Expanding first-line renal cell carcinoma treatment to patients with favorable risks: A sharing of local cases
Renal cell carcinoma (RCC) is the most prevalent type of kidney malignancy, accounting for 90% of all cases.1 Characterized by susceptibility to both immunotherapeutic and anti-angiogenic approaches, RCC can be treated with a combination of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) in the first-line setting and has gradually become a new standard of care for metastatic RCC.2 In the KEYNOTE-426 study, the combination of pembrolizumab and axitinib has significantly improved the overall survival (OS), progression-free survival (PFS) and confirmed objective response of RCC patients, as compared to sunitinib alone.3 In a recent interview with Omnihealth Practice, Dr. So, Tsz-Him, Clinical Assistant Professor, Department of Clinical Oncology, The University of Hong Kong, shared his insight on the clinical management of metastatic RCC and emphasized the importance of maintaining combination therapy throughout the clinical course of RCC.
Managing metastatic RCC in Hong Kong
Until recently, there has been an annual increase of about 2% in RCC incidence world wide in the last two decades.1 The growth of renal tumor remains frequently unnoticed before it reaches a late disease stage.1 In Hong Kong, the number of new kidney cancer cases has increased from 636 in 2015 to 792 in 2018.4 While the incidence rate has been steadily increasing, the age-standardized mortality rate remained stable at 1.4 per 100,000 persons from 2015 to 2018.4 That said, regular health screening has gained popularity in the territory, allowing more RCC cases to be detected at an early malignant stage.
The International Metastatic RCC Database Consortium (IMDC) risk score stratified metastatic RCC patients into favorable, intermediate and poor risk groups according to the estimated median OS.5 Whereas double ICIs are indicated for the intermediate and poor risk groups only, the combination of TKI and ICI is indicated for advanced RCC patients in the first-line setting regardless of IMDC risk.1 As antiangiogenic drugs can lead to the normalization of tumor vasculature and alleviation of hypoxia, TKIs can have profound positive effects on immune-cell infiltration into tumors and improve the efficacy of ICIs, supporting the synergistic antitumor effect of the TKI and ICI combination.6 This article presents two favorable-risk RCC cases which were successfully managed by the combination of TKI and ICI.
A sharing of local cases: Combination therapy in patients with favorable IMDC risk
The first case was a 62-year-old woman who sought medical attention in the clinic in 2019. Her chief complaint was upper right thigh pain. She did not have respiratory symptoms upon her first visit. She had radical nephrectomy of the right kidney due to non-cancer-related nephritis when she was young. In 2004, she was diagnosed with RCC and underwent partial nephrectomy. However, she had recurrent RCC at the same anatomical site in 13 years following the procedure, necessitating another partial nephrectomy.
Positron emission tomography-computed tomography (PET-CT) scan was performed in the initial consultation in June 2019. The radiograph revealed multiple pulmonary nodules in the lungs and metastasis in the right femur and the left adrenal gland. Due to high risk for fracture, she underwent right distal femur osteotomy with fixation. Radiotherapy was given to the right femur after surgery. Subsequent bone biopsy confirmed metastatic RCC.
Considering her stable condition over the last decade, she had favorable IMDC risk score. To align with her request for aggressive treatment, she commenced a combination therapy of pembrolizumab and axitinib in August 2019. This intervention was chosen because double ICIs were excluded from patients with favorable risk. Over the treatment course, she developed pneumonitis and hypertension (160/90mmHg). Antihypertensive medication was prescribed. The dosage of axitinib was gradually reduced from 5mg twice daily (BD) to 2.5mg BD and eventually to 1mg BD. While blood pressure was well controlled, the parallel reduction of axitinib led to visually apparent mass enlargement in the skull, which was subsequently reverted by increasing axitinib dosage to 3mg BD. Attempts to revert to full dosage of axitinib (5mg BD) by alternating dosing schedule with 5mg in daytime and 2.5mg in nighttime were precluded by her uncontrolled blood pressure. Axitinib was thereby maintained at a reduced dose.
In November 2020, the masses on the left adrenal gland and the number of pulmonary nodules in the PET-CT scan have reduced (Figure 1). However, she developed psoas muscle abscess after urethral infection and had to stop the combination treatment for a month for abscess drainage. By December 2020, the masses on the left adrenal gland, the lungs and the skull became bigger. As axitinib was suspected to be associated with urethral fistula, she did not resume combination therapy. Instead, she enrolled in a clinical trial of everolimus as salvage therapy.
The second case was a 73-year-old male who had radical nephrectomy of the right kidney in 2004 due to RCC. In mid-2020, he attended the clinic with persistent cough. PET-CT showed evidence of multiple pulmonary nodules and hepatic metastasis. Histological examination of liver confirmed metastatic RCC. Pembrolizumab plus axitinib was prescribed as he had favorable IMDC risk. By September 2020, he completed four cycles of combination therapy and his tumor size in both liver and lungs have reduced. However, he experienced severe hand-foot syndrome and hence axitinib was withdrawn for one month. After receiving topical lotions, axitinib was reinitiated in October 2020 at a reduced dose of 2.5mg BD. In January 2021, PET-CT showed evidence of further reduction of liver and lung tumor sizes (Figure 2). To address his concern on hand-foot syndrome, axitinib dosage was further reduced to 2mg BD and no new safety signals were identified following the 12 cycles of combination therapy.
