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Table of Contents
EDITORIAL
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 124-126

Current systemic therapy options in advanced clear cell renal cell cancer


Department of Medical Oncology, Homi Bhabha Cancer Hospital and Mahamana Pandit Madan Mohan Malviya Cancer Center, Tata Memorial Center, Varanasi, Uttar Pradesh, India

Date of Submission05-Mar-2021
Date of Decision07-Mar-2021
Date of Acceptance08-Mar-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Akhil Kapoor
Department of Medical Oncology, Homi Bhabha Cancer Hospital and Mahamana Pandit Madan Mohan Malviya Cancer Center, Tata Memorial Center, Varanasi, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_59_21

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How to cite this article:
Kapoor A. Current systemic therapy options in advanced clear cell renal cell cancer. Cancer Res Stat Treat 2021;4:124-6

How to cite this URL:
Kapoor A. Current systemic therapy options in advanced clear cell renal cell cancer. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Sep 18];4:124-6. Available from: https://www.crstonline.com/text.asp?2021/4/1/124/312118



Approval for the use of immunotherapy (IO) combinations in the first-line setting has led to an increase in the upfront use of IO in patients with renal cell cancer (RCC). Nivolumab plus ipilimumab is an approved combination for intermediate- and poor-risk advanced clear cell RCC. In the CheckMate 214 trial, this combination led to an improved overall survival (OS) as compared to sunitinib monotherapy (4-year, OS 53% vs. 43%; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59–0.81).[1] The approval for the use of the combination of IO and vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) has further increased the use of IO in the first-line setting, as ipilimumab is not available in the low- and middle-income countries (LMICs). The use of pembrolizumab plus axitinib is now supported by extended follow-up data from the KEYNOTE-426 trial that reported an OS benefit in the combination arm when compared to the sunitinib monotherapy arm (2-year OS, 74% vs. 65%; HR, 0.68; 95% CI, 0.55–0.85).[2] However, on subgroup analysis, patients with favorable risk based on the International Metastatic RCC Database Consortium (IMDC) risk stratification had similar OS in both the arms. A recent phase-III trial backed the combination of nivolumab plus cabozantinib. The 1-year OS was 85.7% with nivolumab plus cabozantinib versus 75.6% with sunitinib (HR, 0.60; 98.89% CI, 0.40–0.89; P = 0.001).[3] Similar results were observed for all IMDC risk groups and the programmed death-ligand 1 (PD-L1) subgroups. The authors of this study stated that this combination may be preferred in patients who require a rapid treatment response due to the high disease burden.

New data are also available on the combination of pembrolizumab plus lenvatinib. Motzer et al. randomized the patients to receive either lenvatinib 20 mg once daily plus pembrolizumab 200 mg intravenously 3-weekly, lenvatinib 18 mg plus everolimus 5 mg once daily, or sunitinib 50 mg (schedule of 4 weeks on and 2 weeks off).[4] The progression-free survival (PFS) was significantly improved in patients who received pembrolizumab plus lenvatinib (median, 24 months) as compared to those who received sunitinib (median, 9 months; HR, 0.39; 95% CI, 0.32–0.49); likewise, the PFS was significantly improved in patients who received lenvatinib plus everolimus (median, 15 months) as compared to those who received sunitinib (median, 9 months; HR, 0.65; 95% CI, 0.53–0.80). The PFS benefit was consistent across all the subgroups, including age, gender, PD-L1 expression, IMDC risk group, history of nephrectomy, and the presence of sarcomatoid features. Furthermore, the OS was significantly longer for patients who received lenvatinib plus pembrolizumab compared to those who received sunitinib (HR, 0.66; 95% CI, 0.49–0.88). However, there was no significant difference in the OS between the patients who received lenvatinib plus everolimus and those who received sunitinib (HR, 1.15; 95% CI, 0.88–1.50).[4]

The rationale for using the combination of IO with TKI is the dual mode of action, owing to which this combination has the potential to tackle early progression which is more likely to occur when using the IO plus IO combination. Thus, the combination of IO plus TKI is preferred in patients requiring rapid response due to large disease burden or disease at critical sites like the liver or large mediastinal nodes. The dual mode of action explains why the chance of progression at 3–6 months post treatment initiation is higher when using the combination of IO + IO (30%–35%) as compared to pembrolizumab plus lenvatinib (15%). Another noteworthy aspect is that the combination of pembrolizumab plus lenvatinib shows markedly longer PFS (median 23.9 months) as compared to the maximum PFS of 16.6 months with other combinations. The complete response rates with pembrolizumab plus lenvatinib, nivolumab plus ipilimumab, and pembrolizumab plus axitinib have been reported to be 16.1%, 10.7%, and 7%, respectively. However, these are cross-trial comparisons and should not be the sole basis for the selection of one regimen over the other.

