Renal Carcinoma: State-of-the-Art Treament

A Conversation With David I. Quinn, MBBS, PhD, FRACP, and With Arie Belldegrun, MD, FACS, and Allan Pantuck, MD, MS, FACS

Dr. Boxer:  Dr. David Quinn, would you describe the newest medical oncology approach to metastatic renal carcinoma?

Recurrent or metastatic renal cell cancer therapy

The current first line therapy for most patients with good to intermediate risk mRCC is a VEGFrTKI. There are a small group of good performance status patients who should consider high dose interleukin 2 therapy but the toxicity and inpatient therapy commitment precludes many patients. The selection of the specific VEGFrTKI used for first line therapy has evolved. Level 1 evidence has been established for sunitinib in this setting since 2007 but more recently data from the COMPARZ study[1] suggests that pazopanib has similar efficacy to sunitinib with a better side effect profile in many patients. Lower levels of evidence support the use of other VEGFrTKIs such as sorafenib and axitinib and also the VEGF ligand inhibitor, bevacizumab, in the first line setting. For patients with poor risk mRCC, an intravenous mTOR inhibitor has level 1 evidence to support is use over interferon-a. There is lower level evidence to support the use of VEGFrTKIs in the poor risk setting also.

Second therapy selection depends on first line that preceded it and some would argue that the efficacy and tolerability of the first line agent should also inform second line selection. For patients that received first line HDIL2, VEGFrTKIs have level 1 evidence in the second line with axitinib being the common choice based the AXIS study[2] data. For patients that received a VEGFrTKI first line, there is a choice between another VEGFrTKI or an mTORi in the second line. This choice is the subject of division among RCC experts and represents an area of equipoise and debate. Data from the Record-1 study provides level 1 evidence for the oral mTORi everolimus over best supportive care alone after a VEGFrTKI. Data from the AXIS study supports the use of axitinib over sorafenib in this setting. Interestingly, the PFS for everolimus and axitinib after sunitinib therapy in these different trials approximated 4 months. A trial of everolimus versus axitinib after a single VEGFrTKI might be definitive but has not been undertaken. The INTORSECT trial[3] compared the intravenous mTORi temsirolimus to the VEGFrTKI sorafenib after sunitinib therapy. There was minimal difference in the PFS between the 2 agents but patients given sorafenib in this trial had a 4-month better overall survival. Extrapolating these data to clinical practice is difficult although many oncologists have noted benefit for sorafenib with a response to first line sunitinib that exceeded 6 months in the INTORSECT trial. Poor risk patients given temsirolimus in the first line are routinely given a VEGFrTKI in the second line if their performance status is adequate.

Third line therapy is dependent on prior therapy. Both mTORis and VEGFrTKI have activity. Based on RECORD-1[4] everolimus has activity compared to BSC while the recently reported GOLD study[5] showed that use of sorafenib resulted OS of 11 months patients treated with prior VEGF and mTOR directed therapies.

Beyond third line therapy may be warranted in some patients who have had good disease control duration or responses to prior VEGF or mTOR directed agents and good performance status. Many clinicians use sorafenib or bevacizumab in this setting although there is no evidence base to support this.

Dr. Boxer:

Drs. Allan Pantuck and Arie Belldegrun, immunotherapy and vaccination for cancer has been an area of great pursuit and of your interest.  Would please explain your efforts and where you think the new era of treating metastatic RCC?

      Cancer Immunotherapy—the harnessing of the immune system as an effective treatment for cancer--was recently selected by the journal Science as the top scientific achievement Breakthrough of the Year for 2013 (1). With this declaration, we are entering into a new era of enthusiasm about the use of immunotherapy in the treatment of cancer, and this shift will undoubtedly significantly impact upon the treatment of advanced renal cell carcinoma (RCC) as much as any other cancer type over the next decade. Historically, metastatic RCC did not fit the standard oncologic paradigm, and proved to be largely resistant to the usual treatment regimens employed in combating other types of cancer.  Trials of cytotoxic chemotherapy, radiation therapy, and hormones all failed to demonstrate any appreciable effects on survival.  Instead, in the 1980s and 1990s, RCC, along with melanoma, became the model for the development of immune based therapies. 

