Second-line Therapy and Beyond for Advanced Renal Cell Carcinoma M. Dror Michaelson, MD, PhD Clinical Director, Genitourinary Cancer Center Associate Professor of Medicine Massachusetts General Hospital Cancer Center Boston, Massachusetts This program is supported by educational grants from

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Case Study 1 66-yr-old woman presented with R hip pain; films demonstrated a lytic lesion CT scans showed a 9-cm R renal mass, a 4-cm R iliac crest mass, and numerous subcentimeter lung nodules Medical history of obesity, hemorrhoids, and trigeminal neuralgia; no medications, nonsmoker Married with 4 children; no family history of RCC

Case Study 1 Cytoreductive nephrectomy showed clear-cell RCC Following biopsy of R iliac crest, completed XRT course Restaging showed increase in hip, lung, and mediastinal disease Began sunitinib 50 mg on 4/2 schedule and reduced to 37.5 mg after second cycle due to intolerable skin toxicity Restaging showed improvement at all sites Continued skin toxicity; after 3 additional mos with SD, reduced further to 25 mg Mild disease progression; escalated to 37.5 mg; after 3 interrupted mos, had further progression RCC, Renal cell carcinoma; XRT, external beam radiation therapy

Case Study 1: Question This patient has radiographic progression on first-line reduced-dose sunitinib. What systemic therapy would you select at this time? IFN, interferon

Timeline of Development of Targeted Agents for RCC Sunitinib (advanced RCC) Axitinib (advanced RCC after failure of 1 systemic therapy) Pazopanib (advanced RCC) Bevacizumab + IFN-α (metastatic RCC) VEGF pathway inhibitors Sorafenib [advanced RCC] 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 2012 2013 2014 2015 Immunotherapy with IFN-α or IL-2 IFN-a, interferon alpha; IL-2, interleukin 2; mTOR, mammalian target of rapamycin; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor mTOR inhibitors Temsirolimus (advanced RCC) Everolimus (advanced RCC after failure of sorafenib or sunitinib) US Food and Drug Administration.

NCCN Recommendations for Treatment of Clear-Cell RCC Treatment Option NCCN Recommendation First Line Second Line VEGF Inhibitors Sorafenib Selected patients Following cytokine (category 1) Following TKI (category 2A) Sunitinib Advanced RCC (category 1) Pazopanib Following TKI (category 3) Axitinib After cytokines or TKI (category 1) Bevacizumab Following cytokine (category 2A) Following TKI (category 2B) mTORs Temsirolimus Poor prognosis (category 1) Favorable, intermediate prognosis (category 2B) Everolimus Following TKI (category 1) Cytokines IL-2 Selected patients (category 2A) Category 2B IL-2, interleukin 2; mTOR, mammalian target of rapamycin; NCCN, National Comprehensive Cancer Network; RCC, renal cell carcinoma; TKI, Tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor NCCN. Clinical practice guidelines in oncology: kidney cancer. v.1.2013.

Pivotal Phase III Data in Second Line Drug Control Study Design ORR, % PFS, Mos OS, Mos VEGF Inhibitors Sorafenib[1,2] Placebo Randomized 1:1; patients previously treated with IL-2 or IFN-α 10 vs 2 (P < .001) 5.5 vs 2.8 (HR: 0.44; P < .01) 17.8 vs 15.2 (HR: 0.88; P = .146) (17.8 vs 14.3‡; HR: 0.78; P = .029) Axitinib[3] Sorafenib Randomized 1:1; patients previously treated with sunitinib, bevacizumab with IFN-α, temsirolimus, or cytokines 19 vs 9 (P = .0001) 6.7 vs 4.7 (HR: 0.665; P < .0001) 20.1 vs 19.2 (HR: 0.969; P = .374) mTORi Everolimus[4] Randomized 2:1; patients previously treated with VEGFR TKI 2.0 vs 0 4.9 vs 1.9* (HR: 0.33; P < .001)* 5.5 vs 1.9† (HR: 0.32; P < .001)† 14.8 vs 14.4 (HR: 0.87; P = .162) HR, hazard ratio; IF- or IFN- , interferon alpha; IL-2, interleukin 2; mTORi, mammalian target of rapamycin inhibitor; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor *Independent review. †Investigator. ‡Post-crossover placebo-censored OS data. 1. Escudier B, et al. N Engl J Med. 2007;356:125-134. 2. Escudier B, et al. J Clin Oncol. 2009;27:3312-3318. 3. Rini BI, et al. Lancet. 2011;378:1931-1939. 4. Motzer R, et al. Cancer. 2010;116:4256-4265.