In the real-world scenario, especially in the LMICs, an exceedingly small fraction of patients can receive IO combinations in the first line. Thus, in limited-resource settings, the use of IO is largely restricted to the later lines of treatment. Our group recently reported the use of IO to be a mere 1.61% in patients with advanced (recurrent or metastatic) solid tumors in whom there was an approved indication for the use of IO.[5] In the pre-IO era, the outcomes with second-line therapy were disappointing. Data published by our group in 2016 showed an event-free survival of 3.5 months and OS of 6.2 months with second-line targeted therapy for patients with metastatic RCC (mRCC).[6]

The CheckMate 025 trial led to the approval of nivolumab in the second-line setting for mRCC post-TKI in 2015.[7] In patients who have received IO in the first line along with a TKI, the selection of therapy in the second line or beyond becomes intriguing given the absence of data in this setting. Patients who receive pembrolizumab plus axitinib, might develop resistance to VEGFR-targeted therapies. Thus, targeting the resistance mechanisms to VEGFR TKIs, like MET and AXL activation, appears to be a sensible choice. It should be noted that cabozantinib has activity against AXL, RET, MET, and TIE-2 besides VEGFR-1-3 making it a plausible option post IO + TKI combination in the first line.[8] However, the drawback with cabozantinib is its limited availability in the LMICs. Another combination therapy that can be considered in such a scenario is lenvatinib plus everolimus. Lenvatinib is known for its activity against RET, KIT, and PDGFR in addition to VEGFR-1-3.[9] It is well known that activation of the mTOR pathway is a mechanism for the development of RCC. Therefore, combining lenvatinib and everolimus seems to be a good choice. This combination was tried in a phase-II trial on 153 patients who were randomly assigned to receive either lenvatinib (18 mg/day) plus everolimus (5 mg/day), lenvatinib (24 mg/day), or everolimus (10 mg/day). The primary endpoint of this study was PFS. The median PFS for lenvatinib plus everolimus was greater than that for single-agent everolimus (median, 14.6 vs. 5.5 months; HR, 0.40; 95% CI, 0.24–0.68) and single-agent lenvatinib (median, 14.6 vs. 7.4 months; HR, 0.66; 95% CI, 0.39–1.10).[10] The OS was also numerically improved with the combination (median, 25.5 vs. 15.4 months; HR, 0.55; 95% CI, 0.30–1.01); this did not reach statistical significance as the trial was not powered to answer the same. In a real-world case series of 7 patients who were treated with lenvatinib plus everolimus, 3 (43%) showed a partial response; the PFS was in the range of 3–15 months, and OS was in the range of 4–17 months.[11]

The study by Abbas et al. provides small, but real-world data on the use of IO in the second line in patients with mRCC treated with VEGFR TKIs in the first line.[12] Out of all eligible patients, 38% (19/50) received IO. Though this number is low in comparison to that reported from the western countries, it is still much higher than that reported by the previous real-world studies of IO from India. However, as these data were obtained from a single center, the percentage of patients receiving IO is highly dependent on the economic status of the patient population the center is catering to. In this study, the median PFS and OS of the patients with mRCC receiving nivolumab in the second line were 8 months (95% CI, NR-NR) and 13 months (95% CI, 10.4–15.5), respectively, while the objective response rate (ORR) was 26.3%. It should be noted that the median OS in this study was nearly half of that in the CheckMate 025 study (25.8 months [95% CI, 22.2–29.8]). However, the median PFS and ORR were comparable to that in the CheckMate 025 study. This can be explained most likely by the limited therapy options post progression on nivolumab in the study by Abbas et al. Another important difference from the CheckMate 025 study was that Abbas et al. included only patients who had received at least four doses of nivolumab as opposed to one dose in the CheckMate 025 study. This inclusion criterion is expected to have led to the selection of a subgroup of patients with better outcomes by excluding the early progressors, however, as is evident from the PFS and OS, this did not occur with the patients in the study by Abbas et al. The authors have provided the real-world data of efficacy and toxicities of IO in a resource-constrained setting and they should be lauded for this effort.