In both RCC cases, pembrolizumab plus axitinib was considered not only because it was indicated for advanced RCC in the first-line setting regardless of IMDC risk or programmed death-ligand 1 (PD-L1) presence, but also due to axitinib’s anti-angiogenic activity.1 Indeed, RCCs are largely driven by pathological overexpression of VEGF, a neovascularization factor, and would require anti-angiogenic therapy for effective disease management.7 Compared to TKI monotherapy, the recently published analysis of the KEYNOTE-426 study showed that, after a median follow-up of 30.6 months (IQR=27.2-34.2), pembrolizumab plus axitinib (n=432) has significantly improved OS (median not reached vs. 35.7 months; HR=0.68; 95% CI:0.55-0.85; p=0.0003) and PFS (median 15.4 months vs. 11.1 months; HR=0.71; 95% CI: 0.60-0.84; p<0.0001) when compared to sunitinib alone (n=429) in the first-line RCC setting (Figure 3).3
Notably, pembrolizumab plus axitinib led to clinically relevant confirmed objective response (60% vs. 40%; p<0.0001*) and complete response (CR) rate (9% vs. 3%), as compared to sunitinib alone.3 While CR is not commonly observed in practice, most patients would respond well to combination therapy as shown in the illustrated cases with very good partial response (VGPR) that resulted in stable disease. In terms of safety, the most frequent (≥10%) treatment-related adverse event was hypertension at 22% in patients treated with pembrolizumab plus axitinib and 20% in those treated with sunitinib.3
When considering treatment for patients with different IMDC risks, combination therapy may be prescribed to favorable-risk RCC patients when aggressive treatment is appropriate. While a significant OS benefit was only observed in patients with intermediate or poor IMDC risks in the KEYNOTE-426 study, a significantly higher proportion of patients receiving pembrolizumab plus axitinib had an objective response when compared to sunitinib, regardless of IMDC risk categories or the presence of PD-L1 (Figure 4).3 In this connection, the European Association of Urology (EAU) 2020 RCC guidelines also recommend pembrolizumab plus axitinib to treatment-naïve patients with any IMDC-risk clear-cell metastatic RCC.1
Especially in private practice where resources are limited, Dr. So stated that TKI plus ICI is generally preferred over other ICI regimen due to a more predictable safety profile and the side effects can be more easily managed. With gradual and dose-dependent response, the side effects of TKI are manageable by dose reduction or comedication. On the other hand, severe immune-related adverse events from double ICIs such as hepatitis can have a sudden onset and require a lengthy period of steroid management before RCC treatment can be resumed. As exemplified in the first illustrated case, treatment interruption for even only 1 month can result in significant disease progression. After adjusting the axitinib dosage with hypertensive medication, combination therapy can be maintained for the illustrated patient with continuous control of the disease.
Compared to other TKIs such as pazopanib or cabozantinib, axitinib has a short half-life of 2.5-6.1 hours and its plasma concentration can be quickly reduced if withheld, and it allows quick recovery from axitinib-related adverse events if present.8 As shown in both cases, Dr. So pointed out that the efficacy of combination therapy can be maintained following the optimal axitinib dose adjustment. In the first illustrated case, the patient had remained asymptomatic with good quality-of-life throughout the 15 months of pembrolizumab plus axitinib treatment that was only interrupted due to her nonefficacy related abscess drainage surgery. In fact, the patient had requested to reinitiate combination therapy soon after surgery to manage the growing mass on her skull. Given how well she had responded to pembrolizumab plus axitinib, it is believed that upfront double ICIs would not be able to manage her disease and would likely be given TKI monotherapy afterward.Similarly, the hand-foot syndrome in the second illustrated case was easily managed by axitinib dose reduction and topical emollient.
As grade 3 or worse adverse events are rarely associated with pembrolizumab in practice, and that the combination of pembrolizumab plus axitinib is shown to be well-tolerated with no new safety signals after its initial approval by the United States Food and Drug Administration in 2019, Dr. So reiterated that TKI plus ICI should be considered when aggressive RCC management is warranted even among patients with favorable IMDC risks.9 “Most importantly, RCC treatment should not be interrupted for an extended period of time in order to achieve successful disease control. Combination therapy with TKI and ICI allows a flexible dosing strategy and can enable a continuous treatment to manage metastatic RCC,” Dr. So concluded.
In the management of metastatic RCC, either double ICIs or the combination of TKI and ICI can be considered. Considering the majority of RCCs are VEGF-driven, anti-angiogenic TKI remains critical in delaying the disease progression. Where double ICIs therapy is not indicated for patients with favorable IMDC risks, the anti-angiogenic TKI was essential in limiting the tumor size. As in the illustrated cases, patients of favorable risks with gradual side effects can be managed by dose reduction and co-medication for symptomatic relief. With the KEYNOTE-426 study supporting the safety and efficacy of the combination therapy of pembrolizumab and axitinib, this regimen should be incorporated in the clinical management of favorable-IMDC-risk RCC patients who desire for aggressive treatment to limit their RCC progression.