Immunotherapy-Based Combinations Remain the Focus of Frontline Treatment in Metastatic RCC

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Partner | Cancer Centers | <b>UC San Diego Health Moores Cancer Center</b>

Rana R. McKay, MD, discusses the evolution of frontline treatment options for metastatic RCC, and the key clinical trials that have shifted the treatment paradigms in metastatic castration-resistant prostate cancer, nonmetastatic castration-resistant prostate cancer, and advanced prostate cancer.

Immunotherapy-based doublets such as nivolumab (Opdivo) plus ipilimumab (Yervoy) and pembrolizumab (Keytruda) plus axitinib (Inlyta) have become standard of care in the frontline setting for patients with metastatic renal cell carcinoma (RCC), replacing single-agent VEGF TKIs, according to Rana R. McKay, MD, who added that investigating immunotherapy-based triplets could be the next area of focus for first-line treatment in RCC.

“The field is changing,” McKay said in an interview with OncLive® following a State of the Science Summit™ on RCC and prostate cancer. “These forums are excellent for keeping clinicians updated about the evidence-based, revised practice guidelines for patients who have advanced RCC and prostate cancer. Engaging in multidisciplinary discussion with medical oncologists, radiation oncologists, and surgeons to optimize therapy for patients is key.”

In the interview, McKay, who chaired the event, discussed the evolution of frontline treatment options for patients with metastatic RCC, and the key clinical trials that have shifted the treatment paradigms in metastatic castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer (nmCRPC), and advanced prostate cancer. McKay is a medical oncologist and associate professor of medicine at the University of California San Diego, Moores Cancer Center.

OncLive®: At the event, you shared insights on newly diagnosed metastatic RCC. What key highlights were shared during your presentation?

McKay: We ran through some recent advancements in kidney cancer and prostate cancer. The specific topic that I addressed was the evolving first-line space in advanced RCC. There has been a tremendous amount of change over the past decade, [specifically] within the past 5 years, in how we treat patients with RCC. Historically, we treated patients with RCC with VEGF TKI monotherapy [in the frontline setting]. Starting in 2018, that shifted to immunotherapy[-based] doublets [following] the results of the [phase 3] CheckMate-214 trial [NCT02231749].

On the heels of that study, a series of other trials [evaluating immunotherapy vs VEGF TKIs] have read out, including the [phase 3] KEYNOTE-426 [NCT02853331], CLEAR [NCT02811861], and CheckMate-9ER [NCT03141177] trials. The immunotherapy combinations [investigated in these trials] have also demonstrated improvements in overall survival [OS].

We delved into the nuances of where we are now [regarding frontline] treatment and the differences between these regimens [in terms of] efficacy and toxicity. The biggest thing for clinicians is knowing what to pick when a patient is in front of you. How do you decide what kind of therapy to give them? We delved into some of the data around that.

Could you elaborate further on how the CheckMate-214, KEYNOTE-426, CheckMate-9ER, and CLEAR trials advanced the frontline treatment paradigm in RCC? What factors go into picking a regimen for a specific patient?

There are 4 key clinical trials that have largely changed the way we treat kidney cancer in the modern era for patients with advanced metastatic disease. CheckMate-214 looked at the combination of nivolumab plus ipilimumab vs sunitinib [Sutent]. KEYNOTE-426 looked at the combination of pembrolizumab plus axitinib vs sunitinib.

CheckMate-9ER looked at nivolumab plus cabozantinib [Cabometyx] vs sunitinib. Lastly, the CLEAR trial was a 3-arm study that included the combination of pembrolizumab plus lenvatinib [Lenvima] vs lenvatinib plus everolimus [Afinitor] vs sunitinib.

All 4 of these studies demonstrated improvements in OS with the immunotherapy[-based] doublet compared with standard-of-care sunitinib. However, they’re all slightly different. Immunotherapy/VEGF combinations are better in the short term. The objective response rates are higher compared with dual immunotherapy. The progression-free survival [PFS] is higher compared with dual immunotherapy. The primary progressive disease rate is lower compared with dual immunotherapy.

However, when I look at the combination of nivolumab plus ipilimumab, the long-term durability [is more pronounced]. The 60-month PFS rate was 30% [with that combination]. [The challenge of picking between these treatments is] balancing the short gains and the long gains.

What additional advancements do you hope to see in the frontline treatment of metastatic RCC?

We are beginning to see the effects of triplet therapy. The data from the [phase 3] COSMIC-313 trial [NCT03937219] were recently presented at the 2022 ESMO Congress, looking at the triplet of nivolumab/ipilimumab plus cabozantinib vs nivolumab/ipilimumab alone.

Although the trial was positive for an improvement in PFS, we need to wait and see what ends up happening with OS. The regimen is toxic, and with a toxic regimen, you can sometimes compromise the amount of treatment given, which affects efficacy.

