Pembrolizumab Data Highlight Potential for Adjuvant Immunotherapy in RCC

Christopher W. Ryan, MD

Although immature data from the phase 3 KEYNOTE-564 trial (NCT03142334) have not yet demonstrated an overall survival (OS) benefit for pembrolizumab (Keytruda) vs placebo in adjuvant renal cell carcinoma (RCC) treatment following nephrectomy, the disease-free survival (DFS) benefit demonstrated in data from the study have shown the potential for the use of immunotherapy in this setting, according to Christopher W. Ryan, MD.

“What we don’t know is if [giving] adjuvant treatment early on, as opposed to saving immunotherapy if a patient relapses with metastatic disease, will make a difference in OS. However, it is reasonable to consider adjuvant therapy and give benefit to the doubt that it may one day show improved OS, based on the compelling DFS benefit that we have seen in [KEYNOTE-564],” said Ryan, who chaired an OncLive^® State of the Science Summit™ on genitourinary (GU) cancers.

In an interview with OncLive^®, Ryan, a professor of medicine in the School of Medicine at the Oregon Health & Science University in Portland, Oregon, discussed the role of adjuvant pembrolizumab in RCC, the use of immunotherapy-based combinations in the frontline setting for metastatic RCC, and key data presented at the 2023 Genitourinary Cancers Symposium in bladder cancer and prostate cancer.

OncLive^®: What treatment approaches have been reinforced in contemporary data sets in metastatic RCC?

Ryan: I covered high-level data, which indicate that checkpoint inhibitor–based treatment is standard of care for patients with metastatic RCC in the first-line setting. [These combinations] have and continue to improve OS for patients [with metastatic disease].

When approaching a patient with metastatic disease and choosing an immunotherapy-based regimen, we essentially have 2 choices: either a dual checkpoint inhibitor combination, namely ipilimumab [Yervoy] and nivolumab [Opdivo], or a PD-1 inhibitor plus a TKI, of which we have several choices. Topline data and FDA approvals have showed improved OS with 4 different combination therapies that are currently commercially available.

Choosing among those treatments, my take-home message was that there is really no wrong choice. You can’t really make a mistake in choosing amongst these regimens, [which] include ipilimumab plus nivolumab, pembrolizumab [Keytruda] plus axitinib [Inlyta], nivolumab plus cabozantinib [Cabometyx], and pembrolizumab plus lenvatinib [Lenvima] as approved choices that have all shown improvements in OS.

There are some differences when we look at these [combinations] side by side, and we always have to be cautious about making cross-trial comparisons, although we do it frequently in oncology. There are some differences that seem to emerge on the surface when comparing ipilimumab and nivolumab with immunotherapy/TKI combinations. These include higher response rates with immunotherapy/TKI combinations. However, for patients who have a response to ipilimumab and nivolumab, those responses seem to be very durable as we get longer follow-up.

The bottom line is, there’s not a wrong choice [between these combinations]. OS is improved across the board with these regimens as first-line treatment.

How did the KEYNOTE-564 trial support the use of adjuvant pembrolizumab in patients with RCC at high risk for recurrence?

Adjuvant therapy is a topic that I’m very interested in. I have spent a portion of my career studying this, and results from the phase 3 EVEREST trial [NCT01120249] were presented [at the 2022 ASCO Annual Meeting]. [This] was the first enrolling trial of an adjuvant mTOR inhibitor [everolimus (Afinitor)]. However, there have been a number of placebo-controlled adjuvant trials launched, completed, and reported since our new generation of RCC therapies became available beginning in 2005. To sum this up, there have been 5 trials of a TKI, only one of which—the [phase 3] S-TRAC trial [NCT00375674] of sunitinib [Sutent]—showed benefit.

Now, we have data emerging on adjuvant immunotherapy. The KEYNOTE-564 trial was the first of these adjuvant trials with immunotherapy to report out, looking at a year of adjuvant pembrolizumab after nephrectomy, which has shown a DFS benefit. No difference has been seen [in OS] yet, but OS benefit will likely take a number of years to potentially see. However, early readout of the DFS benefit led to the FDA approval of [adjuvant] pembrolizumab in high-risk patients following nephrectomy [in November 2021].

