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Key Studies in Genitourinary Cancers: Independent Conference Coverage of the 2020 ASCO Virtual Scientific Meeting

Daniel P. Petrylak, MD
Elizabeth R. Plimack, MD, MS
Released: September 1, 2020

Renal Cell Carcinoma

KEYNOTE-426: Study Design

Elizabeth R. Plimack, MD, MS:
The KEYNOTE‑426 study is a pivotal randomized, open-label phase III trial of patients with newly diagnosed or recurrent stage IV clear-cell RCC with measurable disease, and no previous systemic therapy for advanced disease (Capsule Summary).[1] The trial randomized 861 patients to receive pembrolizumab plus axitinib or sunitinib as the standard-of-care control arm. Results from the first interim analysis were published in 2019, at which point the study met its primary endpoint of extended OS and PFS with the combination regimen.[2] An updated analysis presented at the ASCO 2020 meeting provides information on the durability of those initial results. 

KEYNOTE-426: Subsequent Anticancer Therapy in Patients Who Discontinued Study Treatment

Elizabeth R. Plimack, MD, MS:
Of those who discontinued pembrolizumab plus axitinib, 55% received subsequent anticancer therapy compared with 69% of those who discontinued sunitinib.[1] It is important to note that there are multiple reasons why someone may not receive subsequent therapy. One is that they might need it but not have access to it through their healthcare system. Another is that they may be doing so well on their previous therapy that they don’t need subsequent therapy. A third reason is that they may decompensate after their initial therapy and not be well enough to receive subsequent therapy. It is therefore difficult to interpret data on subsequent therapy without knowing more about these factors.

KEYNOTE-426: Updated OS and PFS (ITT)

Elizabeth R. Plimack, MD, MS:
Updated OS and PFS data remained consistent with previous observations in the intention-to-treat (ITT) analysis that included patients in all risk groups.[1] The OS remained superior with pembrolizumab plus axitinib vs sunitinib (HR: 0.68; 95% CI: 0.55-0.85; P < .001), as did PFS (HR: 0.71; 95% CI: 0.60-0.84; P < .0001). The difference in OS was pronounced at the initial analysis, with an HR of 0.53, and the space between the curves has narrowed somewhat in the updated analysis. However, it is important not to discount the early improvement in survival seen with the combination regimen; that difference represents real patients who, even though they may not make it to the tail of the curve, gain additional survival time with pembrolizumab plus axitinib compared with sunitinib.

The data cutoff for the updated analysis stops at 24 months and the data become unstable beyond that point, so we have not yet seen the tail end of the survival curve. Twenty-four months is also the point at which patients stop pembrolizumab per protocol. So it will be interesting to see how these curves look at the next update 1 or 2 years from now.

KEYNOTE-426: Response (ITT)

Elizabeth R. Plimack, MD, MS:
The ORR in the ITT group was clearly superior with pembrolizumab plus axitinib (60.2% vs 39.9%; P < .0001).[1] As expected, some PRs became CRs over time, and thus the CR rate has improved to 8.8% in this analysis.

KEYNOTE-426: OS, PFS, and ORR in IMDC Favorable-Risk Group

Elizabeth R. Plimack, MD, MS:
There was no evidence of a divergence in OS curves among patients with International Metastatic RCC Database Consortium (IMDC) favorable-risk disease.[1] This may mean that pembrolizumab plus axitinib does not have a benefit over sunitinib in favorable-risk patients, but it is also possible that because these patients do so well in general, the follow-up is not yet long enough to show any survival difference between arms. That will be an important question for future analyses.

There was, however, a PFS benefit (HR: 0.76) and a clear ORR benefit with pembrolizumab plus axitinib (69.6%) in favorable-risk patients compared with sunitinib (50.4%). This may be the highest response rate we have seen in this patient population.

