emilia, Italy. &ldquo;Several preclinical studies have documented an increase in peripheral antitumor immunity with an increased tumor antigen release, improved antigen presentation, and T-cell infiltration in the irradiated tumor,&rdquo; she said.

Tumor PD-L1 expression can also be induced by radiation; inhibition of the PD-1/PD-L1 axis with nivolumab has been shown to improve antitumor immunity by blocking tumor-mediated suppression of cytotoxic T cells. In addition, radiation may have an abscopal effect on metastases.

On the trial, eligible patients had progressive disease after &le;2 prior antiangiogenic therapies and measurable metastatic sites with at least 1 suitable for SBRT.

Patients received hypofractionated radiation in 1 tumor at a dose of 10 Gy &times; 3 fractions, started 7 days after the first infusion of nivolumab. Nivolumab was given as a fixed dose of 240 mg on day 1 of every 14 days for 6 months. In responding patients, the nivolumab dosage was then increased to 480 mg every 4 weeks until progressive disease or unacceptable toxicity.

A total of 69 patients were treated with at least 1 dose of nivolumab, 2 of whom didn&rsquo;t receive SBRT and 4 of whom did not complete the first cycle of treatment. Twelve centers in Italy participated in the study.

Histology was clear cell in 79.7% of patients and nonclear cell in 14.5%, with unknown histology in 5.8%. Some 82.6% of patients enrolled were male. Median age at therapy initiation was 67 years (range, 43-85). The International Metastatic RCC Database Consortium risk score was intermediate in 68.1%, good in 20.3%, and poor in 11.6%. More than half of patients (50.7%) had &ge;3 metastatic sites and 33.4% had 2 metastatic sites. In total, 56 patients (81.2%) received nivolumab as second-line therapy and 13 (18.8%) received it in the third line. The most common first-line therapy was sunitinib (65.2%). About three-fourths of those included on the study (76.9%) had prior nephrectomy.

The most frequent sites of SBRT were lung (37.7%), lymph nodes (11.6%), and bone (11.6%). At the time of this analysis and with a median follow-up of 15 months (range, 0-25.6), the median number of nivolumab doses received was 12 (range, 1-32). Fifty-four patients (78.3%) discontinued treatment, most often due to disease progression (55.2%).

When sites of metastases were stratified by whether they received SRBT, the ORR was 26.9% in irradiated sites and 17.4% in nonirradiated sites. Masini said what was &ldquo;interesting was the very high disease control rate in the irradiated metastases, 82%, whereas in the past, metastatic kidney cancer has been considered resistant to therapy,&rdquo; said Masini. The disease control rate in nonirradiated sites was 59.4%.

The ORR was significantly higher in patients with clear cell versus nonclear cell histology (20.4% vs 0%;

Grade 3/4 toxicities related to nivolumab were experienced by 17 patients (24.6%), with the most frequent events being diarrhea (5.8%), an increase in amylase/lipase (4.3%), and fatigue (4.3%). Six patients (8.7%) were hospitalized due to treatment-related serious adverse events.

Analysis of the correlation between efficacy with PD-L1 expression and molecular alterations in tumor tissue samples as well as in circulating tumor DNA is ongoing, she said.

Randomized perioperative trials of radiation therapy for kidney cancer have been negative, but SBRT is a different approach that &ldquo;has established a footprint in renal cancer,&rdquo; although the data to support it are weak, said discussant Thomas Powles, MD, director of Barts Cancer Center in London, United Kingdom. &ldquo;If this was a drug, we probably wouldn&rsquo;t be using SBRT the same way as we are now. The robustness of the data in renal cancer is not there.&rdquo;

The median PFS in NIVES is not much different from the 4.6-month median PFS in the CheckMate 025 study with nivolumab alone, he pointed out.

The immunogenic effect of SBRT may be different in kidney cancer and other tumor types in which it has shown efficacy, such as in lung and bladder cancer, said Powles.

&ldquo;We are in an era where I think we are keen to believe that this [the effect of radiotherapy on the immune cycle] exists, but that doesn&rsquo;t mean that we should be adopting it just because we can give radiation therapy and SBRT,&rdquo; he said. &ldquo;Just because we can do it, doesn&rsquo;t mean we should be doing it without robust data.&rdquo;

Masini C, Iotti C, De Giorgi U, et al. Nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in pretreated patients (pts) with metastatic renal cell carcinoma (mRCC): First results of phase II NIVES study. Presented at: GU Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 613.

Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma.

. 2015;373(19):1803-1813. doi: 10.1056/NEJMoa1510665.

