Fleeting Efficacy of mTOR Inhibitors in RCC Produces the Need for Unique Combinations

In advanced renal cell carinoma (RCC), use of mTOR inhibitors has resulted in modest success, so optimal effective combinations and strategies are being explored. Findings from several recent studies help shed more light on this class of agents, including novel combinations and development of second- and third-generation mTOR inhibitors.

mTOR Inhibitors in RCC

RCC comprises several histological and molecular subtypes, of which clear cell RCC (ccRCC) is the most common, as it is present in approximately 80% of cases.1 mTOR is known to contribute to cancer cell proliferation and survival, and the mTOR signaling pathway is often activated in advanced RCC. In addition, mTOR promotes tumor angiogenesis and is known to regulate the expression of hypoxia-inducible factors in RCC.²

Approximately 28% of ccRCC tumors display gene mutations that activate the PI3K/AKT/mTOR signaling pathway, which correlate with worse outcomes.³ In addition, an analysis of 66 chromophobe RCC (a form of non-ccRCC) tumors revealed that 15 (23%) displayed genetic modifications that altered the mTOR signaling pathway.⁴

Currently, 2 mTOR inhibitors are approved for use in metastatic RCC: temsirolimus (Torisel) and everolimus (Afinitor).5 The FDA approved temsirolimus in 2007 based on the findings of the randomized phase 3 trial, ARCC (NCT00065468), in patients with previously untreated advanced RCC and multiple unfavorable prognostic factors.^6,7 Subsequently, in 2016, the FDA approved everolimus in combination with lenvatinib (Lenvima), a multitargeted kinase inhibitor, for advanced RCC following 1 prior antiangiogenic therapy.^8-10

Additional Data on Lenvatinib and Everolimus

In addition to mTOR inhibitors, systemic treatment approaches for advanced RCC include VEGF pathway inhibitors and immune checkpoint inhibitors (ICIs).⁵

Thus, the effective use of mTOR inhibitors in combination with these agents is an area of ongoing research interest.

As noted, the lenvatinib/everolimus combination is approved for use, specifically in patients who have received first-line VEGF tyrosine kinase inhibitors (VEGFR-TKIs), but the efficacy of the lenvatinib/everolimus combination after use of ICIs is unclear. In a recent study, Wiele et al retrospectively reviewed records of 55 patients with heavily pretreated metastatic RCC whose prior therapies included VEGF-TKIs and ICIs. They found that lenvatinib, either alone or in combination with everolimus, was clinically active and well tolerated, suggesting that these agents are a viable treatment option in this patient population.¹¹

Similarly, a real-world longitudinal retrospective study examined records of pretreated patients who received the lenvatinib/ everolimus combination. Patients whose most recent therapy was an ICI (n = 25) had a median progression-free survival (PFS) of 6.4 months (95% CI, 4.1-10.8) vs 5.7 months (95% CI, 4.1-10.5) for those treated with a TKI (n = 31); the median overall survival (OS) was 14.8 months (95% CI, 10.2-23.9).¹² Lenvatinib/everolimus showed efficacy regardless of previous treatment in this heavily pretreated patient population, according to the investigators.

Lenvatinib/everolimus was also evaluated in a case series involving 7 patients with metastatic ccRCC who demonstrated primary resistance to treatment with a VEGF-TKI, ICI, or a combination of both.¹³ Of 7 patients, 2 had received prior TKI therapy, 3 had prior ICI therapy, and 2 had prior TKI and ICI therapy. PFS ranged from 3 to 15 months and OS ranged from 4 to 17 months in these patients, demonstrating the potential use of lenvatinib/ everolimus in the setting of resistant disease.

Lenvatinib/everolimus has also demonstrated efficacy in the first-line treatment of non-ccRCC, which accounts for approximately 20% of RCC cases.¹⁴ A 2021 publication detailed results of a phase 2 study (NCT02915783) that enrolled 31 patients, of whom 20 had papillary RCC, 9 had chromophobe RCC, and 2 had unclassified RCC. Lenvatinib/everolimus showed an objective response rate of 26% (95% CI, 12%-45%), suggesting that further study in the non-ccRCC setting is warranted.