KEYNOTE-426: OS, PFS, and ORR in IMDC Intermediate-Risk/Poor-Risk Group

Elizabeth R. Plimack, MD, MS:
In clinical practice, most patients with RCC are in the IMDC intermediate-risk and poor‑risk categories; in this study, 68% to 69% of patients had intermediate-risk or poor-risk features.[1] These individuals are also the patients whose disease is the hardest to treat, and it was in this group that the OS benefit with the combination regimen really showed. At 2 years, 69% of patients receiving pembrolizumab plus axitinib were still alive compared with 56% of those receiving sunitinib (HR: 0.63) A similar benefit was also seen with regard to PFS (34% with pembrolizumab plus axitinib vs 23% with sunitinib; HR: 0.69).

KEYNOTE-426: OS by Depth of Response

Elizabeth R. Plimack, MD, MS:
One of the interesting things presented in this updated analysis was a post hoc analysis of the relationship between depth of response and OS.[1] For patients receiving pembrolizumab plus axitinib, the deeper the response—as measured by percent shrinkage of target lesions—the better the OS. This relationship was not seen as clearly in the sunitinib arm.

KEYNOTE-426: Treatment-Emergent Adverse Events of Incidence ≥ 20% in Either Arm

Elizabeth R. Plimack, MD, MS:
Treatment-emergent adverse events (TEAEs) were in line with the previous analysis.[1] The toxicity profiles of a VEGF inhibitor plus immune checkpoint inhibitor (ICI) regimen are similar to that of a VEGF inhibitor alone, with the addition of some IRAEs, and that is what was seen here. Overall rates of TEAEs, grade 3-5 TEAEs, and death were similar between the 2 arms.

Putting This Into Context―CheckMate 214 vs KEYNOTE-426: OS for Intermediate/Poor-Risk Disease

Elizabeth R. Plimack, MD, MS:
What are the implications of these data for clinical practice? KEYNOTE-426 is often discussed alongside another large phase III first‑line trial, CheckMate 214, which compared nivolumab plus ipilimumab vs sunitinib in RCC, and was updated at the 2020 ASCO GU meeting.[1,3] If we compare OS data for intermediate-risk and poor‑risk patients from the most recent analyses of both studies, outcomes in KEYNOTE‑426 appear to be a little bit better at 2 years, with the usual caveats regarding comparisons between trials. In both trials, the median OS of sunitinib was between 26 and 29 months. In the CheckMate 214 trial, the median OS for nivolumab plus ipilimumab was 47 months, whereas in the KEYNOTE-426 trial, the median OS was not yet reached. However, patients in CheckMate 214 have been followed  for longer and there appears to be a plateau at the tail end of the OS curve with nivolumab plus ipilimumab, which we do not yet see in KEYNOTE-426 at this point in follow-up.

CheckMate 214 vs KEYNOTE-426: Response Rate for IMDC Intermediate-Risk/Poor-Risk Disease

Elizabeth R. Plimack, MD, MS:
The ORR for intermediate-risk and poor-risk patients appears to be a little higher with pembrolizumab plus axitinib in KEYNOTE-426 (55%) than with nivolumab plus ipilimumab in CheckMate 214 (42%).[1,3] However, the percentage of patients who experienced primary progression, with tumor growth while on treatment, is more striking: 27% for nivolumab plus ipilimumab and approximately half that, 15%, for pembrolizumab plus axitinib. In clinical practice, for a patient who particularly needs a response due to rapidly progressing disease or to ameliorate symptoms, pembrolizumab plus axitinib appears to be the better choice compared with nivolumab plus ipilimumab, based on this cross-study comparison.

CheckMate 214 vs KEYNOTE-426: PFS for IMDC Intermediate-Risk/Poor-Risk Disease

Elizabeth R. Plimack, MD, MS:
Our goal for first-line therapy for our patients with RCC is to obtain long‑term, durable PFS and OS. In CheckMate 214, we see a pretty clear plateau in the PFS curve for nivolumab plus ipilimumab in intermediate-risk and poor-risk patients at approximately 30 months of follow-up.[3] With pembrolizumab plus axitinib in KEYNOTE-426, it is not quite clear yet if there is any plateau.[1] Again, KEYNOTE-426 patients have only been followed to 24 months in the most recent analysis, so we will be looking very closely again over the next few years to see if there is a plateau in survival in these groups.

