Immunotherapy Plus TKI Yields Impressive Results for Subgroups With Advanced RCC

Daniel George, MD

Cochair, DCI Center for Prostate & Urologic Cancers

Director of Genitourinary Oncology

Duke Cancer Institute

Professor of Medicine, Medical Oncology

Duke Cancer Center

Durham, NC

CASE SUMMARY

• A 61-year-old man, married, father of 2 grown children and 5 grandchildren who live nearby, active lifestyle (daily walks, golfs regularly)
• History of low-volume, indolent metastatic clear cell renal cell carcinoma (ccRCC), status post left nephrectomy and adrenalectomy
• The patient was observed based on low volume and indolence of disease and patient preference.
• Three years after nephrectomy: continued indolent growth on scans, increased total tumor burden, new paratracheal lymph node (2.0 × 1.5 cm), and more than 10 pulmonary nodules on CT scan
• Lung biopsy confirmed metastatic ccRCC.
• Laboratory values within normal limits and ECOG performance status of 0

Targeted Oncology: What data support the treatment of a patient like this using nivolumab (Opdivo) and cabozantinib (Cabometyx)?

GEORGE: The choice of this regimen is based on the [phase 3] CheckMate 9ER study [NCT03141177]. This was a pivotal trial in [patients with] previously untreated metastatic RCC with a clear cell component. The patients could have mixed histology and any International Metastatic RCC Database Consortium [IMDC] risk score, but patients were stratified by their risk score, PD-L1 expression, and geographic region. It was a balanced population, and they were looking at progression-free survival [PFS] as a primary end point and overall survival [OS], objective response rate [ORR], and safety as secondary end points.¹

The results of the latest, 44-month follow-up, in terms of PFS…were dramatic. [These results] suggest to me that there’s a benefit, not only in your poorest-risk patients, [who] are progressing in the first 6 to 12 months, but also an even greater proportional benefit in your favorable-risk patients, [who] are going on to respond for years in some cases. At the median, there was a doubling of the PFS [at 16.6 months for nivolumab plus cabozantinib vs] 8.4 months for patients on sunitinib [Sutent], with an HR of 0.58 [95% CI, 0.48-0.71].²

This translated into a median OS of 49.5 months [in the combination arm]. This is vitally important because, with nivolumab available in the refractory setting, even when this study was started there were opportunities for patients to cross over, and yet the sequential use isn’t as good and doesn’t make up for the combination approach up front.

You see that survival difference early with the patients [who died] within the first 18 months, and you see that survival benefit later, with the patients living 3 years or more; so we’re seeing proportionally the same benefit throughout. It is encouraging to me that this isn’t just a transient benefit but is a substantial benefit. And the sunitinib arm did well, with a 35.5-month median OS…. But the nivolumab plus cabozantinib arm, with an almost 50-month median OS, [was] remarkable, and there are still probably a lot more data to come in this population.²

Do you recommend nephrectomy for most patients with stage IV RCC?

A lot of our patients with stage IV RCC have already undergone a nephrectomy, just like the patient in the case we are discussing here. For the patients [who] present with metastatic disease, we generally start with systemic therapy because the systemic therapy is working so well.

The exception, to me, would be the patient [who] has a large primary tumor and tiny, low-volume metastasis in a single organ site…. Those would be the types of cases where I think we’d still justify the nephrectomy up front, but for the majority of patients [who] present with metastatic disease, we’re starting with systemic therapy and then adding in the nephrectomy as they respond, as a sort of consolidative therapy.

In the CheckMate 9ER trial, how did the IMDC risk groups fare with respect to PFS and OS?

In patients with favorable risk, there was no [OS] difference between the arms. They certainly fared no worse [with the experimental regimen], but there was no difference…. In the patients with intermediate and poor risk, there was a clear separation in OS, with a median OS of 49.5 months vs 29.2 months in the experimental and control arms, respectively [HR, 0.65; 95% CI, 0.51-0.83]. There was a clear PFS benefit for the patients with intermediate and poor risk, at 16.4 months vs 7.1 months, respectively [HR, 0.55; 95% CI, 0.45-0.69] and also for the patients with favorable risk, at 21.4 months vs 13.9 months, respectively [HR, 0.75; 95% CI, 0.50-1.13]. As you get out past 18 months, the difference in OS gets a little wider.²

So, we need longer follow-up, but it does look like we’re getting a benefit by adding the immunotherapy to the TKI [tyrosine kinase inhibitor] in the favorable-risk patients. The question is, when is that going to translate into an OS benefit? So far, we haven’t seen that.