AXIS Trial: Axitinib Superior to Sorafenib in Second-line mRCC Therapy 1.0 Median PFS, Mos (95% CI) 6.7 (6.3-8.6) 4.7 (4.6-5.6) 0.9 Axitinib Sorafenib 0.8 0.7 Stratified HR: 0.665 (95% CI: 0.544-0.812; P < .0001) 0.6 Probability of PFS 0.5 0.4 0.3 0.2 0.1 CI, confidence interval; HR, hazard ratio 2 4 6 8 10 12 14 16 18 20 Months Pts at Risk, n Axitinib Sorafenib 361 362 256 224 202 157 145 100 96 51 64 28 38 12 20 6 10 3 1 1 0 0 Rini BI, et al. Lancet. 2011;378:1931-1939.

RECORD-1: Everolimus (RAD001) in mRCC Placebo (n = 138) Patients with mRCC following failure of VEGFR therapy, clear-cell histology, previous therapy with sunitinib or sorafenib within 6 mos, Karnofsky PS ≥ 70 R A N D O M I Z A T I O N Everolimus (RAD001) 10 mg QD (n = 272) QD, per day; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor Reference Escudier B, Szczylik C, Eisen T, et al. Randomized Phase III Trial of The Multi-kinase Inhibitor Sorafenib (BAY-43-9006) in Patients With Advanced RCC. Paper presented at: The European Cancer Conference; October 30-November 3, 2005; Paris, France. Primary endpoint: PFS(central review) Secondary endpoints: safety, response rates, OS, QoL Motzer RJ, et al. Lancet. 2008;372:449-456.

Progression-Free Survival 100 Median PFS, Mos Everolimus: 4.0 Placebo: 1.9 P < .0001 80 60 Probability of PFS (%) 40 20 PFS, Progression free survival Everolimus Placebo 2 4 6 8 10 12 Mos Pts at Risk, n Everolimus Placebo 272 138 132 32 47 4 8 1 2 0 0 0 0 0 Motzer RJ, et al. Lancet. 2008;372:449-456.

INTORSECT Study Design Patients with mRCC and PD on first-line sunitinib (N = 512) Stratification factors: Duration of sunitinib therapy (≤ or > 6 mos) MSKCC risk group Histology (clear cell or non–clear cell) Nephrectomy status RANDOMIZE Temsirolimus 25 mg IV weekly* (n = 259) Primary endpoint: PFS (per IRC) Sorafenib 400 mg oral BID* (n = 253) BID, twice daily; IRC, independent review committee; mRCC, metastatic renal cell carcinoma; MSKCC, Memorial Sloan Kettering Cancer Center; PD, progressive disease; PFS, progression-free survival. Treat until PD, unacceptable toxicity, or discontinuation for any other reason 1:1 *Dose reductions were allowed: temsirolimus (to 20 mg, then 15 mg), sorafenib (to 400 mg/day, then every other day). ClinicalTrials.gov. NCT00474786.

PFS (IRC Assessment) 1.0 0.9 Median PFS, Mos (95% CI) 0.8 Temsirolimus 4.28 (4.01-5.43) 0.7 Sorafenib 3.91 (2.80-4.21) 0.6 Probability of PFS 0.5 Stratified HR: 0.87 (95% CI: 0.71-1.07; log rank P = .1933) 0.4 0.3 0.2 CI, confidence interval; HR, hazard ratio; IRC, internal review committee; PFS, progression-free survival. 0.1 5 10 15 20 25 Mos Pts at Risk, n Sorafenib 252 72 22 11 6 Temsirolimus 259 96 28 9 5 Hutson T, et al. ESMO 2012. Abstract LBA22.

Overall Survival 1.0 0.9 Median OS, Mos (95% CI) 0.8 Temsirolimus 12.27 (10.13-14.80) 0.7 Sorafenib 16.64 (13.55-18.72) 0.6 Probability of OS 0.5 Stratified HR: 1.31 (95% CI: 1.05-1.63; log rank P = .014) 0.4 0.3 0.2 CI, confidence interval; HR, hazard ratio; OS, overall survival. 0.1 10 20 30 40 50 Mos Pts at Risk, n Sorafenib 253 158 74 34 13 Temsirolimus 259 132 54 22 8 Hutson T, et al. ESMO 2012. Abstract LBA22.