Stereotactic body radiotherapy combined with nivolumab was associated with &ldquo;high&rdquo; disease control and overall survival rates in a phase II study of pretreated patients with metastatic renal cell carcinoma, according to lead investigator Cristina Masini, MD, who presented the data at the 2020 Genitourinary Cancers Symposium.

Effects of SBRT Plus Nivolumab Result in Responses for Certain RCC Subgroups

Nivolumab (Opdivo) plus gemcitabine and cisplatin administered in the neoadjuvant setting to patients with muscle-invasive bladder cancer resulted in a pathologic nonmuscle-invasive rate (PaR) of 66% and a pathologic complete response rate (pCR) of 49%,

according to findings from Bladder Cancer Signal Seeking Trial (BLASST-1).

The combination was safe, with no added toxicities or deaths, and did not cause delays to cystectomy or lead to unexpected surgical complications, said Shilpa Gupta, MD, at the 2020 Genitourinary Cancers Symposium.

&ldquo;Results are encouraging, and long-term follow-up will further confirm safety,&rdquo; said Gupta, associate professor of genitourinary oncology at Cleveland Clinic.

Neoadjuvant cisplatin-based chemotherapy regimens are associated with rates of pCR of about 30%.

The survival advantage with neoadjuvant chemotherapy occurs primarily in patients who achieve pathologic downstaging of their tumors.

&ldquo;However, a significant number of patients still relapse [which] contributes to early mortality,&rdquo; Gupta said. &ldquo;There is an unmet need to improve pathologic response rates with novel combination therapies and biomarker-driven approaches for better patient selection.&rdquo;

Prior studies of single-agent neoadjuvant immunotherapy in muscle-invasive bladder cancer have suggested benefit, namely the PURE-01 and ABACUS trials,

she said. The neoadjuvant immunochemotherapy combination of pembrolizumab (Keytruda) plus gemcitabine/cisplatin was also shown to be active in a phase I/IIb trial. Nivolumab is already approved for treatment in patients with metastatic urothelial cancer that progresses after platinum-based chemotherapy.

Patients eligible for BLASST-1 had cT2 to T4aN&le;1, M0 disease with a predominant urothelial cancer histology. Patients were fit, determined to be candidates for radical cystectomy, and all were deemed eligible for cisplatin. The cutoff for creatinine clearance was &ge;50 mL/min.

After diagnosis of muscle-invasive disease, patients received 4 cycles of gemcitabine/cisplatin. Cisplatin was given at 70 mg/m

on day 1 every 21 days. Split doses of cisplatin were allowed at the discretion of the investigator. Gemcitabine was given at 1000 mg/m

on days 1 and 8 every 21 days for 4 cycles. Nivolumab was added on day 8 of each cycle at a fixed dose of 360 mg/m

every 3 weeks. Patients underwent cystectomy at 6 to 8 weeks following completion of systemic therapy. CT and fluorodeoxyglucose (FDG)PET scans were obtained prior to study treatment, and tissue and blood were collected for correlative analyses. Repeat CT/FDG-PET was performed and tissue collected at the end of treatment. The primary objective was pathologic response, defined as the pathologic nonmuscle-invasive rate at surgery.

Forty-one patients were enrolled (63% male, 37% female) at 3 sites, with a median age of 66 years (range, 45-82). Clinical stage was T2N0 in 90%, T3N0 in 7%, and T2-4N1 in 3%. Two patients (4.8%) received prior Bacillus Calmette-Guerin treatment. Thirty-eight patients completed all 4 cycles of treatment, 2 completed 2 cycles, and 1 completed only 1 cycle. Any patient who received at least 1 cycle was evaluable. Forty patients underwent cystectomy; 1 patient withdrew consent after 1 cycle and was lost to follow-up, but was included in the intent-to-treat analysis. All patients underwent cystectomy within 8 weeks of completing therapy.

Of the 27 patients who were downstaged to a nonmuscle-invasive state, 14 (51.8%) were downstaged to pT0, 2 (7.4%) were downstaged to pT1, 5 (18.5%) to pTa, and 6 (22.2%) to pTis. The pCR rate, defined as downstaging to pT0 or pTis, was 49% (20 of 41).

Fifteen of the 39 tumors (39%) assessed for PD-L1 status were positive. &ldquo;There was no correlation between PD-L1positive status and response,&rdquo; said Gupta. Ten of 15 patients (67%) with PD-L1&ndash;positive tumors had downstaging compared with 17 of 24 (71%) with PD-L1&ndash;negative tumors.