This [approval] has opened options for patients to consider whether to pursue adjuvant treatment. The uptake of pembrolizumab in the adjuvant setting has been vigorous. It is certainly something I discuss with my patients. It must be put into the context of the [current] absence of an OS benefit [though].

Bottomline, [adjuvant pembrolizumab] is an option, it’s FDA approved, and it’s something to discuss with high-risk patients after surgery.

Sarmad Sadeghi, MD, PhD, of Keck School of Medicine, USC Norris Comprehensive Cancer Center, discussed the frontline treatment in metastatic urothelial cancer. How might long-term follow-up data from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) influence clinical practice?

Dr Sadeghi gave a good overview of where we are with treating [patients with] advanced bladder cancer and highlighted JAVELIN Bladder 100 as a practice-changing, paradigm-changing trial for bladder cancer. Maintenance immunotherapy with avelumab [Bavencio] after response or stable disease to frontline chemotherapy has been shown to improve OS compared with best supportive care only after chemotherapy. Updated data from this study were presented at the 2023 Genitourinary Cancers Symposium that showed [the sustainability] of this OS benefit. That presentation showed an interesting breakdown for [patients given] cisplatin and gemcitabine [vs] carboplatin and gemcitabine as frontline chemotherapy in this trial, and both showed OS benefit with the addition of avelumab [maintenance].

Not unexpectedly, survival just comparing those [chemotherapy regimens] was longer both in the avelumab [arm] and the best supportive care arm for the cisplatin-containing vs the carboplatin-containing regimen, speaking to what’s been a debated concept for a number of years. That is whether cisplatin is better than carboplatin. However, this probably [has more to do with the] patients who get carboplatin, who tend to have other medical comorbidities. Overall, these data showed better outcomes for patients with cisplatin-based therapy vs carboplatin-based therapy.

However, the important take-home message is that [maintenance] avelumab improved OS, regardless of choice of [chemotherapy]. As these data continue to mature, if this OS benefit presumably continues to pan out with the tail on the curve, it will continue to emphasize the importance of considering maintenance immunotherapy after chemotherapy for patients with metastatic bladder cancer.

Alexandra Sokolova, MD, of Oregon Health & Science University, discussed genetic testing and PARP inhibitors in prostate cancer. How has the advent of PARP inhibitors in this space confirmed the importance of genetic testing to determine optimal treatment strategies?

Dr Sokolova is a prostate cancer specialist, and her research focuses on genetic determinants of prostate cancer risk. She gave an overview of the importance of germline testing in patients with localized high- and very high–risk disease in node-positive prostate cancer, as well as metastatic castrate-sensitive and castrate-resistant prostate cancer.

The reason this germline testing is important is because we now have effective targeted treatments with PARP inhibitors for patients who harbor variations in the DNA damage repair genes. These [PARP inhibitors] include olaparib [Lynparza] and rucaparib [Rubraca]. [These are] agents that have shown improvements in radiographic progression-free survival [rPFS] in men who harbor mutations in homologous recombination repair genes.

Having these treatments has made an impact on the field, [because they] are applicable to approximately 20% of men with advanced prostate cancer who harbor one of these mutations. Dr Sokolova reviewed data that were presented at the 2023 Genitourinary Cancers Symposium regarding some of these agents.

For example, the [phase 3] TRITON3 trial [NCT02975934] evaluated rucaparib vs physician’s choice of docetaxel or a second-generation androgen receptor [AR] pathway inhibitor in patients who had received 1 prior AR pathway inhibitor. [This trial] showed a benefit in rPFS, especially in patients who harbor BRCA mutations as opposed to ATM mutations.

Knowledge of the potential genetic determinants that are driving an individual’s prostate cancer is increasingly important. Specifically whether a man harbors one of these germline mutations and what type. Now we can get more specific in choosing therapies that are going to be personalized for [an individual’s] cancer treatment.

