Clinical Conference

Dana Assis, MD Tuesday March 22, 2016

Case 70 yo male first presented to Bellevue 2009 – no hx of routine medical care previously. Diagnosed with HTN and DM. Followed for one year then lost in 2010. In 2012 diagnosis of clear cell renal cancer diagnosed in at Mt. Sinai. Had left kidney resection. Returns to Bellevue 2015 with diagnosis of SCC neck in setting of b/l PE. On workup also found to have pulmonary metastatic disease with pleural effusion consistent with metastatic RCC. Plan at that time from oncology sunitinib/pazopanib

Renal cell carcinoma

• Disease incidence • Majority of cases occur sporadically • Pathology: Clear cell, papillary • 1/3 patients undergo nephrectomy will have

recurrence • Focus on treatment of advanced/metastatic

RCC

Therapy for advanced renal cell carcinoma • Before 2005

• IL-2 • After 2005

• VEGF-pathway inhibitors • First line setting: sunitinib, pazopanib, bevacizumab (target VEGF)

• Median disease free survival 8-11 months • After progression w/first line: Sorafenib, axitinib

• Overall improvement in progression free survival (3-5 months) but not in overall survival

• mTOR inhibitors • Everolimus:

• Median progression free survival approx 5 months • overall survival approx 15mo no benefit when compared to placebo

Molecular Pathways

HIF Hypoxia Inducible Factor VHL von Hippel-Lindau HGF Hepatocyte growth factor

Newer agents

• Nivolumab • Inhibits T cell checkpoint regulator programmed death 1

(PD-1) • Monoclonal Ab to PD-1

• Cabozantinib • Multi kinase inhibitor targeting VEGFR, MET, RET, AXL • Oral small molecule inhibitor TK • Use medullary thyroid cancer

• PD-L1 expression associated with poor prognosis in RCC

• Over expression of PD-L1 inhibits activity of CD8 cells

• Iwai et al: Mouse model PD-1 deficient mice -myeloma suppressed

• Hematogenous spread of melanoma cells was inhibited in PD-1 deficient mice

Int. Immunol. (2005) 17 (2): 133-144.

PD-1

• Nivolumab • Total patients 821 Open Label RCT • Primary end point overall survival • Secondary end points

– Objective response rate – Progression free survival – Association overall survival and tumor expression

PD-L1 – Adverse events

• Inclusion criteria – Dx advanced or metastatic disease – No more than 3 prev therapies – Disease progression – Karnofsky score 70

• Exclusion criteria – Mets CNS, prev rx mTOR inhibitor, required

glucocorticoids

• Patient population – Age 62, 70% M, 80% W, baseline functional status

Primary endpoint

Results • Median overall survival Nivolumab 25 months

compare to Everolimus 19.6 months • HR death 0.73 (CI 0.57 to 0.93) • Death in 183 patients of 410 Nivolumab • Death in 215 patients of 411 Everolimus

Secondary endpoints

• Partial response – 24% or 99 patients in Nivolumab – 5% or 20 patients in Everolimus

• Complete response – 1% or 4 patients in Nivolumab – <1% or 2 patients Everolimus

Adverse Events • Everolimus group:

fatigue, stomatitis, anemia

• Nivolumab group: fatigue, nausea, pruritus

• Grade 3 or 4 event – 19% v 37%

Nivolumab group 21.8 months Everolimus group 18.8 months HR 0.79 CI 0.53 to 1.17

Nivolumab group 27.4 months Everolimus group 21.1 months HR 0.77 CI 0.6 to 0.97

Summary • Overall survival was longer • Fewer grade 3 or 4 adverse events

http://canceres.info/?farmaco=cabozantinib

• Primary endpoint progression free survival • Open label Phase 3 trial • Included 658 patients

– Only 375 patients required to achieve primary end point

• Patient population – Age 60s, White, Male

• Inclusion – Advanced/metastatic ccRCC – Prior treatment VEGFR, progression of disease – Brain mets ok if stable – No limit to previous anticancer therapy – Karnofsky score 70

• Exclusion – Therapy mTOR or cabozantinib – Uncontrolled clinically significant illness

Results • Median progression free survival

– Cabozantinib 7.4 months vs 3.8 months Everolimus

– HR 0.58 CI 0.45 to 0.75 P<0.001

• Objective tumor response – 21% Cabozantinib v 5% Everolimus (P <0.001)

• Overall survival – trend toward longer survival with cabozantinib P value needed at interim analysis not reached

• Median follow up 7.6 and 4.4 months • Adverse events

– Grade 3 or 4 68% Cabozantinib (HTN, diarrhea, fatigue) and 58% with everolimus (anemia, fatigue, hyperglycemia)

Summary • Progression free survival statistically

significant • Not powered for overall survival • Higher AE but equal in both groups

Ongoing trials

• Atezolizumab in combination with Bevacizumab (or as monotherapy) versus Sunitinb in partipitants with untreated advanced RCC

• Nivolumab combined with ipilimumab versus sunitinib in previously untreated advanced or metastatic renal cell carcinoma

Thank You