Response by molecular subtyping demonstrated that a patient with a claudin-low tumor, characterized by high immune infiltration and basal marker expression, had a complete response to treatment (pT0N0); another patient who was luminal infiltrated by subtyping, characterized by high stromal infiltration and modest luminal marker expression, was a nonresponder (pT3N2).

Gene signature scores were generated for 50 cancer hallmarks. In the patient who had a claudin-low tumor, &ldquo;high immune signature activity was seen&rdquo; with high expression of immune190 signature, interferon gamma, interferon alpha, and inflammation markers, she said. Conversely, in the patient with luminal-infiltrated subtype disease, strong angiogenesis activity and low proliferation was seen.

Most treatment-related adverse events (AEs) were attributed to chemotherapy, said Gupta. &ldquo;The majority of the hematologic toxicities were consistent with what we see with gemcitabine and cisplatin. Most of these were grade 1/2 anemia, neutropenia, and thrombocytopenia,&rdquo; she said. The total number of patients with anemia was 10 (24%), 20 (48%) for neutropenia, and 13 (31%) for thrombocytopenia.

Grade 1/2 fatigue was reported by 60% and grade 1/2 nausea was reported by 70%. Increases in the levels of alanine aminotransferase and aspartate aminotransferase were observed in 24% of patients each. Six (14%) patients had acute kidney injury, and all but 1 was grade 1/2 in severity.

Immune-related AEs were rash in 1 patient, hypothyroidism in 1, inflamed lymph nodes in 2 (both were complete responders; benign on biopsy), and Guillain Barre Syndrome in 1.

&ldquo;Ongoing biomarker analyses will help determine predictors of response and resistance to chemoimmunotherapy in muscle-invasive bladder cancer,&rdquo; Gupta said. The ongoing phase III ENERGIZE trial is being conducted to confirm these results (NCT03661320).

<< View more from the 2020 Genitourinary Cancers Symposium

Gupta S, Sonpavde G, Weight CJ, et al. Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy.

2020;38(suppl 6; abstr 439). doi: 10.1200/JCO.2020.38.suupl_6.439.

Yin M, Joshi M, Meijer RP, et al. Neoadjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and two-step meta-analysis.

. 2016;21(6):708-715. doi: 10.1634/theoncologist.2015-0440.

Sonpavde G, Goldman BH, Speights VO, et al. Quality of pathologic response and surgery correlate with survival for patients with completely resected bladder cancer after neoadjuvant chemotherapy.

. 2009;115(18):4104-4109. doi: 10.1002/cncr.24466.

Bhindi B, Frank I, Mason RJ, et al. Oncologic outcomes for patients with residual cancer at cystectomy following neoadjuvant chemotherapy: a pathologic stage-matched analysis.

. 2017;72(5):660-664. doi: 10.1016/j.eururo.2017.05.016.

Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II study.

. 2018;36(34):3353-3360. doi:10.1200/JCO.18.01148.

Powles T, Rodriguez-Vida A, Duran I, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS).

2018;36(suppl 15; abstr 4506). doi: 10.1200/JCO.2018.36.15_suppl.4506.

Nivolumab plus gemcitabine and cisplatin administered in the neoadjuvant setting to patients with muscle-invasive bladder cancer resulted in a pathologic nonmuscle-invasive rate of 66% and a pathologic complete response rate of 49%.

Neoadjuvant Nivolumab Plus Chemotherapy Results in High Response Rates in Muscle-Invasive Bladder Cancer

The combination of durvalumab (Imfinzi) and olaparib (Lynparza) may have activity as neoadjuvant therapy in the treatment of muscle-invasive bladder carcinoma (MIBC). In a single-arm phase II study (NCT03534492), the pathologic complete response rate (pCR) with the combination was 50%,

reported Juan Francisco Rodriguez-Moreno, MD, at the 2020 Genitourinary Cancers Symposium.

The combination was well tolerated, with only 3 grade-4 adverse events (AEs) and only 3 treatment interruptions in 27 patients evaluated for safety.

The trial enrolled 29 patients with cT2 to T4a resectable muscle-invasive bladder cancer who were treated for 6 to 8 weeks prior to planned cystectomy with durvalumab given 1500 mg every 4 weeks for up to 2 months (up to 2 doses/cycles) plus olaparib administered at 150 mg twice daily for up to 56 days (2 cycles of 28 days each cycle). The 20 patients who were to undergo cystectomy were evaluated for treatment efficacy; 27 patients were evaluated for safety.