      The first iteration in the development of cancer immunotherapy treatment regimens, the use of non-specific cytokine treatments that included interleukin-2 (IL-2) and interferon (IFN), created an important treatment option for patients with metastatic RCC that remained the mainstay of treatment for nearly 15 years. Until the approvals of the first anti-angiogenic VEGF tyrosine kinase inhibitors in 2005 and 2006, high-dose, bolus intravenous (IV) IL-2 was the only treatment approved by the United States Food and Drug Administration (FDA) for patients with metastatic RCC, an approval granted by the FDA in 1992 for its ability to produce durable complete responses in a small subset of patients.    Data from seven phase II clinical trials involving a total of 255 patients with metastatic RCC demonstrated an overall response rate of 15%, which included complete response (CR) in 7% of the patients and partial response (PR) in 8% of the patients (2,3).  Subsequent modern trials with high-dose, bolus IL-2 such as the Cytokine Working Group’s Select trial, have demonstrated response rates nearing 30% and of greater quality and durability (4).  Taken together, these studies clearly demonstrated the benefit that immunotherapy can provide for a subset of patients with metastatic RCC. 

Although immunotherapy was once the standard of care, the advent of oral therapies that target angiogenesis and other signal transduction pathways and that produced significant clinical benefits in larger patient subsets prompted a reassessment of the role of immunotherapy in advanced RCC. Due to their broad activity and relatively tolerable toxicity profiles, the last 10 years saw a shift away from the use of cytokine-based treatment of mRCC to the use of these newer targeted oral therapies. In contrast to the results achieved with IL-2, however, the cytostatic molecularly targeted therapies (eg, sorafenib, sunitinib, everolimus) do not produce durable remissions when therapy is discontinued, and treatment resistance inevitably develops. In the past years, however,  an improved understanding of immunology and tumor biology have led to the development of novel immunotherapeutic treatment strategies that include vaccines such as Provenge, the first and thus far only therapeutic cancer vaccine to achieve FDA approval (in 2010), as well as immune checkpoint inhibitors (eg ipilimumab approved in 2011, nivolumab), and the adoptive transfer of engineered T cells (eg tumor infiltrating lymphocytes, or T cells engineered to express a recombinant T cell receptor or chimeric antibody receptor) (5 for a review of current novel combination strategies integrating immunotherapies in GU malignancoies). It is the latter two strategies in particular that have generated the newfound enthusiasm for cancer immunotherapy.

Checkpoint Blockade to Eliminate Immune Suppression

Since the groundbreaking work of James Allison and others in the 1990s unravelling the molecular mechanisms governing the host response to tumors and identifying the signaling pathways involved in limiting the immune response, a successful therapeutic strategy has emerged based on the development of various agents that enhance the anti-cancer immune response by taking the breaks off these immunosuppressive, inhibitory (“checkpoint”) pathways (reviewed in 6). To date, the most clinically important checkpoint molecules mediating tumor-induced immune suppression are cytotoxic T-lymphocyte antigen-4 (CTLA-4) as well as the programmed death-1 (PD-1) receptor and its ligands. CTLA-4 acts as a signal dampener acting primarily within the lymph nodes to regulate the early activation of naive and memory T cells. PD-1, by contrast, is induced on T cells after activation in response to inflammatory signals and limits T-cell function in peripheral tissues (7). The anti–CTLA-4 monoclonal antibody (mAb) ipilimumab improved survival in a phase 3 trial in patients with metastatic melanoma (8) and was subsequently approved by the United States Food and Drug Administration in 2011 for the treatment of patients with that indication. However, the fully human anti–PD-1 mAb BMS-936558/MDX-1106/ONO-4538 (nivolumab), has already demonstrated impressive antitumor activity in phase 1/1b studies of not only RCC, but also castrate resistant prostate cancer, non–small cell lung cancer (NSCLC), and colorectal cancer (CRC) (9). What is notable about the clinical results using checkpoint inhibitor therapy is the high level of anti-tumor activity (eg, the spectrum of tumors that appear to be responsive, and the durability of the responses). For example, reductions in tumor size of more than 80% in the majority of patients in one study (10), and in another study of patients with advanced melanoma, four year survival in approximately 20% of subjects (8).

