GU ASCO 2019
Encapsulating Highlights Through the Lens of a Key Opinion Leader With Insights, Forecasts and Take Home Messages
Nicholas J. Vogelzang, MD, FASCO, FACP, medical oncologist with Comprehensive Cancer Centers of Nevada (CCCN). He serves as Associate Chair of the Genitourinary Committee for US Oncology Research. The author and co-author of hundreds of peer-reviewed articles in the oncology literature, he serves as Vice Chair of GU Committee SWOG, a worldwide network of researchers that design and conduct cancer clinical trials. Dr Vogelzang is also Clinical Professor of Medicine at University of Nevada School of Medicine as well as Clinical Professor at UNLV School of Medicine, Las Vegas, Nevada.
This is GU ASCO 2.0, a fresh, intuitive, yet evidence-based analysis. In this wide ranging interview, Dr Vogelzang drills beyond the data to build a translational framework for inter-preting results presented at GU ASCO as he highlights the potential impact of emerging results on clinical practice during this interview with the Kidney Cancer Journal.
Q: Comparing this year’s meeting of GU ASCO to several years of similar scientific sessions, what impressions did you come away with this year? In your analysis last year for the Kidney Cancer Journal you did not see any major shift in the treatment paradigm. Was this year different?
Dr Vogelzang: Yes, I thought it was a very exciting time in contrast to earlier years. The fact that avelumab/ axitinib and the pembrolizumab/axitinib studies were presented and that the nivolumab/ipilimumab (nivo-ipi) combination was updated made for a lot of hallway and backroom discussion. We have all been looking for a bit of advantage of one regimen over another and what we would do in the ‘real world.’ When my colleagues and I met at seminars with representatives from three major companies, Eisai, Merck and Pfizer, they expressed excitement as well.
Q: How would you characterize the obstacles that still need to be overcome in clinical trials?
Dr Vogelzang: The crux of the matter is that we do not have cross-trial comparisons. We have four dual agent trials all of which were superior to the standard agent sunitinib given on the 4/2 schedule—pembrolizumab/ axitinib, avelumab/axitinib, atezolizumab/bevacizumab and nivo-ipi. If one compares them in a table format by patient characteristics, primary and secondary end points, there are multiple imbalances.
Q: If the comparisons are difficult to equate, what strikes you from a clinical standpoint as most dramatic?
Dr Vogelzang: The bottom line on this is that avelumab/ axitinib and atezolizumab/bevacizumab did not hit (yet) the overall survival endpoint. They hit PFS which is by every account an FDA approvable endpoint. On the other hand, pembrolizumab/axitinib not only hit PFS but also hit an OS endpoint, which is wonderful since the RCC research community does not ordinarily achieve OS. Now, when you look at nivo-ipi, it initially hit overall survival in the intermediate and poor risk subgroups of patients. Data presented at GU ASCO provided some evidence for utilizing nivo-ipi in good risk patients as well, because of increased number of complete responses compared with sunitinib, and the durability of those complete responses. In his presentation and based on these updated results from CheckMate 214, Nizar Tannir recommended that nivo-ipi may be used for all patients with mRCC, regardless of risk classification. Dr Tannir indicated that OS was equivalent but that there were more CRs in the nivo-ipi group vs sunitinib. What is the upshot of the 2019 studies? It seems that pem-brolizumab/axitinib and nivo/ipi are the top 2 regimens of choice because of their improvement in OS. Avelumab/axitinib and atezolizumab/bevacizumab are strong contenders because of their excellent tolerability and PFS advantage. If they show a survival advantage with future follow-up they will be considered equal to the other regimens.
Q: It seems that we have gone far beyond the earlier treatment algorithms that to a large degree dictated therapeutic choices. It’s a far more complicated calculus now. Can you delve a bit further into the relative merits of PFS and OS with relation to patient subgroups and the benefit of these therapies based on prognostic risk factors? Isn’t PFS considered a surrogate marker for OS?
Dr Vogelzang: Yes, PFS is considered a surrogate for OS and that’s what is sort of ironic. When the bar gets raised as it has been lately, you start going beyond PFS per se to consider factors such as the overall survival advantage for nivo-ipi in pre-specified subgroups. In that context, and bringing in data from the other studies, it looks like pembrolizumab/axitinib had an OS advantage in all three subgroups—favorable, intermediate and poor risk. The intermediate risk group is the big category by percent and none of the three studies subdivided the intermediates into intermediate-favorable and intermediate-unfavor-able risk. The Italian group Iacovelli et al (Clin Genitourinary Cancer 2018 Oct 16(5) 355-359) reporting on 846 patients, showed striking differences in the survival of intermediate-favorable patients (one risk factor =34 mos OS),real-intermediate (2 risk factors= 20 mos OS) and poor-intermediate (> 2 risk factors = 9 mos OS). This was first proposed by Sella et al (CGC 2017), and thus seems to be an important refinement of the MSKCC and IMDC risk groups. However, the studies did use retrospective analyses of sunitinib and pazopanib trials, not immuno-therapy trials. Thus, if the studies are imbalanced in regards to these subgroups, differences in outcomes could be expected.