However, with where the field is going now, we must better understand patient selection and therapy sequencing. We recently have had [several] new approvals. There are not many treatment options [currently] in phase 3 trials that will change the frontline landscape. [Instead], we need to figure out how to better utilize the agents that we have.

Sumanta Kumar Pal, MD, FASCO, of City of Hope, discussed second- and later-line treatment in metastatic RCC. What role has VEGF inhibition played post-immunotherapy?

Given that the frontline treatment landscape for patients with advanced RCC has been changing [with the use of] immunotherapy doublets as opposed to VEGF monotherapy, many of the studies that informed what we do in the second-line space are somewhat antiquated. They were all conducted in a time where patients were getting VEGF monotherapy in the frontline and may not have received immunotherapy.

The phase 3 AXIS trial [NCT00678392], the phase 3 METEOR trial [NCT01865747], and a phase 2 study [NCT01136733] of lenvatinib plus everolimus, all inform what to do in the second-line space, but [these studies were] largely conducted in the TKI era.

There are a series of retrospective studies that have looked at VEGF inhibition post-immunotherapy. One prospective trial looked at axitinib post-immunotherapy.

There have been other studies that have looked at immunotherapy post-immunotherapy, such as the [phase 2] HCRN trial [NCT03117309], the [phase 2] TITAN-RCC study [NCT02917772], and the [phase 2] OMNIVORE trial [NCT03203473] with ipilimumab layered onto nivolumab, based on a patient’s imaging response. Largely, [the layering] strategy can produce some responses, but they are limited, and the complete response rate is nearly 0. Data with nivolumab and ipilimumab in the second-line setting from the [phase 2] FRACTION-RCC trial [NCT02996110] demonstrated an objective response rate of 15.2%.

What’s exciting is the series of [ongoing] trials looking at how to better strategize therapy in the second line. The [phase 3] TiNivo-2 study [NCT04987203] is looking at tivozanib [Fotivda] and nivolumab vs tivozanib. The [phase 3] CONTACT-03 trial [NCT04338269] is looking at atezolizumab [Tecentriq] plus cabozantinib vs cabozantinib. These are all being conducted in the post-immunotherapy setting.

Belzutifan [Welireg] is being investigated in the refractory setting in a phase 3 trial [NCT04195750] compared with everolimus. [Belzutifan] is the potential new kid on the block. It already has FDA approval for cancers linked with Von Hippel-Lindau disease, and it is being tested for sporadic RCC.

Stephanie Berg, DO, of Dana-Farber Cancer Institute, discussed advances in metastatic hormone-sensitive prostate cancer (mHSPC). How has treatment expanded by building off the androgen deprivation therapy (ADT) and docetaxel backbone?

The treatment of mHSPC shifted, starting in 2015, when the results of the [phase 3] CHAARTED trial [NCT00309985] and the [phase 2/3] STAMPEDE trial [NCT00268476] were released, which looked at therapy escalation for patients with mHSPC. Prior to that time, we were largely treating mHSPC with ADT alone.

[Results from CHAARTED and STAMPEDE] catapulted us over the next decade into a series of studies that have investigated hormonal agents being escalated in the frontline setting [with the addition of agents such as] abiraterone acetate [Zytiga], enzalutamide [Xtandi], apalutamide [Erleada], and docetaxel. More recently, [investigators have looked] at the triplet of ADT, docetaxel, and an androgen receptor [AR] pathway [inhibitor].

The [phase 3] PEACE-1 trial [NCT01957436] looked at the addition of abiraterone to [ADT and docetaxel] in the frontline setting. The [phase 3] ARASENS trial [NCT02799602] looked at the addition of darolutamide [Nubeqa] to the backbone of ADT/docetaxel.

There are some patients who could be candidates for triplet therapy. We need to better understand patient selection and who should get what treatment. It is no longer standard of care for patients to get ADT/docetaxel. We’ve now demonstrated in multiple large studies that adding a hormonal agent to that backbone of ADT/docetaxel improves outcomes. The key strategies here are [combining] ADT with a hormonal agent or ADT and docetaxel with a hormonal agent.

Prostate-specific membrane antigen [PSMA] imaging is going to change how we further define mHSPC. We will find metastases earlier, and patients are going to have lower-volume disease. There are a lot of questions about metastasis-directed therapy in this context, [along with] potential therapy discontinuation for those patients who can achieve a prostate-specific antigen [PSA] level less than 0.2 ng/mL or an undetectable PSA level. Do they need to continue therapy in an indefinite fashion, or can therapy be discontinued, then reinitiated at a later point? These are all questions that the field has.