How did the combination of nivolumab plus cabozantinib affect ORR?

With that combination, there was a much higher ORR. Not that sunitinib was bad, [with an ORR of 28.4%], but with the combination, there was a doubling of ORR [to 55.7%]. And with the combination, there was a [12.4%] complete response rate, a [43.3%] partial response rate, and a [32.5%] stable disease rate, and only [5.6%] of the patients were nonresponsive. And the time to response was very quick, 2.8 months, much faster than with sunitinib [4.2 months], and the duration of response was [23.1 months], much longer than with sunitinib [15.1 months].³ All of this suggests that a response is going to happen sooner and is more likely to happen with this combination.

My patients [who] are struggling early on, in that first month or so, sometimes need to see this. I’ll get a scan at 6 weeks, because if the median time to response is 2.8 months, a significant portion of patients are going to have a 30% decline or more. So, we can see at least some evidence of response at 6 weeks. I don’t do that routinely, but if I have a patient [who’s] struggling and really having a hard time tolerating the medicine, it’s motivating for them to see this and know that the drugs are working and that their tumor is hurting more than they are.

How did PFS and OS vary with respect to site of metastasis (liver, bone, and lung)?

For [patients with the metastasis to the] liver with the combination, the PFS benefits were dramatic, [with] a median of 10.9 months [HR, 0.51; 95% CI, 0.33-0.79]... and it does suggest that there’s a larger benefit in this subpopulation. There was a particularly dramatic PFS benefit for those with bone metastasis as well, with a median of 18.2 months compared with 4.4 months for sunitinib [HR, 0.38; 95% CI, 0.25-0.59].

A TKI alone does a poor job of controlling bone metastasis, but with cabozantinib, and particularly with nivolumab plus cabozantinib, the benefit translated into an OS benefit as well [HR, 0.64; 95% CI, 0.39-1.04]. For lung metastases…there was a dramatic difference in PFS [HR, 0.51; 95% CI, 0.40-0.64] and OS [HR, 0.63; 95% CI, 0.46-0.86] associated with lung metastasis, maybe not as dramatic as with lung and liver, but there was still an OS benefit.⁴

How often do you see a mixed response, and how do you handle it?

When I see a mixed response, I like to biopsy the site of progression because I want to know what’s driving that, and that’s in multiple cancer types. If it’s a single site, there’s a lot of ablative approaches we’ll do, and because the patients are showing response otherwise, I’ll keep it going. When you have multiple areas of progression and multiple areas of response, you can’t do that.

When you see multiple areas of progression, you’ve got to change [the treatment strategy], and it doesn’t matter if you got response. The response isn’t going to kill them, it’s the progressive disease that will. It’s important to recognize that, and don’t forget to scan the brain. When you’re seeing new, progressive sites of disease, you’ve got to scan the brain, because you could also find it there, at least with kidney cancer.

How do the adverse events (AEs) of the regimens on this study compare?

AEs are key. Some things like diarrhea were more pronounced in the experimental arm, but hand-foot syndrome was a little bit less, hypertension was the same, hypothyroidism was more pronounced, and the nausea was less, as were some of the mucosal issues. I think some of these results were just [a reflection of] sunitinib vs cabozantinib. There were more cytopenias with the sunitinib, but the liver function test [LFT] results went up with nivolumab plus cabozantinib. So, there are different things to consider. Rash was more pronounced with the combination as well, but all in all, the grade 3 and grade 4 toxicities were similar across the board, with a little more of the cytopenias and stomatitis with sunitinib and a little more of an effect on LFT results with the combination.

The number of patients who discontinued treatment due to treatment-related adverse events was [10.6%] for nivolumab, [9.1%] for cabozantinib, and [7.5%] for both. So, over 90% of patients were able to tolerate one or the other drug, and three-fourths of patients were able to tolerate both drugs. Dose reductions did happen in approximately half of the patients, but [clinicians shouldn’t be afraid if they] have to dose reduce. Most of the time, we can keep our patients on this therapy.⁵

_REFERENCES

_{1. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982}

_{2. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl 6):603. doi:10.1200/JCO.2023.41.6_suppl.603}

_{3. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(7):888-898. Published correction appears in Lancet Oncol. 2022;23(7):e319. Published correction appears in Lancet Oncol. 2022;23(9):e404.}

_{5. Apolo AB, Powles T, Burotto M, et al. Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial. J Clin Oncol. 2021;39(suppl 15):4553. doi:10.1200/ JCO.2021.39.15_suppl.4553}

_{6. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl 6):350. doi:10.1200/JCO.2022.40.6_suppl.350}