Q: In looking at the pivotal studies presented at GU ASCO, to what extent do various discrepancies in patient characteristics among the trials tend to skew the results and what’s the impact, if any?
Dr Vogelzang: When you review the results of the three studies, we cannot really explain these differences because the studies did not subdivide the intermediate risk groups. All the studies were well balanced, large studies, but to some extent it depends on where the studies obtained the patients. In the US, patients generally present earlier than patients in Eastern Europe and Russia and may have fewer poor risk features. Also there is likely to be more third-line and fourth line treatments which may impact OS
Q. So what was the impact of GU ASCO on your practice? When you returned to your office and the next metastatic RCC patient walks in the door, what’s your plan?
Dr Vogelzang: At various roundtables held outside the symposia’s agenda for attendees, I made the point and others tended to agree that nivo-ipi is readily available and has a survival advantage for all three of the risk groups—good, intermediate, and poor risk, based on CheckMate 214. If you then look at avelumab/axitinib which did not yet have that advantage and which is still pending FDA approval, we all started looking at the side effect profiles. Avelumab/axitinib, for example, had fewer side effects than nivo-ipi which in turn appeared to have fewer side effects than pembrolizumab/axitinib.
Q: But don’t you need to tolerate the side effects to obtain benefit?
Dr Vogelzang: Yes, maybe, but for the good risk patients, I’m not sure we need to have side effects because patients do reasonably well with a TKI. Remember, sunitinib and pazopanib are still very good drugs for good-risk patients.
Q: If a community oncologist asked you for a summary of sorts, what take-home messages would you suggest? And what are the key factors to be mindful of as you define and refine your strategies?
Dr Vogelzang: For my good risk and favorable intermediate patients I’m probably going to use the VEGF inhibitor axitinib upfront with either pembrolizumab or avelumab. A lot of it depends on what drugs are covered by what health plan. For the unfavorable-intermediate group and for the poor risk group I’m going to use nivo-ipi. So there is this refinement in my thinking going on. If you think about the biology of this disease, perhaps the patients with the bad genetics (BAP deletions) or more significant mutational burdens, will probably need a bigger immunological hit, therefore, nivo-ipi. Those patients with small deletions in 3p, and VEGF driven, will probably do extremely well with axitinib and a checkpoint inhibitor.
Q: A poster at GU ASCO examined the use of nivo-ipi after nivolumab alone. Is there likely to be an advantage in that subset?
Dr Vogelzang: There were definite responses there, and it suggests that the combo of nivo-ipi has some advantages over nivo alone. I am not sure how much of an advantage but there is some benefit there. However, toxicities are higher with nivo-ipi. Nevertheless, the duration of response may be better with the combination compared to nivo alone. That comparative study should be done.
Q: Let’s return to the issue of prognostic factors and how to more effectively drill down and integrate them into decision making with all these combinations available. What do you foresee happening in this regard?
Dr Vogelzang: Ultimately we will get a prognostic signature. The prognostic signature will be, how good is good and how poor is poor? On this spectrum from very good to very poor we will need to position our therapeutic agents. I always tell my colleagues, you have no idea who is going to walk in the door the next day. When you see these patients, they are ‘disasters’ from a clinical perspective. In these cases, it should probably be a decision to give these patients nivo-ipi. But you may not want to wait long enough to get the insurance approval. You may want to start them on a TKI immediately, just to put out the fire in these patients. This is where the cancer is just blowing up.
Q: Which TKI?
Dr Vogelzang: Based on what I’ve seen, I usually try to get axitinib or cabozantinib, but remember, axitinib by itself does not have first-line indication. I’ll need to put in the order for axitinib/avelumab or axitinib/pembrolizumab and hopefully not wait too long to get the drugs approved. Every insurance company makes you wait three days for no good reason. So ultimately, the decision often comes down to mundane, nitty gritty details, like, how long is it going to take to get these drugs approved? What are the underlying immunological side effects? Are you comfortable giving nivo-ipi to someone with possibly underlying autoimmune disease? There’s a certain granular aspect to the process of making these choices and I literally do not always know the obvious thing to do. For financially challenged people, the co-pays are important. I will write a prescription for one of the high-cost drugs and I’ll tell the patient, “I hope you get it in two weeks.” That may be fine for a good risk patient but in poor risk patients I don’t want to wait two weeks where the average survival is eight months. I want those patients to start on the drug tomorrow.
Q: Let’s touch upon second-line therapy. What guidelines can you offer there?
Dr Vogelzang: In the second line we’re looking at a lot of cabozantinib use. It’s the go-to drug for a patient who progresses through nivo-ipi. In the last four months I have had three patients with no response to nivo-ipi. One of the patients is already dead—died in less than four months. We’re not curing these poor-risk patients. If the patient rapidly progresses on nivo-ipi, I’ll give them cabozantinib. And even cabozantinib, although a great drug, will have an uphill battle to delay cancer progression. Here’s another case: one of my poor-risk patients is an architect but his disease progressed rapidly through nivo-ipi. When I put him on cabozantinib, he had a 3 cm neck node. It has decreased to about 1.5 cm. It’s still there and feel it every time I see him. He has a big primary intact, lots of nodal disease and lung metastases. If cabozantinib fails, I will use lenvatinib/everolimus next. My current sequence tends to be nivo-ipi, second line cabozantinib, and third line lenvatinib/everolimus.