The STAMPEDE trial also looked at the role of primary-directed radiation therapy for all-comers, but there was a benefit in people with low-volume disease. [Primary-directed radiation therapy] is another modality that can be offered to patients who present with de novo metastatic disease. We know that patients who present with synchronous metastases vs metachronous metastases have a different disease trajectory and can have more aggressive disease.

Michael Schweizer, MD, of the University of Washington School of Medicine, discussed therapeutic strategies in mCRPC and nmCRPC. What therapeutic strategies were discussed and how do they differ between metastatic and nonmetastatic disease?

For CRPC, we break it down into nonmetastatic and metastatic disease. The patient population who presents with nmCRPC is shrinking with the advent of more advanced imaging, where we’re able to detect metastases at an earlier time point. Nonetheless, patients that are on ADT with a rapid doubling time and don’t have any evidence of metastases on conventional imaging can be candidates for hormone therapy escalation with the addition of either apalutamide, enzalutamide, or darolutamide. All 3 of those agents have been heavily investigated in large phase 3 trials for patients with [nmCRPC].

For patients with mCRPC, there’s a handful of options that can be considered. The [phase 4] CARD trial [NCT02485691] was an excellent study that looked at cabazitaxel [Jevtana] vs a hormonal agent in patients that have seen prior docetaxel or a prior hormonal agent. [CARD] demonstrated the benefit of switch therapy with cabazitaxel.

Recently, we saw data presented from the [phase 3] VISION trial [NCT03511664], leading to the FDA approval of lutetium Lu 177 vipivotide tetraxetan [Pluvicto; formerly 177Lu-PSMA-617], a beta-emitting radiopharmaceutical that targets PSMA-expressing cells. That is a life-prolonging therapy for patients.

Further, what is key for patients who have mCRPC is undergoing somatic tumor profiling and germline profiling. Germline profiles are indicated for a broad patient population in those with prostate cancer. This is important because patients could be a candidate for PARP inhibitor therapy with either olaparib [Lynparza] or rucaparib [Rubraca], or they could be a candidate for pembrolizumab should they have a microsatellite instability–high tumor. It’s always imperative to make sure that that genomic profiling gets done and gets repeated throughout somebody’s treatment course in the mCRPC setting.

Helen H. Moon, MD, of Kaiser Permanente, discussed novel therapies in advanced prostate cancer. Which novel therapies continue to be of interest in this space?

There are a lot of novel therapies that are currently being investigated for advanced prostate cancer. Some of the key ones include CDK4/6 inhibitors. Specifically, abemaciclib [Verzenio] is being looked at in this context. There are currently 3 studies that are ongoing: the [phase 2] CYCLONE 1 trial [NCT04408924] is looking at the refractory setting, the [phase 2/3] CYCLONE 2 trial [NCT03706365] is looking at the frontline CRPC setting, and the [phase 3] CYCLONE 3 trial [NCT05288166] is looking at the mHSPC setting with abemaciclib. Abemaciclib is a CDK4/6 inhibitor, and it has approvals in breast cancer in the adjuvant setting and in the advanced setting as monotherapy or combined with estrogen therapy.

Other agents include the AR degraders. It is going to be interesting to see how those data evolve, and what patient population [could] receive this therapy. PSMA bispecific antibodies or CAR T-cell therapies are also being investigated. They are still early on in phase 1 testing, but there is some excitement around those treatments.

There are also other kinds of radioligand therapies that are being developed. A lot of different kinds of drugs with novel mechanisms of action are being explored for patients with advanced CRPC. It is an exciting time.

Is there any ongoing research at the Moores Cancer Center that you would like to highlight?

I am going to talk about 2 studies that are about to launch. We have recently demonstrated that PARP inhibitors improve outcomes for patients with mCRPC who harbor germline or somatic BRCA1/2 mutations. One of the key questions is how to prevent patients from getting metastatic disease. How can we cure more people when they have localized disease?

We’re in the midst of launching a trial called NEPTUNE, which is looking at neoadjuvant ADT plus olaparib for 6 months prior to prostatectomy for patients who have somatic or germline BRCA1/2-mutated prostate cancer. This is a niche trial looking for a signal of early activity for olaparib for patients who have localized prostate cancer with the goal of trying to induce pathologic responses to ultimately increase cure rates.

Another study is also being conducted called the [phase 2] CANOPY trial [NCT05502315]. This is a study of nivolumab plus cabozantinib for patients with mCRPC. We saw some early promising data of atezolizumab plus cabozantinib from the [phase 1/2] COSMIC-021 trial [NCT03170960], and there is a large study called the phase 3 CONTACT-02 trial [NCT04446117] looking at the combination of atezolizumab plus cabozantinib. In [CANOPY], we are going to be looking at nivolumab plus cabozantinib for patients with advanced prostate cancer, given the preclinical work and rationale for that combination. That study is hopefully going to be enrolling patients starting later this fall.