Use of Immunotherapy Considered in Later Lines of RCC Therapy

Randy F. Sweis, MD (Moderator)

Assistant Professor of Medicine

Duchossois Center for Advanced Medicine - Hyde Park

UChicago Medicine

Chicago, IL

CASE SUMMARY

A 54-year-old man with a history of metastatic renal cell carcinoma (mRCC) had undergone a left nephrectomy and adrenalectomy. He had clear cell RCC (ccRCC) and metastases in his adrenal gland. Four years later, the patient had a recurrence of his cancer. A biopsy showed lung nodules consistent with ccRCC. In retrospect, it had been present on scans for at least 2 years prior.

The patient was observed based on the low volume and indolence of the disease and on his preference. Eighteen months later, a reexamination showed continued indolent growth on scans, with an increased total tumor burden, and a new paratracheal lymph node (2.0 × 1.5 cm). A decision was made to initiate systemic therapy with pembrolizumab (Keytruda) plus axitinib (Inlyta).

On follow-up, the patient’s disease was stable. The patient reported moderate diarrhea (well controlled with antidiarrheal medication) and mild fatigue. After cycle 6, he developed fatigue, mild shortness of breath, and mild cough without chest pain.

At approximately week 18, a chest CT scan confirmed grade 3 pneumonitis. Pembrolizumab treatment was held, and intravenous steroids were administered. Pembrolizumab then was discontinued, and the patient continued on axitinib.

Fourteen months after the initiation of systemic therapy, the patient reported increasing back pain, mild nausea, weight loss, and new onset of persistent rib pain. Imaging confirmed disease progression: the paratracheal lymph node had been 20 × 15 mm and was now 25 × 28 mm; there were new mediastinal and hilar nodal involvement, new retroperitoneal nodes, and new lytic lesions. He had an ECOG performance status of 1.

The patient was given 60 mg of cabozantinib (Cabometyx) once a day. Four months later, disease progression was documented. The patient wanted to continue active therapy.

DISCUSSION QUESTION

• What do you consider when choosing the next line of therapy for a patient like this?

JOSÉ PAREDES, MD: As far as I know, there is no study showing that if you fail one TKI [tyrosine kinase inhibitor], then you are going to fail the other ones. I am looking at it like you look at multiple myeloma with immunomodulatory drugs or proteasome inhibitors. Do we know that if you have failed one particular TKI that that necessarily means that you are not going to be using that class of therapy?

RANDY F. SWEIS, MD: No. In fact, the data would suggest the opposite, that there is efficacy. The first line therapies were all TKI, pazopanib [Votrient], sunitinib [Sutent], and then cabozantinib got approved with the METEOR study [NCT01865747], for example. That is one TKI given right after another and there is efficacy there. Similarly, with lenvatinib [Lenvima] plus everolimus [Afinitor], it was post TKI. There is well established efficacy, though maybe not as good in the later lines as if you give it up front. But most of these drugs have second-line data to support their use. You don’t exclude the class.

[Additionally], there’s a rare patient where, if you cycle through enough therapies, you can sometimes go back to the first one and get a response on occasion. That is probably because the spectrum is very different across the kinases that it [targets], and you [may] rescue some of the resistance by switching. That’s one of the nice things about having lots of options because you can cycle through them, even though they are in the same class.

TIM KUZEL, MD: [I chose] ipilimumab [Yervoy] plus nivolumab [Opdivo]. There are multiple studies that have shown a 15% to 20% significantly durable response rate post–single-agent TKI or single-agent checkpoint inhibitor in ccRCC.¹ For a good performance status in a younger patient who is interested in more than what tivozanib [Fotivda] offers in a few months, I’d definitely discuss ipilimumab plus nivolumab if they haven’t had significant toxicity previously with pembrolizumab.

ALAN TAN, MD: I agree with Dr Kuzel on the salvage ipilimumab plus nivolumab in second line and beyond. Response rates are low, [somewhere] in the 11% to 20% range,¹ but if [the patient is] relatively asymptomatic and going for that long, durable response, it is reasonable as a careful discussion. There are not many complete responses [CRs]. Michael B. Atkins, MD’s study had CRs,² but the rest of the studies across the board didn’t have any CRs.