ECOG performance status was 0 in 55.2% of enrolled patients and 1 in 44.8%. Median patient age was 71 years. TNM stage was pT2 in 82.2% of patients, pT3 in 7.1%, and pT4 in 7.1%. About 14.3% of patients presented with nodal spread.

Ten patients (50%) had a pathologic complete response (pCR), defined as absence of tumor in the bladder and lymph nodes.

&ldquo;The study was not designed to assess the efficacy of the combination. With this consideration, the data on efficacy are very interesting because a pCR rate of 50% is superior to other therapies in the neoadjuvant setting,&rdquo; said lead author Rodriguez-Moreno, medical oncologist at HM Hospitales  HM CIOCC, Madrid, Spain.

The principal aim of the study was to characterize the impact of the combination on the molecular profile but the biomarker data are currently being analyzed, he said. &ldquo;We hope that these data will be available at the ESMO 2020 meeting in Madrid,&rdquo; he said.

Standard of care for muscle-invasive bladder cancer is radical cystectomy, which is rarely curative, he said. Although cisplatin-based neoadjuvant chemotherapy is the perioperative standard, only a few patients can benefit from this approach. New neoadjuvant treatments are therefore needed.

Recent evidence suggests that immune checkpoint inhibitors could be incorporated in this setting, said Rodriguez-Moreno, and immune checkpoint inhibitors have been approved by the FDA for the treatment of patients with advanced bladder cancer who are refractory or ineligible for platinum-based chemotherapy. However, response rates to single-agent immune checkpoint inhibition in patients with MIBC top out at about 30%, he said.

Durvalumab had demonstrated activity in patients with advanced urothelial carcinoma who were pretreated with platinum-containing chemotherapy and is being evaluated as first-line treatment both as monotherapy and in combination with tremelimumab.

Preliminary results from a single-arm trial of durvalumab combined with tremelimumab in patients with high-risk MIBC who were ineligible for cisplatin-based neoadjuvant chemotherapy were presented at the 2019 ASCO meeting. Of 21 patients who had completed cystectomy, the pCR rate was 43% (9 of 21) and the disease was downstaged in 14 (67%) patients.

PARP inhibitors such as olaparib amplify DNA damage to augment tumor mutational burden and may make bladder tumors more immunogenic by increasing neoantigen production and upregulating PD-L1 expression. In this way, olaparib and durvalumab may exert synergistic activity, said Rodriguez-Moreno.

Tumor samples were collected at the time of diagnosis and cystectomy. Some 21.4% of specimens showed pathologic progressive disease.

One patient experienced pruritus, a grade 1 immune-related adverse event (AE). AEs attributed to olaparib include grade-1 nausea and vomiting and grade-1 anemia.

The most common grade-3 AEs were infection (18.5%) followed by wound evisceration (7.4%). Other grade-3 AEs were anemia, neutropenia, asthenia, hematuria, pulmonary embolism, and hypertension, each experienced by 1 patient. The 3 grade-4 AEs were wound evisceration, hemorrhage, and septic shock (1 patient each). The 3 treatment interruptions were due to personal decision, progressive disease, and an exacerbation of chronic obstructive pulmonary disease.

Pre- and post-treatment blood samples are being analyzed for PD-L1 expression and pattern of immune infiltration. Whole exome sequencing is being performed in all tumor samples.

Rodriguez-Moreno JF, de Velasco G, Bravo Fernandez I, et al. Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB Trial. Presented at: GU Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 542.

Gao J, Siefker-Radtke AO, Navai N, et al. A pilot presurgical study evaluating anti-PD-L1 durvalumab (durva) plus anti-CTLA-4 tremelimumab (treme) in patients (pts) with high-risk muscle-invasive bladder carcinoma (MIBC) who are ineligible for cisplatin- based neoadjuvant chemotherapy (NAC).

. 2019;37 (suppl 15):4551.Abstr 4551. doi: 10.1200/JCO.2019.37.15_suppl.4551.

The combination of durvalumab and olaparib may have activity as neoadjuvant therapy in the treatment of muscle-invasive bladder carcinoma.

Wayne Kuznar | Authors

Articles

Patients With Metastatic RCC Receive TKIs or mTOR Inhibitors After Immunotherapy

Effects of SBRT Plus Nivolumab Result in Responses for Certain RCC Subgroups

Neoadjuvant Nivolumab Plus Chemotherapy Results in High Response Rates in Muscle-Invasive Bladder Cancer

Durvalumab Plus Olaparib Combo Shows 50% Pathologic Complete Response in MIBC