According to lead author Thomas E. Hutson, DO, PharmD, director of the Urologic Oncology Program, cochair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center, and professor of medicine at Texas A&M School of Medicine in Dallas, this combination demonstrated promising anticancer activity, “with an objective response rate of 44% in patients with chromophobe non-ccRCC—higher than 0% to 10% typically observed with the use of immunotherapy. In addition, the tolerability profile was similar to the established safety profiles of the study-drug combination in RCC, with no new safety signals,” he told Targeted Therapies in Oncology™.

Combining mTOR Inhibitors With Other Therapeutic Classes

Several studies have also evaluated mTOR inhibitors in combination with various novel agents. In the phase 2 ENTRATA trial (NCT03163667), 69 patients with advanced RCC and at least 2 prior therapies received everolimus either alone or combined with telaglenastat, an orally bioavailable glutaminase inhibitor.¹⁵ At a median follow-up of 7.5 months, median PFS was 3.8 months with the everolimus/ telaglenastat combination vs 1.9 months with everolimus monotherapy, suggesting that further study of this regimen is warranted.

A phase 1 dose-escalation study (NCT01582009) evaluated everolimus in combination with histone deacetylase inhibitor panobinostat (Farydak) in 21 patients with advanced ccRCC who had progressed on VEGFR-TKIs. Investigators established a phase 2 dose that was safe and well tolerated, but the approach did not appear to improve outcomes relative to everolimus monotherapy.¹⁶ However, an evaluation of serum levels of microRNA 605 (MIR605) known to regulate gene expression in the cancer-related p53-MDM2 axis, revealed differential expression that correlated with treatment response, suggesting that MIR605 might serve as a biomarker to better select patients for treatment with this combination.

A recent phase 1 study (NCT00655655) of VEGFR inhibitor vatalanib combined with everolimus demonstrated reasonable toxicity and clinical activity in patients with advanced solid tumors.¹⁷ This trial included but was not limited to patients with RCC and explored the utility of dynamic contrastenhanced MRI as a predictive biomarker. Zhu et al concluded that “future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase 1 trial.”

Strategies that alternate mTOR and VEGF blockade have also been evaluated, with the randomized phase 2 SUNRISES study (NCT01784978) being the first to evaluate this approach.¹⁸ The investigators compared sunitinib (Sutent) and everolimus delivered in alternating cycles vs standard sequential administration (sunitinib followed by everolimus upon disease progression) in first-line metastatic ccRCC. Despite a trend toward better tolerability, the alternating approach did not appear to improve efficacy or prevent resistance to VEGFR blockade, the authors noted.

Non–Clear Cell RCC

A subset of recent studies evaluating patients with RCC have excluded patients with nonccRCC; therefore, the optimal treatment of this group of patients is unclear.¹⁹ As noted above, lenvatinib/everolimus has demonstrated efficacy in the first-line treatment of non-ccRCC.¹⁴ In addition, Osterman and Rose systematically reviewed the literature between 2000 and 2019 to assess the efficacy of various systemic treatment options, including mTOR inhibitors, in locally advanced or metastatic non-ccRCC.¹⁹ The 31 studies selected included the ASPEN (NCT01108445) and ESPN trials (NCT01185366), which compared first-line treatment with everolimus vs sunitinib and included results for a subgroup of patients with chromophobe RCC.^20,21 In the overall cohort, sunitinib tended to promote longer survival compared with everolimus; however, the opposite was true in patients with chromophobe RCC. That subgroup experienced numerically longer median PFS with everolimus than with sunitinib in both trials, at 11.4 months (80% CI, 5.7-19.4) vs 5.5 months (80% CI, 3.2-19.7) in ASPEN and not reached vs 8.9 months (95% CI, 2.9-20.1), respectively, in ESPN. The results suggest some efficacy of mTOR inhibitors in non-ccRCC, particularly in the chromophobe subtype.¹⁹

Adjuvant Use of mTOR Inhibitors

Everolimus has recently also been evaluated in the adjuvant setting. At the 2022 American Society of Clinical Oncology Annual Meeting, Ryan et al reported results from the phase 3 EVEREST study (NCT01120249), evaluating the use of adjuvant everolimus in patients who had surgery for RCC.²² The study included 1545 patients who were randomly assigned to receive everolimus or placebo within 12 weeks of radical or partial nephrectomy. Recurrence-free survival (RFS) was improved with everolimus vs placebo (HR, 0.85; 95% CI, 0.72-1.00; P = .0246), falling just short of the predetermined significance level (P = .022). The 6-year RFS estimate was 64% for everolimus vs 61% for placebo. Brian I. Rini, MD, Ingram Professor of Cancer Research, professor of medicine, and chief of clinical trials at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, noted that EVEREST was a large phase 3 trial that evaluated everolimus vs placebo in patients with resected kidney cancer at higher risk of recurrence.

