Maintenance Therapy, Adjuvant and Escalated Approaches Garner Excitement in GU Cancers

Petros Grivas, MD, PhD

Efforts to move beyond chemotherapy alone for patients with advanced urothelial cancer, shift effective treatments into the curative setting in renal cell carcinoma (RCC), and effectively escalate treatment for patients with high-risk and high-volume prostate cancer have been successfully met, explained Petros Grivas, MD, PhD, in an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on genitourinary malignancies.

However, there is much to be explored, Grivas added, including but not limited to immunotherapy-based combinations, biomarkers of response, and treatment sequencing.

In the interview, Grivas, co-chair of the event, and physician at the Seattle Cancer Care Alliance; associate professor in the Department of Medicine in the Division of Oncology and clinical director of the Genitourinary Cancers Program at the University of Washington School of Medicine; and associate member of the Clinical Research Division at Fred Hutchinson Cancer Center, discussed the key takeaways from the virtual meeting. The event covered the effects of recent and emerging research on current standards of care in the treatment of patients with metastatic urothelial cancer and RCC.

OncLive^®: How would you define attempts to improve upon outcomes with platinum-based chemotherapy for patients with newly diagnosed metastatic urothelial cancer?

Grivas: The field is evolving very fast, and there have been attempts to improve upon chemotherapy alone in the frontline setting for patients with advanced urothelial cancer. Cisplatin-based chemotherapy has produced great results. However, we want to improve upon them. The response rate with gemcitabine and cisplatin is about 55%, and the response rate with carboplatin and gemcitabine is about 40% to 45%. However, the durability of that response is not usually that long. The median progression-free survival [PFS], historically, has been between 7 and 8 months. Overall survival [OS], historically, was about 15 months, so there is a need to improve upon those outcomes.

In recent years, several studies have looked at different approaches, [such as] combinations of chemotherapy plus immunotherapy. [However,] the IMvigor130 trial [NCT02807636] with chemotherapy plus atezolizumab [Tecentriq] and the KEYNOTE-361 trial [NCT02853305] with chemotherapy plus pembrolizumab [Keytruda] have not shown what we had expected. We have not seen a significant OS benefit by combining chemotherapy with checkpoint inhibition.

We did have 2 switch maintenance trials from chemotherapy to a checkpoint inhibitor in patients who had achieved a response or stable disease to platinum-based chemotherapy. The first trial was led by Matthew Galsky, MD, of Mount Sinai and looked at pembrolizumab compared with placebo with a crossover design. This was a small phase 2 trial of about 107 patients that showed significant a PFS benefit but no OS benefit. There was a signal that maintenance therapy might be the way to go but [that trial] did not change practice because the OS was not prolonged.

That brought us to the JAVELIN Bladder 100 trial [NCT02603432] that we published in the New England Journal of Medicine in September 2020, and we presented with Thomas Powles, MBBS, MRCP, MD, of the Barts Cancer Centre, at the 2020 ASCO Virtual Scientific Program in the plenary session. This trial was designed such that patients with a response or stable disease after gemcitabine plus cisplatin or gemcitabine plus carboplatin were randomized to avelumab [Bavencio], a PD-L1 inhibitor plus best supportive care vs best supportive care alone. The avelumab arm had a significant prolongation in OS, with a hazard ratio of 0.69 in all-comers regardless of PD-L1 expression, and the median OS was significantly prolonged. The median OS difference was more than 7 months, favoring avelumab. The PFS benefit was also significant regardless of PD-L1 expression, favoring avelumab, and the benefit was seen across the board in different subsets of patients based on the treatment by subgroup interaction test that we did.

Some subsets benefitted more than others, but across the board the benefit was notable, and this changed practice. Now, after platinum-based induction chemotherapy, those with a response or stable disease [receive] switch maintenance avelumab. [Preferably, patients should receive] cisplatin-based [chemotherapy], [but] if they can’t get cisplatin, many of us use carboplatin/gemcitabine followed by avelumab maintenance.