Adoptive Immunotherapy

Adoptive immunotherapy refers to the passive transfer of immune cells with antitumor activity into a tumor-bearing host.  Currently, there are 3 main strategies that have been extensively studied for the adoptive immunotherapy of cancer.  The first use of adoptive immunotherapy of cancer was based on the use of tumor infiltrating lymphoctyes (TIL).  The anti-tumor activity of TIL is thought to be mediated through interaction between the tumor cell and the T cell receptor (TCR) and is MHC restricted (11).  Though early trials of TIL in mRCC such as the UCLA experience combining TIL with low dose IL-2 plus IFN demonstrated the feasibility of this approach, with an intriguing 35% response rate that includes durable remissions (12), a subsequent  multi-center phase III trial randomizing subjects with mRCC to low dose IL-2 alone vs. low dose IL-2 plus TIL was negative (13). After randomization of a total of 160 subjects, intent to treat analysis revealed response rates of 9.9 vs. 11.4% (IL-2 vs, IL-2/TIL).  Moreover, this trial was fraught with difficulty especially with regards to the successful preparation of TIL at a centralized facility.  Of the subjects randomized to the TIL arm, 41% did not receive these cells due to processing difficulties.  To date, TIL therapy has proven effective only in the treatment of metastatic melanoma, primarily since it has not proven to be possible to consistently and successfully isolate, culture, establish, and expand large populations of tumor-reactive T cells having anti-cancer activity from the tumors of the majority of patients having other tumor types. 

The other two strategies of adoptive T cell immunotherapy have found ways to circumvent this problem (14). T cell receptor (TCR) therapy utilizes patients easily acquired peripherally acquired T cells which are then genetically engineered using viral vectors to transduce and express a specific recombinant T cell receptor capable of recognizing a specified tumor antigen (eg CAIX, MART-1, NY-ESO, etc). Already, clinical trials of TCR therapies has shown unexpected anti-cancer activity in a number of solid tumor indications including melanoma, and other unanticipated cancer types such as colorectal and synovial sarcoma (15, 16).  While TCR-transduced T cells are engineered to express a particular TCR, they still require tumor recognition in the context of MHC restriction and can therefore be utilized only in a subset of patients and are vulnerable to the well-known mechanism of tumor evasion by the immune recognition, MHC down regulation. The last strategy for adoptive T cell therapy circumvents these issues as well. In this final option, peripherally acquired T cells are transduced by a “chimeric” antigen receptor (CAR) that combines the variable region of an antibody domain with a CD3 T-cell signaling molecule, with more recent second and third generation CAR iterations also including other co-stimulatory molecules such as CD28 and 4-IBB (17). The ability of the CAR receptor to recognize tumor antigens and engage native TCR-mediated activation is derived from non-MHC restricted antibody binding, which is capable of antigen recognition and binding with exquisite sensitivity. Moreover, like TCR, clinical trials of modern CAR have demonstrated great potential across a spectrum of tumor types, with the greatest success thus far being seen in a variety of hematologic malignancies expressing the CD19 antigen (18, 19).

The use of TCR and CAR technology has only yet begun to be applied to RCC (20). The next decade will witness a new renaissance in the use of immunotherapy of RCC based on combinations of non-specific immunotherapies such as IL-2, targeted immunotherapies utilizing engineered T cells, augmentation of the anti-cancer immune response through the use of immune checkpoint blockade, and likely even combinatory approaches simultaneously using standard molecularly targeted approaches.

*Acknowledgements: The authors (AP&AB) are scientific founders, equity holders, and Executive/Director (AB) of Kite Pharma Inc., a Los Angeles based biotechnology company dedicated to the development of adoptive TCR and CAR engineered T cell cancer therapies.

