Illustrative Case Series

Renal Cell Carcinoma: A Revolution in Molecularly Targeted Therapy

Guest Discussant: Robert Fenton, MD, PhD Clinical Associate Professor, Clinical Research Committee Member, University of Maryland, Marlene and Stewart Greenebaum Cancer Center. Dr. Fenton reports no financial relationship relevant to this field of study.

Case History and initial evaluation

A 52-year-old male presented to his primary care physician in February 2006, complaining of decreasing exercise endurance. The patient was a runner, and typically ran 5-8 miles three or four times a week. During the past month, he noted difficulty in completing the longer runs, and initially attributed this to a persistent cold and URI. The patient's PMH was unremarkable, and he was taking no medications. He had a colonoscopy when he turned 50 years old, which was negative. His mother was alive, with some osteoarthritis and hypertension, and his father died from coronary artery disease. His two sisters were both alive and well. The patient is a retired Army major who currently teaches aerospace engineering at the local university. He is married with two children, both in college. Review of symptoms was notable for a lack of weight loss or other constitutional symptom, his appetite was excellent, and he denied cough, chest pain, neurologic symptoms, blood in stool or urine, arthritis, or muscle pain. On physical exam, the heart rate was 60, BP 110/70, respiratory rate 10, O2 saturation 99%, and he was afebrile. Physical exam was completely normal. Laboratory studies showed a normal metabolic panel, with creatinine of 1.1 and normal LFTs. His CBC was remarkable, with a hemoglobin level of 10.5 g/dL, hematocrit of 31%, 245,000 platelets, and a WBC of 5.2, with a normal differential. The MCV was 77 fL. A urinalysis demonstrated TNTC RBC.

Diagnosis and surgery: Role of adjuvant therapy in RCC

The patient's exertional dyspnea was almost certainly due to microcytic anemia, and the likely cause was bleeding from somewhere in the urinary system. The patient was referred to a urologist, who performed a cystoscopic exam that showed a normal bladder, suggesting that the bleeding was arising from higher up. A CT scan was performed with IV contrast. This demonstrated a 9 cm mass in the upper pole of the left kidney that abutted the renal pelvis, but appeared to be confined to the kidney. There was no evidence for invasion of the renal vein or IVC, and a few regional LN were slightly enlarged (1-1.5 cm diameter). Chest and head CT and a bone scan were negative for metastatic renal cell carcinoma (RCC). The patient was taken to the OR, and a left radical nephrectomy was performed. The primary tumor measured 9 x 7 x 6 cm, was centrally necrotic and highly vascular, and extended into the perinephric fat but not into Gerota's fascia. There was no invasion into the renal vein. Five perinephric LN were removed, and all were negative. Histology showed this to be a clear-cell tumor, pathologic grade 2. The final diagnosis was clear-cell RCC, T3N0M0, stage 3. The patient made an unremarkable recovery from surgery, with correction of his anemia. In discussions with his oncologist, he was informed that his chances of relapse were as high at 50%, but that there was no evidence that adjuvant treatment would significantly lower this risk, as a number of randomized studies with IFNa and/or IL-2 had failed to demonstrate a reduction in disease recurrence.1,2 There were no compelling adjuvant clinical trials available for this patient in 2006.

First-Line therapy in rcc patients with excellent performance status

The patient was asymptomatic until March 2007, when he developed a chronic cough that did not respond to azithromycin. CT scan of the chest demonstrated 10 pulmonary nodules, all 1-2 cm in diameter scattered throughout both lung fields. CT of the abdomen and head, and a bone scan, were negative. Given that the patient's performance status was 90%, he was referred to the local university for consideration of high dose IL-2 therapy. The patient was told that for good-prognosis patients (KPS > 80, disease-free interval >1 year, no hypercalcemia, increased LDH, or anemia) with lung metastases only, there was a 10% chance of long-term, disease-free survival.3,4 He received 14 doses of IL-2 at 600,000 IU/kg q8h, and left the hospital after one week. After a 10-day break, he was admitted for more high-dose IL-2, receiving only 11 doses due to hypotension, capillary leak-induced pulmonary edema, and a creatinine of 6. He made a full recovery after cessation of IL-2. He received two more courses of this treatment, and follow-up CT scans revealed a complete resolution of all pulmonary disease. The patient refused a final cycle of IL-2, and he was followed for recurrence with q3 month CT scans.