“The [investigators] are to be congratulated on putting together an enormous cooperative group phase 3 trial,” he told Targeted Therapies in Oncology™. “There was no significant benefit [of adjuvant everolimus] overall, although more benefit was observed in some subsets, such as higher-risk patients.”

He added that these data must be considered in light of the data on adjuvant pembrolizumab (Keytruda),²³ which is now a standard of care with more dramatic and significant RFS benefits. “I don’t think adjuvant everolimus will be adopted as a standard.”

Overcoming Mechanisms of Resistance

Second- and third-generation mTOR inhibitors are being developed to provide more substantial inhibition of mTOR.²⁴ mTOR consists of 2 multiprotein complexes: mTORC1 and mTORC2. Temsirolimus and everolimus inhibit mTORC1 but not mTORC2. Second-generation mTOR inhibitors (mTOR kinase inhibitors) block both mTORC1 and mTORC2, but they may not be effective at preventing the feedback activation of PI3K.²⁵ Second-generation agent vistusertib (AZD2014) was compared against everolimus in the phase 2 ZEBRA trial (NCT01793636) in patients with metastatic ccRCC refractory to VEGF-targeted therapy²⁶ but demonstrated poor PFS compared with everolimus (1.8 months vs 4.6 months; P < .01). Likewise, sapanisertib, another second-generation agent, was evaluated in a recent phase 2 study (NCT03097328) of 38 patients with refractory metastatic RCC.27 Sapanisertib had minimal activity in treatmentrefractory metastatic RCC.

Third-generation mTOR inhibitors are currently being evaluated preclinically. RapaLink-1, an agent that links rapamycin and the mTOR kinase inhibitor, MLN0128, showed greater in vitro and in vivo therapeutic efficacy compared with temsirolimus.²⁴

mTOR is frequently activated in RCC, but RCC is heterogeneous, with many complex pathways in addition to mTOR activation that drive its growth. mTOR inhibitors exert both immunostimulatory and immunosuppressive effects, so investigating these activities will be essential. Nonetheless, multiple approved and experimental combinations have demonstrated a therapeutic response in RCC, highlighting their therapeutic potential of this class of agents.

_REFERENCES:

_{1. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumoursof the urinary system and male genital organs-part A: renal, penile, and testicular tumours.Eur Urol. 2016;70(1):93-105. doi:10.1016/j.eururo.2016.02.029}

_{2. Faes S, Demartines N, Dormond O. Mechanistic target of rapamycin inhibitors in renal cell carcinoma:potential, limitations, and perspectives.Front Cell Dev Biol. 2021;9:636037. doi:10.3389/fcell.2021.636037}

_{3. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma.Nature. 2013;499(7456):43-49. doi:10.1038/nature12222}

_{4. Davis CF, Ricketts CJ, Wang M, et al. The somatic genomic landscape of chromophobe renal cell carcinoma.Cancer Cell. 2014;26(3):319-330. doi:10.1016/j.ccr.2014.07.014}

_{5. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2023. Accessed July 1, 2022. https://bit.ly/3O7AUey}

_{6. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271-2281. doi:10.1056/NEJMoa066838}

_{7. FDA approves new drug for advanced cancer. Science Daily. May 31, 2007. Accessed July 27, 2022. https://bit.ly/3PGDj1p}

_{8. Lenvatinib in combination with everolimus.FDA. May 16, 2016. Accessed July 2, 2022. https://bit.ly/3Q1NeOL}

_{9. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol.2015;16(15):1473-1482. doi:10.1016/S1470-2045(15)00290-9}

_{10. Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol.2016;17(1):e4-e5.doi:10.1016/S1470-2045(15)00543-4}

_{11. Wiele AJ, Bathala TK, Hahn AW, et al.Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies.Oncologist. 2021;26(6):476-482. doi:10.1002/onco.13770}

_{12. Vogelzang NJ, Monnette AM, Wang Y, et al. Real-world clinical effectiveness of lenvatinib/everolimus in a heavily pretreated advanced/metastatic renal cell carcinoma population in the US community oncology setting..2021;19(6):531-539. doi:10.1016/j.clgc.2021.05.002}