References:

1.Couzin-Frankel J: Cancer Immunotherapy. Science 2013;342a;1432-1433. Gleave ME, Elhilali M, Fradet Y, et al. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group. N Engl J Med. 1998;338:1265-1271.

2. Fyfe et al: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13688-696.

3. Fisher RI, Rosenberg SA, Fyfe G: Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000;S155-57.

4. McDermott DF et al: The high-dose aldesleukin (HD-IL-2) “SELECT” trial in patients with metastatic renal cell carcinoma [abstract 4514]. Presented at the American Society of Clinical Oncology Annual Meeting, Chicago, USA; June 4-8, 2010.

5. Drakaki A, McDermott DF: Novel immunotherapies in GU malignancies. Curr Oncol Rep 2013;15224-231.

6. McDermott DM, Atkins M. PD-1 as a Potential Target in Cancer Therapy. Cancer Medicine 2013; 2(5): 662–673.

7. Topalian, SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1 (PDL-1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012;24:207-212.

8.  Hodi et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 2010; 363:711-723.

9. Topalian et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2013; 366:2443-2454.

10. Wolchok JD et al: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-133.

11. Finke, JH, Rayman, P, Hart, L, et al. Characterization of tumor infiltrating lymphocyte subsets from human renal cell carcinoma: specific reactivity defined by cytotoxicity, interferon gamma secretion, and proliferation.  J. Immunother. 15, 91, 1994.

12. Figlin, R.A., Pierce, W.C., Kaboo, R., et al. Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2, and cytokine-primed or CD8(+) selected tumor infiltrating lymphocytes from primary tumor. J. Urol. 158, 740-5, 1997.

13. Figlin, R.A., Thompson, J.A., Bukowski, M.D., et al. A multi-center, randomized, phase III trial of CD8+ tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J. Clin. Oncol. 17(8), 251-9, 1999.

14. Humphries C. Honing that killer instinct. Nature 2013;504:S13-S15.

15. Robbins PF et al: Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011 Mar 1;29(7):917-24.

16. Parkhurst MR et al: T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011 Mar;19(3):620-6.

17. Sampson JH et al: EGFRvIII mCAR-mediated T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Can Res 2013.

18. Kochenderfer JN et al: B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric antigen receptor transduced T cells. Blood 2012:1192709-2720.

19. Porter et al: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. New Engl J Med 2011;365:725-733.

20. Lamers et al: Treatment of Metastatic Renal Cell Carcinoma With Autologous T-Lymphocytes Genetically Retargeted Against Carbonic Anhydrase IX: First Clinical Experience. J Clin Oncol 2006;24: e20-e22.

{C}[1]{C} Pazopanib versus sunitinib in metastatic renal-cell carcinoma.

Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R,Pandite LN, Choueiri TK. N Engl J Med. 2013 Aug 22;369(8):722-31. doi: 10.1056/NEJMoa1303989

{C}[2]{C} Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.

Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Lancet. 2011 Dec 3;378(9807):1931-9. doi: 10.1016/S0140-6736(11)61613-9. Epub 2011 Nov 4.

[3]{C} Randomized Phase III Trial of Temsirolimus Versus Sorafenib As Second-Line Therapy After Sunitinib in Patients With Metastatic Renal Cell Carcinoma. JCO Oct 20, 2013:3791-3799; DOI:10.1200/JCO.2012.47.4940.

{C}[4]{C} Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N,Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Lancet. 2008 Aug 9;372(9637):449-56. doi: 10.1016/S0140-6736(08)61039-9. Epub 2008 Jul 22

{C}[5]{C} ESMO @ ECC 2013: Similar Phase III Results Reported for Dovitinib vs. Sorafenib Treatment in Patients with Metastatic Renal Cell Carcinoma http://www.esmo.org/Conferences/European-Cancer-Congress-2013/News/Similar-Phase-III-Results-Reported-for-Dovitinib-vs.-Sorafenib-Treatment-in-Patients-with-Metastatic-Renal-Cell-Carcinoma