VEGF-Pathway inhibitors in rcc: Concept of oncogene addiction

In November 2008, CT scans showed recurrence of bilateral pulmonary nodules and the development of enlarged para-aortic LN just above the level of the right renal artery. The patient complained of mild low-back pain, but his KPS was 90%. The patient was educated about a new class of drugs, the tyrosine kinase inhibitors (TKI), which demonstrated antitumor benefit in randomized, Phase-III trials. These were sorafenib and sunitinib, oral small-molecule inhibitors of tyrosine kinases that prevented tumor growth by blocking angiogenesis through inhibition of the vascular endothelial growth factor (VEGF) receptors. Unlike bevacizumab, which binds to the ligand VEGF, these competed with ATP binding in the active site of the kinase, blocking phosphorylation of downstream targets. Due to the inactivation of the von Hippel Landau gene in 90% of clear-cell tumors (by genetic or epigenetic silencing), the transcription factor HIF-1 is up-regulated, inducing the constitutive transcription of VEGF and other genes normally activated in response to hypoxia and nutrient deprivation.5,6 Sorafenib, a broad-spectrum inhibitor of VEGFR, platelet-derived growth factor (PDGF) receptor, FMS-like tyrosine kinase (FLT)-3, fibroblast growth factor (FGF) receptor-1, and the serine/threonine kinase Raf, demonstrated activity in the Phase-III TARGET trial of previously treated stage-IV RCC patients. Compared to placebo, patients receiving Sorafenib (400 mg po BID) had a PFS of 5.5 vs. 2.8 mo (HR 0.44), and OS of 17.8 vs. 15.2, which was not significant due to the crossover design of the study.7 Importantly, sorafenib was as effective in patients older than age 70, without increased toxicity.8 Interestingly, in a randomized, Phase-II study of previously untreated patients, sorafenib did not show any improvement over IFNa.9 Sunitinib, with activity directed against VEGFR, platelet-derived growth factor receptor (PDBFR), and c-KIT (the receptor for stem cell factor), demonstrated increased activity as first-line treatment when compared to IFNa, with an overall response rate of 39% vs. 8%, PFS advantage of 11 vs. 5 mo (HR 0.54), and a significant OS benefit of 26.4 vs. 21.8 mo.10

Because the patient had received cytokine therapy, it was elected to treat him in the second-line therapy with sorafenib, 400 mg PO BID. After 14 days of treatment, the patient was seen in the clinic complaining of localized erythema at pressure points of his fingers and the soles and proximal MTP of his feet, which had become so symptomatic that walking was quite painful. The painful areas were marked by circumscribed regions of hyperkeratosis, consistent with a diagnosis of sorafenib-induced hand-foot syndrome, grade 2. The patient was instructed to avoid touching hot water or surfaces, to use padded running shoes, and to apply urea cream gently to the affected areas of his hands and feet twice a day. The sorafenib dose was lowered to 400 mg once a day for 7 days, during which time the toxicity resolved to grade 1. He was then restarted on the BID schedule, continuing the supportive care to hands and feet, with ultimate slow resolution of the hand-foot symptoms over the next few months. CT scans taken at two-month intervals demonstrated a small decrease in diameter of most of the pulmonary lesions and LN without reaching partial response criteria; there was no evidence of tumor growth and no new lesions. The patient complained of mild fatigue (grade 1) and had an increase in blood pressure that did not require treatment. There was no diarrhea or myelosuppression.