OS by Duration of Previous Sunitinib (ITT Population) Previous Sunitinib Use Temsirolimus (n = 259) Sorafenib (n = 253) HR (95% CI) P Value* < 90 days, n (%) Median OS, mos (95% CI) 38 (15) 8.0 (5.3-14.7) 29 (12) 10.3 (5.7-13.8) 1.11 (0.64-1.93) .708 90-270 days, n (%) Median OS, mos (95% CI) 99 (38) 11.6 (10.1-16.1) 97 (38) 16.8 (11.1-19.8) 1.32 (0.95-1.84) .096 > 270 days, n (%) Median OS, mos (95% CI) 121 (47) 14.4 (10.9-17.6) 126 (50) 17.6 (15.3-22.9) 1.40 (1.02-1.92) .036 *Unstratified log rank test. HR, hazard ratio; TKI, tyrosine kinase inhibitor; ITT, intention to treat (?); OS, overall survival. Longer time on first-line TKI predicts for greater benefit from second-line TKI Hutson T, et al. ESMO 2012. Abstract LBA22.

Case Study 2 77-yr-old man underwent CT scan due to L flank pain Scans showed a 7-cm L renal mass and multiple lung nodules up to 1.2 cm Medical history of HTN and nephrolithiasis; on amlodipine, metoprolol, and aspirin Retired oral surgeon; nonsmoker No family history of RCC aaaaaa HTN, hypertension; RCC, renal cell carcinoma; L, left

Case Study 2 Cytoreductive nephrectomy showed clear-cell RCC, grade 4/4 Scans 9 mos later showed increase in lung nodules, new mediastinal and hilar adenopathy, and new liver metastases Began sunitinib 37.5 mg; scans after 2 cycles showed SD Struggled with fatigue, diarrhea, malaise, rash; admitted with dehydration after cycle 3 Resumed treatment after 3-wk break; scans after 2 more cycles showed disease progression in liver RCC, renal cell carcinoma

Case Study 2: Question 3 Radiographic progression on frontline TKI has been demonstrated. What would you recommend at this time?

Case Study 2: Question 5 After 8 mos on everolimus, he develops R facial droop and slurred speech that resolve after 5 mins. MRI as shown. Restaging scans show improvement in lung and liver metastases. Following SRS, what would you recommend? MRI, magnetic resonance imaging; SRS, stereotactic radiosurgery (?) He remains on everolimus 14 mos later with SD and no toxicity other than grade 1 pneumonitis

Second-line Post-TKI Results Agent PFS, Mos OS, Mos Comments Everolimus 4.9 (5.4 in second line only) 14.8 Second and third line Temsirolimus 4.3 12.3 Shorter OS than sorafenib Axitinib 4.8 15.2 Substantially higher in non-sunitinib subgroups Sorafenib 3.4 (AXIS) 3.9 (INTORSECT) 16.5 (AXIS) 16.6 (INTORSECT) Consistent low PFS but high OS results Placebo 1.9 14.4 80% crossover to everolimus (5.0 mos PFS) Motzer RJ, et al. Cancer. 2010;116:4256-4265. Rini et al, Lancet Oncology. 2011;378:1931-1936. Hutson T, et al. ESMO 2012. Abstract LBA22. Motzer RJ, et al. Cancer. 2010;116:4256-4265. Rini et al, Lancet Oncology. 2011;378:1931-1936. Hutson T, et al. ESMO 2012. Abstract LBA22.

PERCY Quattro Trial in mRCC: OS 1.0 Median OS, Mos 0.9 MPA 14.9 0.8 IFN 15.2 0.7 IL-2 15.3 0.6 IFN + IL-2 16.8 Survival (%) 0.5 0.4 0.3 0.2 Reference Negrier S, for the French Immunotherapy Intergroup. Results of randomized trial PERCY Quattro in patients with metastatic renal cell carcinoma of intermediate prognosis. Paper presented at: ASCO; May 13-17, 2005; Orlando, FL. 0.1 8 12 18 24 30 36 42 48 Mos From Randomization 492 pts enrolled Primarily intermediate risk Negrier S, et al. Cancer. 2007;110:2468-2477.

Current Management of Advanced RCC First-line Therapy Second-line Therapy Favorable risk Sunitinib or pazopanib (or other TKI) Everolimus or axitinib (or TKI, temsirolimus, bevacizumab) Intermediate risk Poor risk Temsirolimus Unknown ((sunitinib, clinical trial, supportive care) NCCN. Clinical practice guidelines in oncology: kidney cancer. v.1.2013.

Second-line Trials to Watch Phase III BMS-936558 (anti-PD1) vs everolimus Phase III cabozantinib (XL184) vs everolimus Phase III dovitinib vs sorafenib (completed, third line) Phase III everolimus with or without bevacizumab (CALGB, closed)

Conclusions Both VEGF and mTOR-directed drugs have important activity in second-line treatment of RCC OS for RCC is clearly longer than historical controls Predictive factors of response have not been defined Mechanisms of resistance to VEGFR and mTOR therapy remain poorly understood Clinical trial enrollment remains an important priority for RCC patients mTOR, mammalian target of rapamycin; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor.

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