In a retrospective study that compared axitinib with nivolumab in the second-line treatment of RCC post first-line treatment with a TKI, the clinical benefit rate for axitinib was 82.9%, while that for nivolumab was 56.4% (P = 0.014).[13] Besides, the PFS for axitinib was significantly better than that for nivolumab (median, 10.3 months vs. 7.3 months; P = 0.067). In another retrospective study on 17 patients who were given axitinib as third-line treatment post-TKI and second-line nivolumab, axitinib showed reasonable therapeutic efficacy with a median PFS of 12.8 months.[14] In a clinical scenario where a patient has had good PFS with first-line VEGFR TKI, the use of axitinib appears to be an acceptable option in the second-line, whereas in patients with short PFS, the use of nivolumab in the second line is preferred over everolimus.

The unavailability of ipilimumab and cabozantinib in India limits the treatment choices for our patients. Besides, in the absence of Indian data, it becomes very difficult to apply the findings from the studies conducted in the western countries directly to our patients who are ethnically and physically different from the western population. Thus, there is an urgent need to form collaborations so that LMICs can conduct meaningful studies and do not have to depend on the western countries for data.[15] Also, the optimum selection of therapies for RCC will require the development of biomarkers that can predict the benefit from IO and/or TKI in a particular patient.



 
  References Top

1.
Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: Extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol 2019;20:1370-85.  Back to cited text no. 1
    
2.
Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): Extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 2020;21:1563-73.  Back to cited text no. 2
    
3.
Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2021;384:829-41.  Back to cited text no. 3
    
4.
Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021. doi: 10.1056/NEJMoa2035716.  Back to cited text no. 4
    
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Noronha V, Abraham G, Patil V, Joshi A, Menon N, Mahajan A, et al. A real-world data of immune checkpoint inhibitors in solid tumors from India. Cancer Med 2021;10:1525-34.  Back to cited text no. 5
    
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Zanwar S, Joshi A, Noronha V, Patil VM, Sable N, Popat P, et al. Patterns of care and outcomes for second-line targeted therapy in metastatic renal cell carcinomas: A registry based analysis. Indian J Cancer 2016;53:579-82.  Back to cited text no. 6
[PUBMED]  [Full text]  
7.
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-13.  Back to cited text no. 7
    
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Cochin V, Gross-Goupil M, Ravaud A, Godbert Y, Le Moulec S. Cabozantinib: Mechanism of action, efficacy and indications. Bull Cancer 2017;104:393-401.  Back to cited text no. 8
    
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Fala L. Lenvima (lenvatinib), a multireceptor tyrosine kinase inhibitor, approved by the FDA for the treatment of patients with differentiated thyroid cancer. Am Health Drug Benefits 2015;8:176-9.  Back to cited text no. 9
    
10.
Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, 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;16:1473-82.  Back to cited text no. 10
    
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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;18:252-700.  Back to cited text no. 11
    
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Abbas W, Aggarwal A, Pankaj P, Jain R. Real-world data of second-line immunotherapy in metastatic clear cell renal cell carcinoma: A retrospective study. Cancer Res Stat Treat 2021;4:55-60.  Back to cited text no. 12
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13.
Suzuki K, Terakawa T, Furukawa J, Harada K, Hinata N, Nakano Y, et al. Clinical outcomes of second-line treatment following prior targeted therapy in patients with metastatic renal cell carcinoma: A comparison of axitinib and nivolumab. Int J Clin Oncol 2020;25:1678-86.  Back to cited text no. 13
    
14.
Ishihara H, Takagi T, Kondo T, Fukuda H, Tachibana H, Yoshida K, et al. Efficacy of axitinib after nivolumab failure in metastatic renal cell carcinoma. In vivo 2020;34:1541-6.  Back to cited text no. 14
    
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Noronha V. Making a case for cancer research in India. Cancer Res Stat Treat 2018;1:71-4  Back to cited text no. 15
    




 

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