_{13. Hamieh L, Beck RL, Le VH, Hsieh JJ. The efficacy of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma exhibiting primary resistance to front-line targeted therapy or immunotherapy. Clin Genitourin Cancer. 2020;18(4):252-257.e2. doi:10.1016/j.clgc.2020.03.003}

_{14. Hutson TE, Michaelson MD, Kuzel TM, et al. A single-arm, multicenter, phase 2 study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. Eur Urol. 2021;80(2):162-170. doi:10.1016/j.eururo.2021.03.015}

_{15. Lee CH, Motzer R, Emamekhoo H, et al. Telaglenastat plus everolimus in advanced renal cell carcinoma: a randomized, double-blinded, placebo-controlled, phase 2 ENTRATA trial. Clin Cancer Res. 2022;clincanres.0061.2022. doi:10.1158/1078-0432.CCR-22-0061}

_{16. Wood A, George S, Adra N, Chintala S, Damayanti N, Pili R. Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma. Invest New Drugs. 2020;38(4):1108-1116. doi:10.1007/s10637-019-00864-7}

_{17. Zhu M, Molina JR, Dy GK, et al. A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors. Invest New Drugs. 2020;38(6):1755-1762. doi:10.1007/s10637-020-00936-z}

_{18. Rodriguez-Vida A, Bamias A, Esteban E, et al. Randomised phase IIstudy comparing alternating cycles of sunitinib and everolimus vs standard sequential administration in first-line metastatic renal carcinoma (SUNRISES study). BJU Int. 2020;126 (5):559-567. doi:10.1111/bju.15165}

_{19. Osterman CK, Rose TL. A systematic review of systemic treatment options for advanced non-clear cell renal cell carcinoma. Kidney Cancer. 2020;4(1):15-27. doi:10.3233/kca-190078}

_{20. Tannir NM, Jonasch E, Albiges L, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016;69(5):866-874. doi:10.1016/j.eururo.2015.10.049}

_{21. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016;17(3):378-388. doi:10.1016/S1470-2045(15)00515-X}

_{22. Ryan CW, Tangen C, Heath EI, et al. EVEREST: everolimus for renal cancer ensuing surgical therapy—aphase III study (SWOG S0931, NCT01120249). J Clin Oncol. 2022;40(suppl 17):LBA4500.doi:10.1200/JCO.2022.40.17_suppl.LBA4500}

_{23. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma.N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391}

_{24. Kuroshima K, Yoshino H, Okamura S, et al. Potential new therapy of Rapalink-1, a new generation mammalian target of rapamycin inhibitor, against sunitinib-resistant renal cell carcinoma. Cancer Sci.2020;111(5):1607-1618. doi:10.1111/cas.14395}

_{25. Feldman ME, Apsel B, Uotila A, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009;7(2):e38. doi:10.1371/journal.pbio.1000038}

_{26. Powles T, Wheater M, Din O, et al. A randomised phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer. Eur Urol. 2016;69(3):450-456. doi:10.1016/j.eururo.2015.08.035}

_{27. Pezzicoli G, Filoni E, Gernone A,Cosmai L, Rizzo M, Porta C. Playing the devil’s advocate: should we give a second chance to mTOR inhibition in renal clear cell carcinoma? -ie strategies to revert resistance to mTOR inhibitors. Cancer Manag Res. 2021;13:7623-7636. doi:10.2147/CMAR.S267220}

_{28. McGregor BA, Xie W, Adib E, et al. Biomarker-based phase II study of sapanisertib (TAK-228): an mTORC1/2 inhibitor in patients with refractory metastatic renal cell carcinoma.JCO Precis Oncol. 2022;6:e2100448. doi:10.1200/PO.21.00448}

_{29. Gnarra JR, Tory K,Weng Y, et al.Mutations of the VHL tumour suppressor gene in renal carcinoma.Nat Genet.1994;7(1):85-90.doi:10.1038/ng0594-85}

_{30. Cowman SJ, Fuja DG, Liu XD, et al. Macrophage HIF-1α is an independent prognostic indicator in kidney cancer.Clin Cancer Res.2020;26(18):4970-4982. doi:10.1158/1078-0432.CCR-19-3890}

_{31. Sakamoto H, Yamasaki T, Sumiyoshi T, et al. Functional and genomic characterization of patient-derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma.Cancer Med. 2021;10(1):119-134. doi:10.1002/cam4.3578}