mtor inhibitors in first-line or subsequent treatment of rcc

The patient did well with stable disease until October 2009, when his pulmonary lesions progressed and he developed two new 3 cm liver metastases. Bone scan and head CT remained negative. A discussion was held with the patient. One option was to change treatment to another therapy targeting the VEGF-pathway. This could be sunitinib, or the recently FDA-approved agent pazopanib, which has a spectrum of activity and efficacy similar to sunitinib, but appears to be more tolerable (e.g., less fatigue).11 However, there is currently little data for the use of further VEGF-targeted therapy after Sorafenib failure. In principle, if his tumor had become refractory to VEGF-pathway inhibition, it would be more efficacious to target a distinct signaling pathway that was required by tumor cells for survival and/or proliferation. Recent clinical studies have demonstrated an important role for the PI3K/Akt/mTOR pathway in RCC, and Phase-III trials have demonstrated the efficacy of the mTOR inhibitors temsirolimus and everolimus in first- and second-line therapies, respectively. mTOR is a protein kinase that regulates cellular protein translation by sensing nutrient availability. By phosphorylating p70S6K and 4E-BP1, it promotes the translation of specific classes of mRNA, including the mRNA encoding HIF-1.12 Hence, inhibiting mTOR can have anti-angiogenic activity by indirectly blocking VEGF production, but can also have direct effects on tumor cell metabolism. In a Phase-III study of previously untreated poor-prognosis RCC patients, temsirolimus (given IV at 25 mg/week) demonstrated a PFS advantage of 5.5 vs. 3.1 mo compared to IFNa, and a significant increase in OS from 10.9 to 7.3 mo.13 Toxicities included rash, mucositis, asthenia, nausea, hyperglycemia, anemia, and rare hypersensitivity reactions. Everolimus was tested in patients who had progressed on sunitinib or sorafenib and, in a placebo- controlled, randomized study, demonstrated a PFS advantage of 4.0 vs. 1.9 mo (HR 0.3), with 63 vs. 32% SD, and 1% vs. 0% responses, demonstrating the tumor-static nature of this class of agents.14 Toxicities included lymphopenia, hyperglycemia, hyperlipidemia, stomatitis, and rare pneumonitis. Temsirolimus and everolimus were FDA-approved for treatment in the first line for poor-risk patients and after failure of VEGF-targeted therapies, respectively. With the Phase-III data in mind, this patient was treated with everolimus, receiving 10 mg PO qd. He tolerated this well, with only grade 2 hyperglycemia treated with glypizide. In January 2010, CT scans demonstrated that the patient's pulmonary and LN metastases, which had progressed on sorafenib, were now stable, without evidence of new lesions. He remains on everolimus and is working full-time with a KPS of 90%. He continued to run during all his outpatient treatments, although he now runs "only" about 10 miles a week.

Key concepts and future clinical research: From rags to riches in RCC

1. High-dose IL-2 is the only RCC therapy with a potential for cure. However, this is limited to a highly select subset of RCC patients.

2. VEGF-targeted pathways are effective, as they target the oncogene addition of RCC caused by loss of the VHL gene product and constitutive activation of the HIF-1/VEGF axis. Multiple VEGF pathway-targeted agents are now FDA-approved (sunitinib, sorafenib, bevacizumab, pazopanib), with others in the pipeline (e.g. axitinib, which has more potent anti-VEGFR activity). Clinical trials will be needed to determine which agent to use in different settings and whether OS can be extended through rational, sequential use of these agents. Combining agents from within this group ("vertical blockade") has been attempted and appears to be very toxic.

3. mTOR inhibitors provide a second molecular target for use in the first-line setting or after progression on VEGF-targeted therapies. Again, the choice of agent, and how to best sequence these with VEGF-targeted therapies to improve OS while maintaining QOL, will be the subject of ongoing and future clinical trials.

References

1. Messing EM, et al. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol. 2003;21:1214-1222.

2. Atzpodien J, et al. Adjuvant treatment with interleukin-2- and interferin-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumor nephrectomy: results of a prospectively randomized trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Br J Cancer. 2005;14: 843-846.

3. Motzer RJ, et al. Survivial and prognostic stratification of 670 patients with advanced renal cell carnicoma. J Clin Oncol. 1999;17:2530-2540.

4. Klapper JA, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113:293-301.

5. Gnarra JR, et al. Mutations in the VHL tumor suppressor gene in renal carcinoma. Nat Genet. 1994;7:85-90.

6. Kim WY, Kaelin WG. Role of VHL gene in human cancer. J Clin Oncol. 2004;22:4991-5004.

7. Escudier B, et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cell global evaluation trial. J Clin Oncol. 2009;27:3312-3318.

8. Eisen T, et al. Sorafenib for older patients with renal cell carcinoma: Subset analysis from a randomized trial. J Natl Cancer Inst. 2008; 100:1454-1463.

9. Escudier B, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1280-1289.

10. Motzer RJ, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584-3590.