There is also significant discussions about the role of checkpoint inhibitors in the frontline setting. Atezolizumab and pembrolizumab have a role there. Atezolizumab, based on the FDA label, has an indication for patients who are not fit for cisplatin, but they have to have PD-L1–high tumors, as well as for patients who are not fit for platinum chemotherapy. Pembrolizumab has now a more restricted label based on the recent FDA update. Pembrolizumab in the frontline setting has approval for patients who are unfit for any platinum. That update of the FDA label was based on the recent results from the IMvigor130 and KEYNOTE-361 trials that evaluated chemotherapy plus atezolizumab vs chemotherapy and atezolizumab vs chemotherapy and chemotherapy/pembrolizumab vs chemotherapy and pembrolizumab vs chemotherapy.

In the DANUBE trial [NCT02516241], the combination of durvalumab [Imfinzi] and tremelimumab did not beat chemotherapy yet and durvalumab alone was not superior to chemotherapy in PD-L1–high patients, but efforts continue. We have now phase 3 trials looking at chemotherapy vs chemotherapy plus durvalumab/chemotherapy plus durvalumab/tremelimumab in the NILE trial [NCT03682068]. CheckMate-901 [NCT03036098] is also ongoing and is looking at ipilimumab [Yervoy]/nivolumab [Opdivo] vs chemotherapy and gemcitabine/cisplatin/nivolumab vs gemcitabine/cisplatin. There’s also the EV-302 trial [NCT04223856] with enfortumab vedotin-ejfv [Padcev]/pembrolizumab, which is a very promising combination vs chemotherapy. We’ll see in the future whether we may be able to move beyond chemotherapy, but for now, chemotherapy seems to hold its place with switch maintenance avelumab, showing the best data we have ever seen in the frontline space.

Sumanta Pal, MD

Sumanta Pal, MD, of City of Hope, and Neeraj Agarwal, MD, of Huntsman Cancer Institute, presented on the treatment landscape in metastatic RCC. How have treatment considerations been affected with the new combinations and agents available?

Drs Pal and Agarwal showed that we have now many options, I call them the embarrassment of riches, in the frontline setting of advanced clear cell RCC. For example, we have ipilimumab/nivolumab, pembrolizumab/axitinib [Inlyta], cabozantinib [Cabometyx]/nivolumab, and pembrolizumab/lenvatinib [Lenvima] for patients who can get immunotherapy.

For favorable-risk patients, Dr Pal favored a VEGF/TKI plus a checkpoint inhibitor, and he made some points about how he goes through decision making, taking into account efficacy, toxicity, level of evidence, quality of life, and patient-reported outcomes [PROs] data. One of his considerations in this setting was cabozantinib/nivolumab. In intermediate- and poor-risk disease, all 4 regimens have a potential role. He mentioned if, for example, someone gets cabozantinib/nivolumab, then you can think about a second-line therapy using lenvatinib or everolimus [Afinitor] or axitinib.

Dr Agarwal commented on subsequent-line therapy, which depends on what the first-line treatment was. Obviously, you want to change the agent. Patients who may potentially have a contraindication to immunotherapy [because of] active immune disease on steroids or immunosuppressive agents, you may start on a VEGF TKI alone. For example, Dr Agarwal gave different scenarios of what subsequent therapies may look like depending on the patient characteristics, their comorbidities, efficacy, safety, level of evidence, and, of course, prior therapies.

The other point that Dr. Pal mentioned in the frontline setting was that if someone is potentially getting nephrectomy and has intermediate- or poor-risk disease, they could start with ipilimumab/nivolumab in that case to have less complications with a VEGF TKI.

The role for nephrectomy, of course, is under debate and depends on the patient’s risk factors. The CARMENA trial [NCT00930033] was based on the VEGF TKI/sunitinib [Sutent] era. A new SWOG trial called PROBE [NCT04510597] is looking at whether there’s a role for nephrectomy in patients starting immunotherapy, so we’ll have more data about this question in the future.

Overall, we see a lot of options. The field of biomarkers is lagging in urothelial and kidney cancer, and that’s an area of opportunity. How can you use biomarkers in the future to help select your patients for initial and subsequent therapies vs clinical criteria, the IMDC [International Metastatic RCC Database Consortium] criteria, and patient and disease characteristics, [which are used currently].