Long-term Data From Phase Ib Study: Support for KEYNOTE-426

Elizabeth R. Plimack, MD, MS:
We do have some long‑term data for the pembrolizumab plus axitinib combination in untreated RCC from a phase Ib study, which were also presented at the ASCO 2020 meeting.[4] This study includes 52 treatment‑naive patients with advanced RCC who were treated with pembrolizumab plus axitinib, and have been followed for a median of almost 5 years. The median OS in the ITT population has not been reached; 73% of patients were still alive at this time point, and 29% were still on treatment. Those data provide a hint that we will see plateaus in PFS and OS with this combination, but we will need to wait for longer follow-up of KEYNOTE-426 to confirm that observation.

KEYNOTE-426: Clinical Implications

Daniel P. Petrylak, MD:
Clearly, PFS data inform our clinical practice, but I think we need to wait to see what happens with longer-term OS.

With these great data, I think the key issue is what therapy should be used in frontline treatment of RCC. Should clinicians choose nivolumab plus ipilimumab, which has its own disadvantages, or should they choose pembrolizumab plus axitinib, which requires careful monitoring for TKI-associated AEs, like hypertension and skin rashes. Each option has a different pattern of toxicities that needs different levels of attention, but both are equally exciting in terms of their efficacy.

Elizabeth R. Plimack, MD, MS:
I use pembrolizumab plus axitinib for most patients with untreated RCC because I think it has the best early data so far, which is important to me. Obviously, I want all my patients to do well, and early benefit is just as important to me, in some ways, as late benefit. So I rarely use nivolumab plus ipilimumab in the frontline setting at this point. As we have discussed, there are data showing the long‑term tail of the survival curve to support nivolumab plus ipilimumab as frontline therapy, but I am optimistic we will see a similar pattern with pembrolizumab plus axitinib, based on the phase I data, and there is certainly early disease control with the immuno-oncology (IO)/VEGF TKI combination.

Daniel P. Petrylak, MD:
I tend to select treatment based on both efficacy and toxicity patterns. For example, if a patient is hypertensive at baseline, or is not going to be easily monitored for hypertension, I tend to choose nivolumab plus ipilimumab. However, I would say my practice is probably about 8:2 in favor of pembrolizumab plus axitinib at this point.

Elizabeth R. Plimack, MD, MS:
I think the other point to make is that there are currently no data to support nivolumab plus ipilimumab in favorable-risk patients.[3] In this setting, We have yet to see evidence of an OS benefit with pembrolizumab plus axitinib compared with TKI‑based therapy. However, there is a benefit with both PFS and response, suggesting that pembrolizumab plus axitinib should be preferred over a single-agent TKI for patients with favorable-risk disease. In rare cases, such as a frail patient with favorable risk disease for whom immune-related toxicity would be a concern, treatment with a TKI alone could also be considered; however, for the most part, I recommend pembrolizumab plus axitinib to patients with favorable-risk RCC in my practice.

The Role of Nivolumab Plus Ipilimumab as Salvage/Rescue Therapy

Elizabeth R. Plimack, MD, MS:
A series of studies presented at the ASCO 2020 meeting investigated the use of nivolumab with or without ipilimumab as salvage therapy for RCC.

FRACTION-RCC is a phase II trial assessing nivolumab plus ipilimumab in patients with advanced RCC. At ASCO 2020, the investigators presented initial data from patients who received nivolumab plus ipilimumab after progression on previous ICI therapy (track 2). Two other trials presented at ASCO 2020—OMNIVORE and HCRN GU16-260—explored the efficacy of starting therapy with nivolumab and adding ipilimumab only for patients who do not achieve a CR or PR, with the goal of avoiding the additional toxicity with ipilimumab for patients who will respond to nivolumab alone. 

