Jury Still Out on Whether Immunotherapy Can Cure Metastatic RCC

The treatment of metastatic renal cell carcinoma (mRCC) has undergone several major changes, with the first approval of targeted therapy in 2005 and the first approval of an immune checkpoint inhibitor in 2015. The success of targeted therapy is limited by the inevitability of acquired resistance, and, similarly, the success of immunotherapy has been limited by the number of patients who respond. Cases of durable complete responses (CRs) with combination therapy that include immunotherapy and, in some cases, targeted therapy, raise the question of whether cure is possible.¹

Prior to the era of targeted therapy, the 5-year survival of patients with advanced RCC was just 7.3%; this has since risen to 11.6%.² Though this is an improvement, this low number highlights the need for treatment options leading to durable responses among a larger number of patients.

Outcomes With Monotherapy

Currently, the only curative therapy for mRCC is high-dose interleukin (IL)-2, which leads to a cure for 5% to 7% of patients.¹ Its use is limited, however, by multiorgan toxicity and the unpredictability of which patients will respond.

Compared with chemotherapy, molecularly targeted therapies shift the survival curve to the right, with rapid responses that typically do not last more than a year.¹ The overall response rate (ORR) of first-line VEGF or VEGF receptor-targeted agents, such as bevacizumab, sunitinib, and pazopanib, range from 30% to 39%, leading to a median progression-free survival (PFS) of 9.2 to 11 months.³ The ORR of the mTOR inhibitor, temsirolimus, is 8.6%, leading to a median PFS of 5.5 months in the first line. The second-line efficacy of these agents is broader, with ORR rates of 1.8% to 57% and a median PFS of 4.9 to 14.6 months.

Immune checkpoint inhibitors shift the survival curve upward, generally resulting in a less rapid but more durable responses than targeted therapies.¹ Nivolumab, the first and only immune checkpoint inhibitor approved for mRCC, resulted in an ORR of 25%, a median PFS of 4.6 months, and a median overall survival (OS) of 25 months in the second line.³ A small subset of patients may, however, have long-term responses with immune checkpoint inhibition.

“What is notable about immunotherapy is that although most patients are not cured and most of them go on to other treatments, the survival is just so long,” Elizabeth R. Plimack, MD, MS, chief of the division of genitourinary medical oncology and director of genitourinary clinical research at Fox Chase Cancer Center in Philadelphia, Pennsylvania, told Cancer Therapy Advisor.

“What we haven’t measured very well is the outcomes of patients who stop treatment, and we will. We will know more in the coming years. In a lot of trials ongoing now, immunotherapy is discontinued at 2 years and then patients are monitored to see if their cancer comes back.”

Outcomes With Combination Therapy

“Kidney cancer is ahead because the combination treatments are well underway,” Dr Plimack said. The combination of immune checkpoint inhibition with other agents — including a second checkpoint inhibitor or targeted therapy — has become the next frontier in mRCC. Multiple phase 1 through 3 trials are underway to evaluate these combinations in the first or second line.

Some attempts at combination treatment resulted in disappointing outcomes. Temsirolimus plus interferon, for example, did not improve ORR, PFS, or OS compared with temsirolimus or interferon alone.³ Other combinations were not well-tolerated. “For the combination of VEGF inhibitors with immunotherapy, again, the early trials were not moved forward due to toxicities, but newer combinations, like with axitinib, seem to be tolerable and they are showing nice early results,” Dr Plimack said.

Combinations that include immune checkpoint inhibitors, however, are beginning to show promising outcomes. Results from the first phase 3 trial of combination immunotherapy were recently presented at the 2017 European Society for Medical Oncology (ESMO) Congress.⁴ In the CheckMate 214 trial, 1096 patients with previously untreated clear cell mRCC were randomly assigned to receive nivolumab plus ipilimumab or sunitinib for a minimum follow-up of 17.5 months. The confirmed ORR for patients with intermediate/poor risk disease was 41.6% compared with 26.5% with sunitinib, with 9.4% of patients showing a compete response. The duration of response was not reached compared with 14.82 months with sunitinib.

Though combination treatments may have greater efficacy, this comes with a greater risk of adverse events. “We know there are higher rates of autoimmune adverse events when we combine ipilimumab and nivolumab compared with a PD-1 inhibitor alone,” Dr Plimack said.

Though these responses may hint at the potential of a cure, Dr Plimack cautions that “these results are encouraging, but they are definitely early.”

Is Cure in the Future?

Dr Plimack noted that though uncommon, CRs are seen among patients with metastatic disease, but CRs seem to occur more often with immune checkpoint inhibitors. She highlighted, however, that “a prerequisite before we can talk about cure is going to be a treatment-free survival period. I don’t think we can call it cure if they are still on active treatment.”

Treatment-free remission, according to Dr Plimack, is “stopping treatment and following the patient with scans and watching their disease control, whether it is a CR or not.” Given that immune checkpoint inhibitors have only been available for 5 years and approved in mRCC for 2 years, it is too early to declare any patients cured. Dr Plimack said that, “in 10 years from now, we may be able to say cure or not.”

References

1. Sabanathan D, Park JJ, Marquez M, Francisco L, Byrne N, Gurney H. Cure in advanced renal cell cancer: is it an achievable goal? Oncologist. 2017;22:1-8. doi: 10.1634/theoncologist.2017-0159
2. Kidney cancer, version 2.2018. National Comprehensive Cancer Network website. http://www.nccn.org/professionals/physician_gls/pdf/kidney_blocks.pdf. Updated November 30, 2017. Accessed December 2017.
3. Sanchez-Gastaldo A, Kempf E, Gonzalez Del Alba A, Duran I. Systematic treatment of renal cell cancer: a comprehensive review. Cancer Treat Rev. 2017;60:77-89. doi: 10.1016/j.ctrv.2017.08.010 0305-7372
4. Escudier B, Tannir NM, McDermott DR, et al. CheckMate 214: Efficacy and safety of nivolumab 1 ipilimumab (N1I) v sunitinib (S) for treatment-naive advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Oral presentation at: 2017 European Society for Medical Oncology (ESMO) Congress. Madrid, Spain; September 8-12, 2017. Abstract LBA5.

This article originally appeared on Cancer Therapy Advisor