Selecting Novel Therapy for Advanced Renal Cell Carcinoma

Earle Burgess, MD:In late 2019 we now have multiple potential options available for frontline treatment of patients with intermediate or poor-risk kidney cancer. Specifically, the combination of ipilimumab and nivolumab, or IPI/NIVO, or the combination of axitinib and pembrolizumab, or AXI/PEMBRO, based on the CheckMate 214 and KEYNOTE-426 studies, respectively, are the current standards of care. For patients who aren’t able to receive an immune checkpoint inhibitor, TKI [tyrosine kinase inhibitor] monotherapy specifically with cabozantinib are the preferred options.

Currently the NCCN [National Comprehensive Cancer Network] has both the ipilimumab, nivolumab and the axitinib, pembrolizumab combos listed as category 1 recommendations for intermediate and poor-risk patients. Cabozantinib is also listed with a category 2A recommendation.

There are differences that should be considered with these 3 different regimens. As I’ve mentioned, ipilimumab, nivolumab, axitinib, pembrolizumab, and cabozantinib have not been directly compared. Based on our earlier discussion we need to consider certain clinical factors when trying to optimize our choice of these 3 options for patients with intermediate or poor-risk disease.

Specifically looking at risk status, in the CheckMate 214 study, about 20% of the patients included in the trial had good-risk disease. However, the primary end point was powered around the intermediate and poor-risk subgroup. Thus far the benefit of ipilimumab, nivolumab compared to sunitinib monotherapy has only been shown in the intermediate and poor-risk patients. We’re talking about a poor-risk patient, but I just want to point out that thus far in the good-risk subgroup, ipilimumab, nivolumab has not shown a benefit, and therefore shouldn’t be used. That’s in contrast with axitinib, pembrolizumab. The primary end point included all risk groups, and approximately 30% of the patients on KEYNOTE-426 trial were of good risk. KEYNOTE-426, as I mentioned, compared axitinib, pembrolizumab to sunitinib monotherapy and established that the combination was superior to sunitinib monotherapy based on overall survival, PFS [progression-free survival], and response rate as well.

For patients who are not candidates for immune checkpoint inhibitors, who have contraindications such as a severe autoimmune condition, monotherapy with cabozantinib may still be considered based on the results of the CABOSUN study.

One of the key questions that we face in the clinic today for patients who are candidates for immune checkpoint inhibitors is the decision on whether to use ipilimumab, nivolumab or axitinib, pembrolizumab. The factors that I think should influence our consideration between ipilimumab, nivolumab and axitinib, pembrolizumab are as follows for intermediate and poor-risk patients specifically.

The burden of disease, and specifically symptomatic burden, should be considered. Again, I caution about comparing across the trials, but in the ipilimumab, nivolumab arm of CheckMate 214 compared to the axitinib, pembrolizumab arm of KEYNOTE-426, ipilimumab, nivolumab had a lower overall response rate compared to the axitinib, pembrolizumab arm. And the rate of progression was also lower in the axitinib, pembrolizumab arm.

For a particular patient who has a high symptomatic burden in whom we need a higher likelihood of response and lack of progression, I may lean toward axitinib, pembrolizumab in lieu of ipilimumab, nivolumab. Conversely we should consider strongly any associated comorbidities, particularly cardiovascular status. For patients who have poorly controlled hypertension, I think caution should be warranted for use of a TKI, in particular, axitinib, pembrolizumab, or cabozantinib monotherapy, as the rates of hypertension were higher in these arms in their respective trials. For someone who has poorly controlled hypertension I may favor ipilimumab, nivolumab in that setting.

We’ve touched on the role of autoimmune disorders. For serious autoimmune disorders I think immune checkpoint inhibitors are contraindicated for milder autoimmune conditions such as controlled rheumatoid arthritis. I think it can be considered. I would lean toward axitinib, pembrolizumab in that setting in effort to limit the risk of flaring the rheumatoid arthritis.

Other considerations are general fitness and frailty as I’ve alluded to. In the CheckMate 214 trial, 30% of patients required high-dose corticosteroids at some point on study for a presumed immune related adverse event. If a patient is unlikely to tolerate high dose corticosteroids, I would lean toward either axitinib, pembrolizumab; or in select cases, TKI monotherapy.

Although there isn’t any correct answer for any 1 patient, all of these options exist for patients with intermediate and poor-risk disease. It ultimately becomes an individualized decision based on the clinical factors that we’ve discussed and a discussion with the patient to select the best choice.

Transcript edited for clarity.

Case: A 68-Year-Old Man With Poor-Risk RCC

A 68-year-old man presented with a 6-week history of painless intermittent hematuria, fatigue and a 7-lb weight loss.

H & P:

• History of medically controlled hypertension and hypercholesterolemia
• 30 pack/year smoking history, social alcohol use  
• Thin, ill-appearing; able to meet activities of daily living but unable to work due to fatigue. He spends more than half the day active on his feet

Labs:

• CBC: Hb 11.4 g/dL, corrected Calcium,11.2 mg/dL, WBC, PLT, LFT all WNL
• BP: 134/92
• Lipid panel: WNL
• U/A: gross hematuria

Imaging:

• CT scan of the chest/abdomen/pelvis showed a left-sided 8.7 (I believe he said 8cm) cm renal mass, para-aortic lymph nodes, and pulmonary metastases

Diagnosis:

• Underwent radical left nephrectomy; found to have Fuhrman grade 4 clear cell carcinoma without sarcomatoid features
• IMDC risk-score: poor

Treatment:

• Initiated treatment with ipilimumab 1mg/kg IV + nivolumab 3mg/kg IV q3w for 4 doses; achieved partial response; received maintenance nivolumab for 6 doses (q4w) followed by disease progression
• Patient was switched to cabozantinib 60mg PO qDay