The other interesting [topic that was presented were] the data Toni Choueiri, MD, of Dana-Farber Cancer Institute and colleagues [presented] from KEYNOTE-564 [NCT03142334] in the adjuvant setting. If someone gets adjuvant pembrolizumab: How does that impact the disease and treatment landscape in the metastatic setting?

The same question regards the potential use of adjuvant nivolumab in urothelial cancer. If someone gets adjuvant nivolumab: How does that impact future therapy? These are open questions. We need to fill these data gaps in kidney cancer and in urothelial cancer.

There was some discussion by Dr Agarwal regarding newly approved agents like tivozanib [Fotivda] and the HIF inhibitor, belzutifan [Welireg], which is being evaluated in clinical trials and has an approval in von Hippel-Lindau disease. The present is very exciting, and the future will be more exciting and promising. Hopefully, we’ll keep improving the outcomes of patients.

Which data sets from the 2021 ESMO Congress caught your eye this year?

In urothelial cancer, the VESPER trial [NCT01812369] in the neoadjuvant setting was very interesting. Six cycles of dose-dense MVAC vs 4 cycles of gemcitabine/cisplatin appears to cause a benefit in disease-free survival and OS. However, there is some question about the dosing of MVAC in that regimen as well as the number of cycles. My personal practice has been if I feel comfortable, I favor dose-dense MVAC plus growth factor every 2 weeks, but I use 4 cycles as a neoadjuvant therapy before radical surgery.

Another interesting dataset came from the NORSE trial [NCT03473743], which was led by Dr Powles and evaluated erdafitinib [Balversa] plus cetrelimab in metastatic urothelial cancer. This work was done in the first line in cisplatin-unfit patients and showed a very promising response rate of 68% with the combination compared with 33% with erdafitinib alone. However, this was a small sample size, so we need a larger data set.

For the NORSE trial with cetrelimab and erdafitinib and the FORT-2 trial [NCT03473756] by Jonathan Rosenberg, MD, of Memorial Sloan Kettering Cancer Center, with atezolizumab/rogaratinib is that there is enough rationale and background to do a phase 3 trial looking at an FGF receptor inhibitor plus a checkpoint inhibitor, but for now, these combinations remain experimental.

In kidney cancer, we also saw very interesting data. Dr Choueiri showed some interesting data with PROs, which are a very important end point in the adjuvant KEYNOTE-564 trial. We also saw some data on intermittent dosing of TKIs that may be potentially less toxic with equal efficacy in the frontline setting. We saw some data with an alternative dose of ipilimumab to mitigate toxicity and Brian Rini, MD, of Cleveland Clinic, gave a nice discussion commenting on such dosing of ipilimumab/nivolumab and considerations [that should be made].

In prostate cancer, we saw practice-changing data from the STAMPEDE trial [NCT00268476]. Patients with high-risk localized prostate cancer, until recently, were receiving ADT [androgen deprivation therapy] plus radiation or radical prostatectomy. ADT plus radiation is a treatment without further escalated therapy. Gerhardt Attard, MD, FRCP, PhD, of the University College London Cancer Institute, and colleagues showed that the addition of abiraterone acetate [Zytiga] improves outcomes in patients getting ADT plus radiation. In patients who do not get prostatectomy and they opt for ADT plus radiation, now abiraterone is a standard-of-care addition in that highest-risk localized prostate cancer population.

Karim Fizazi, MD, PhD, of Gustave Roussy, showed the data from PEACE-1 [NCT01957436] looking at high-volume and low-volume metastatic hormone sensitive prostate cancer and saw that the triplet of ADT plus abiraterone and docetaxel and prednisone was superior to ADT/docetaxel. The data was very clear for high-volume disease but was not as clear in low-volume disease. The trial was practice changing for [patients with] high-volume disease. If you embark on giving ADT plus docetaxel, now you [should] add abiraterone and prednisone [for patients with] high-volume disease. For [patients with] low-volume [disease], this is not clear. You have to look at longer follow-up with more events to see what happens. It’s a debate there. I will probably stick with ADT/abiraterone/prednisone for low-volume disease for now, but other people can debate that, and for high-volume disease, I will probably go for the triplet.

However, the PEACE-1 trial did not answer the question: Is docetaxel adding value to ADT/abiraterone/prednisone? Instead, it tells us that abiraterone adds value to ADT/docetaxel.