Nivolumab Plus Ipilimumab in RCC Progressing After ICI (FRACTION RCC): Study Design

Elizabeth R. Plimack, MD, MS:
The FRACTION‑RCC study is an ongoing international, open-label, randomized phase II trial of patients with histologically confirmed clear-cell advanced RCC. (Capsule Summary).[5] Here, we focus on patients in track 2 of the study, all of whom had received previous ICI therapy, and were randomized to receive treatment with nivolumab plus ipilimumab. The primary endpoints were investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, duration of response (DoR), and probability of PFS up to 24 weeks.

In this cohort of patients from the FRACTION-RCC trial, all patients had previously received an anti–PD-1 or anti–PD-L1 therapy and 41% had also received another immunotherapy. In addition, 80% had also received a TKI.

Nivolumab Plus Ipilimumab in RCC Progressing After ICI (FRACTION-RCC): Efficacy

Elizabeth R. Plimack, MD, MS:
The ORR with nivolumab plus ipilimumab in this trial was 15.2% (95% CI: 6.3% to 28.9%).[5] The disease control rate, which includes CR, PR, and stable disease (SD), was 52.2% (95% CI: 36.9% to 67.1%).

The waterfall plot on this slide shows the range and depth of response among patients receiving nivolumab/ipilimumab after progression on immunotherapy.[5]

In addition, the median PFS with nivolumab plus ipilimumab was 3.7 months (95% CI: 2.2-7.3) for the patients who had previously received ICI therapy. 

Nivolumab Plus Ipilimumab in RCC Progressing After ICI (FRACTION-RCC): TRAEs and Immune-Mediated AEs

Elizabeth R. Plimack, MD, MS:
Twenty-eight per cent of patients had grade 3/4 TRAEs with nivolumab plus ipilimumab, with the most common being diarrhea, increased amylase, rash, and fatigue.[5] Grade 3/4 TRAEs deemed to be immune-related included diarrhea/colitis (11%), rash (2%), and hepatitis (2%). Serious TRAEs occurred in 9%, and 7% of patients discontinued study therapy due to TRAEs.

Phase II HCRN GU16-260 Trial: Nivolumab With or Without Ipilimumab in Untreated RCC

Elizabeth R. Plimack, MD, MS:
The phase II HCRN GU16‑260 trial recruited 126 patients with untreated RCC to receive nivolumab for up to 96 weeks (Part A).[6] Patients with SD or progressive disease (PD) at 48 weeks were allocated to Part B of the study, where ipilimumab was added to  nivolumab for 4 cycles, followed by nivolumab maintenance therapy for 48 weeks. Thirty patients met the criteria for Part B.

The ORR among patients who remained on nivolumab alone was 31.7%, and 13.3% of patients who received salvage ipilimumab achieved a response (all PR). This is in line with the 15.2% ORR among patients who received nivolumab and ipilimumab after previous immunotherapy in FRACTION-RCC.[5]

Phase II OMNIVORE Trial: Nivo With or Without Ipilimumab in Untreated RCC or After Previous TKI Therapy in RCC

Elizabeth R. Plimack, MD, MS:
The OMNIVORE study was a phase II trial conducted in patients with RCC who were either untreated or previously treated, but had not received any previous ICI.[7] Patients received nivolumab and then stopped treatment if/when they achieved a CR or PR within 6 months, or ipilimumab was added to nivolumab for 2 cycles for patients experiencing SD or PD. Those who stopped treatment following CR/PR could also restart nivolumab if they progressed. The ORR with nivolumab alone was 14%, which is much lower than we have seen before. Very few patients—just 4%—had a response after adding ipilimumab.

Twelve patients stopped nivolumab following a CR or PR, and some of these remained in response. Of those 12 patients, 4 ultimately restarted treatment: 3 after PD and 1 while in PR. So, does this mean that nivolumab can be stopped after 6 months in responders? I think it is difficult to reach that conclusion based on these small numbers. If a patient really wants to stop therapy in these circumstances, I think it is reasonable to try because nivolumab can be restarted if needed, and there are other treatments for RCC after frontline nivolumab. 