I picked other. I like lenvatinib plus pembrolizumab, based on a smaller study [KEYNOTE-146; NCT02501096] that showed lenvatinib plus pembrolizumab was able to rescue patients after frontline IO [immunotherapy] regimens.³ The [objective response rate at week 24] was 55% and the progression-free survival is probably rivaling lenvatinib plus everolimus, but with less toxicity without everolimus.

SWEIS: Great thoughts. Maybe with the ipilimumab plus nivolumab, [there is] a low response rate, but potentially, if it is durable, it could be important to patients, especially if they are asymptomatic or have low symptoms. Then lenvatinib plus pembrolizumab is another good and interesting option. We [at the University of Chicago] were involved in that study, as well. It was a single-arm study, but it was pretty compelling.

JOMEL S. LABAYOG, MD: This is where I have a problem with [the National Comprehensive Cancer Network (NCCN) guidelines] because when you request an IO after an IO, we usually get denied. Insurers say no because the NCCN says if you had a prior IO then it makes it difficult to try another one, even if it was given first line and you are looking at third line.4 It makes it difficult to try any IO thereafter. We’ve tried and tried to look at ipilimumab plus nivolumab, but then they ask, does the patient have sarcomatoid [histology]? If we say no, [then we get denied], and you have to try something else. That’s one of the issues.

SWEIS: I would say [ipilimumab/nivolumab] is not my go-to, even if it is a consideration for some patients. I don’t know if Dr Kuzel or Dr Tan are doing that in most patients, or if it [is for] selected patients. It’s mostly based on the response rate being relatively low, and that is probably why it is not in the guidelines. But if you are adhering to the guidelines, it’s never going to be 100% [appropriate for all cases] anyway. But I agree, that’s the nuance that’s missing in the guidelines.

KUZEL: I don’t think that you could [dismiss ipilimumab plus nivolumab based on] the response rate. I think lenvatinib plus pembrolizumab [as subsequent therapy] is interesting. Ipilimumab plus nivolumab is on the NCCN guidelines as a regimen so that I have almost no pushback in terms of giving ipilimumab plus nivolumab in the salvage setting.

SWEIS: The guidelines have lots of options that they delineate. Even lenvatinib plus pembrolizumab is on there [as useful in certain circumstances]. Those are on there, but it still may be harder to get approval. Insurance companies sometimes still deny.

ALKARIM TAJUDDIN, MD: It looks like the old drug temsirolimus [Torisel] is coming back. [Do you have] any experience with that?

SWEIS: I haven’t used it in a long time. I tend to give everolimus with lenvatinib when I give everolimus. But I don’t know if others have been using temsirolimus recently.

TAN: I remember that from fellowship, but I haven’t used it as an attending, and that was 10 years ago. I remember it was [at the time] a category 1 option for patients with Memorial Sloan Kettering Cancer Center poor-risk disease, [but is now category 2B].⁴

STAN NABRINSKY, MD: I used it on 2 patients over the last year. It was 1 patient with clear cell [histology] and 1 with a mixed histology, with partial response in both cases.

SWEIS: Do you remember what line of therapy?

NABRINSKY: Third and beyond.

_References:

_{1. Yang Y, Mori SV, Li M, et al. Salvage nivolumab and ipilimumab after prior anti-PD-1/PD-L1 therapy in metastatic renal cell carcinoma: a meta-analysis. Cancer Med. 2022;11(7):1669-1677. doi:10.1002/cam4.4587}

_{2. Atkins MB, Jegede OA, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naive patients with advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A). J Clin Oncol. 2022;40(25):2913-2923. doi:10.1200/JCO.21.02938}

_{3. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946-958. doi:10.1016/S1470-2045(21)00241-2}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 4.2023. Accessed April 14, 2023. https://bit.ly/2TAx1m3}