Jen-Jane Liu, MD, of Oregon Health & Science University, discussed prostate-specific membrane antigen (PSMA)–PET in early-stage prostate cancer. What are some of the benefits of using PSMA-PET in the localized disease setting?

Dr Liu gave a nice review from the urologist perspective of the technology of PSMA-PET imaging and how that can be used in managing patients with localized prostate cancer. In patients with high-risk, localized prostate cancer, she reviewed the data regarding the imaging and its improved sensitivity and specificity compared with conventional imaging.

[Dr Liu discussed] how this can help, for example, look for limited oligometastatic disease. We know from data that have emerged in recent years that even for patients with limited oligometastatic disease, treatment of the primary tumor may still be indicated. For patients with oligometastatic disease, there’s still utility in treating the primary tumor and potentially targeting these limited sites of metastatic disease, for example, by lymph node dissection or targeted radiation therapy.

Additionally, if widely metastatic disease is detected by this sensitive imaging, that might affect decision making for the utility of local therapy and [prompt] a decision against surgery of the primary tumor. Data are emerging about whether a lymph node dissection could be omitted for patient management, depending on the results of this testing. That’s an evolving topic with multiple factors that can play into a model of predicting uninvolved lymph nodes.

Ultimately, PSMA-PET imaging is helping to visualize what was not able to be visualized before in terms of micro-metastatic disease. Technology is helping us think about how to individualize a treatment plan for a patient based on what’s discovered with this sensitive imaging modality. It’s a rapidly changing field. As experience and data continue to come in, we’re going to see improved options and better outcomes for men facing a diagnosis of prostate cancer.

How have these advances across the GU cancer landscape affected the treatment of patients with these malignancies?

GU oncology continues to be an exploding field in terms of new treatments, new imaging modalities, and new definitions of subsets of cancers based on genetic predisposition and other factors [that help] subdivide our diseases. GU oncology is becoming increasingly complex in a good way.

Each of these diseases, such as prostate cancer, kidney cancer, and bladder cancer, is becoming increasingly nuanced. This is a good thing because it means that there are more therapies and more ways to individualize treatment for patients. The take-home message is there are a lot of data to stay on top of, [as] our treatment options are exploding for patients. An event such as the State of the Science Summit provides a helpful and high-level view of all the advances that we [have seen] in this field in recent years.

Are there are ongoing or planned research efforts at Oregon Health & Science University that you would like to highlight?

We are home to the group chair’s office of SWOG, which is one of the major National Cancer Institute’s supported cooperative groups. The GU committee is a very active committee within SWOG. Dr Sadeghi, who spoke at our program, is chairing one of those trials: [the phase 3] SWOG S1937 trial [NCT04579224], which is looking at pretreated bladder cancer and a combination of chemotherapy drugs. This is a randomized trial in pretreated metastatic bladder cancer of eribulin mesylate [Halaven] with or without gemcitabine vs physician’s choice of chemotherapy. It’s an important study, and I encourage others to be aware of this study and seek it out. This is based on promising data that Dr Sadeghi generated in a phase 2 study [NCT02178241] through the California Consortium.

In kidney cancer, the [phase 3] PROBE trial [NCT04510597] is looking at cytoreductive nephrectomy. [Its role] has been an ongoing debate in the field of RCC. Do we take out the primary tumor in the setting of metastatic disease? This procedure has waxed and waned in and out of favor based on changes in therapy and recent data. However, with the advent of our new checkpoint inhibitors, it remains an open question of whether removing the primary tumor in the setting of metastatic disease is a favorable strategy.

This trial is looking at patients with metastatic RCC [and] treating [them] with induction of standard combination immunotherapy for several months, and then [randomly assigning] patients who have stable disease or a response to either surgery to remove the primary tumor or not, followed by continued immunotherapy. It’s a very important and practical question that faces the field. This is something that’s open around the country, and I would urge others to seek that trial out for their patients.