The Role of Nivolumab Plus Ipilimumab as Salvage/Rescue Therapy: Conclusions

Elizabeth R. Plimack, MD, MS:
If we look at these 3 trials together, I think how we use nivolumab or nivolumab plus ipilimumab in the salvage setting depends on what we consider to be a benefit. The data from HCRN GU16-260 suggest that starting with nivolumab and then adding ipilimumab only in those patients who need it will preserve ORR.[6] In that study, 32% of patients responded to nivolumab alone, and an additional 13% responded when ipilimumab was added. That combined is 44% overall, which compares favorably with the 39% ORR observed with nivolumab plus ipilimumab when given together as first-line therapy in the CheckMate 214 study.[3] Looking only at ORR, then, I think we can achieve a similar result by starting with nivolumab and adding ipilimumab as by starting the 2 together. The CR rate in HCRN GU16-260 was 6%, which does seem a little lower than the 11% rate observed in Checkmate 214.[3,6] The addition of ipilimumab as salvage did not result in any additional CRs, so the long‑term effects on this approach are in question.

It is also difficult to say whether these strategies are comparable with regard to the impact on PFS and OS. Survival data were presented for all these studies, but the patient numbers were very small. I think most people choose nivolumab plus ipilimumab upfront to get that end-of-the-tail effect in PFS and OS, and we may not see this benefit if we start with nivolumab and add ipilimumab.

Overall, I think these data are really interesting and ask important questions, but do not change our practice, which is that if you are going to give nivolumab plus ipilimumab, it is probably best to give the combination upfront.

Daniel P. Petrylak, MD:
I agree. There is a small study in bladder cancer that reached similar conclusions; a 10% response rate when ipilimumab was added as salvage after starting with nivolumab alone.[8] So it appears that this is not the best approach.

SAVOIR: Study Design

Elizabeth R. Plimack, MD, MS:
The SAVOIR study is an open‑label, randomized phase III study conducted in patients with locally advanced or metastatic papillary RCC (PRCC) with no previous use of a MET inhibitor or sunitinib (Capsule Summary).[9,10] Papillary RCC is a subtype of RCC which is typically hard to treat, with a lower response rate to standard therapies than for clear‑cell RCC. The pivotal RCC phase III trials have focused on clear cell RCC and have not included patients with PRCC, so dedicated research looking at this non–clear‑cell subtype is critical, and the authors of SAVOIR should be commended for doing this study. Unfortunately, the study was stopped early by the sponsor after external data predicting no PFS difference with sunitinib in MET-driven vs MET-independent PRCC were reported.[11] Of a planned enrolment number of 180, SAVOIR randomized 60 patients with a confirmed MET-driven tumor to receive either the MET inhibitor, savolitinib, or sunitinib, which is the standard VEGF TKI currently recommended in the NCCN guidelines for untreated advanced PRCC. The conclusions that can be drawn from these data are therefore limited. 

SAVOIR: Survival

Elizabeth R. Plimack, MD, MS:
Use of savolitinib was associated with a numerical PFS (HR: 0.71; 95% CI: 0.37-1.36; P = .313) and OS (HR: 0.51; 95% CI: 0.21-1.17; P = .110) benefit, but these did not meet statistical significance because of the small patient numbers.[9,10] Had this study accrued the planned number of patients, we may have seen a statistical difference based on this trend, but it is difficult to say for certain. 

SAVOIR: Antitumor Activity

Elizabeth R. Plimack, MD, MS:
There appeared to more shrinkage of target lesions with savolitinib than with sunitinib, again based on small patient numbers.[9,10] In addition, the ORR was 27% with savolitinib vs 7% with sunitinib.

The ongoing phase II PAPMET intergroup trial was designed to compare cabozantinib, crizotinib, savolitinib, and sunitinib in patients with advanced PRCC.[12] The savolitinib and crizotinib arms were closed early for futility,[13] which indicates that in this 4‑arm trial, savolitinib did not show enough of a benefit vs sunitinib to warrant continuation. I think we will have to wait to see the results of the PAPMET trial, which has completed accrual and is undergoing analysis, to better understand whether savolitinib has a role in this setting.
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