Q: Among the abstracts attracting interest was the TIVO-3 study involving tivozanib. Do you find this intriguing despite the troubled history of the drug in seeking FDA approval?
Dr Vogelzang: It’s a wonderful drug. The latest results are positive but unfortunately the FDA has withheld approval because of the initial trial where there was inequality in survival due to differential use of second line therapy. It is ironic that it has been approved in Europe. Tivozanib is like other high-potency anti-VEGF agents, lenvatinib and axitinib and would be expected to combine well with immune check point inhibitors.
Q: You have shared your excitement about the new combinations and as we look toward future directions, what is the most pressing need to be addressed by studies before the next GU ASCO meeting?
Dr Vogelzang: It’s an exciting time with improvements in PFS and OS but we still are not able the cure the vast majority of patients with metastatic RCC. The next steps are to compare these various regimens (likely in the co-operative groups), focus on the poor risk patients where progress can be quickly measured and work on 3 drug regimens such as nivo/ipi/cabozantinib or nivo/ipi/axitinib.
Selected Key Abstracts from the GU ASCO Kidney Cancer Meeting
[Editor’s note: abstracts presented here are in abbreviated form. For the full abstracts, please visit the following link: https://meetinglibrary.asco.org/session/11665]
Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab (N+I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). Nizar M. Tannir, Osvaldo Arén Frontera, Hans J. Hammers et al.
Background: N+I showed superior OS v S in ITT (IMDC any risk) and intermediate/poor-risk (I/P) pts with aRCC in CheckMate 214 at 17.5 mo min follow-up.
Methods: Pts with clear cell aRCC were randomized 1:1 to N3 mg/kg + I1 mg/kg Q3W×4 and then N3 mg/kg Q2W, or S 50 mg daily for 4 wk on, 2 wk off. Co-primary endpoints were OS, RECISTv1.1 ORR and PFS per IRRC in I/P pts. PFS and ORR were assessed by investigator (inv) at 30 mo.
Results: At 30 mo min follow-up, OS remains significantly improved in ITT and I/P pts with N+I v S; the HR for OS in favorable (fav) risk pts has improved for N+I v the previous analysis (1.22 [95% CI 0.73–2.04] v 1.45 [99.8% CI 0.51‒4.12]). Per previous IRRC ORR (N+I, 42% [95% CI 37‒47]; S, 27% [95% CI 22‒31]), ORR per inv was higher with N+I v S in ITT and I/P pts. ORR CIs overlapped in fav pts, CR was doubled with N+I v S. Increasing PFS benefit with N+I v S is emerging in ITT and I/P pts; PFS CIs between arms remain overlapping in fav pts. 15% v 9% of N+I and S ITT pts remain on therapy, and 48% v 61% have received 2nd-line systemic therapy; 39% of S pts received subsequent immune-checkpoint inhibitor therapy. Among pts who were alive with CR, 50% v 10% remain on treatment with N+I (n = 56) v S (n = 10). 5 N+I and 7 S additional pts developed Gr 3–4 drug-related AEs; 1 N+I and 3 S additional pts had AEs leading to discontinuation. No new drug-related deaths occurred.
Conclusions: At 30 mo min follow-up, OS and ORR remain improved with N+I v S in ITT and I/P CheckMate 214 pts. No new safety signals emerged with longer follow-up. Clinical trial information: NCT02231749
Results of a phase II study of atezolizumab and bevacizumab in non-clear cell renal cell carcinoma (nccRCC) and clear cell renal cell carcinoma with sarcomatoid differentiation (sccRCC). Rana R. McKay, Bradley Alexander McGregor, Kathryn Gray, et al
Background: The combination of atezolizumab and bevacizumab has demonstrated safety and efficacy in ccRCC. In this multicenter, phase II, open-label, single arm trial we evaluate the efficacy of atezolizumab and bevacizumab in patients with nccRCC and sccRCC with >20% sarcomatoid differentiation.
Methods: Eligible patients had an ECOG performance status of 0-2 and may have received prior therapy. Prior PD-1/PD-L1 therapy was not allowed. Patients underwent a mandatory baseline biopsy and subsequently received atezolizumab 120 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. Patients remained on therapy until radiographic progression, unacceptable adverse events, or withdrawal. The primary end point was overall response rate (ORR) as determined by RECIST version 1.1.
Results: 65 patients were enrolled of whom 52 had ≥1 response assessment and were included in this analysis. 36 patients had nccRCC (papillary n=14, chromophobe n=8, unclassified RCC n=3, collecting duct n=3, translocation n=3, other n=5), and 16 patients had sccRCC. 17 patients received prior systemic therapy, 16 of whom had nccRCC. The ORR was 31% in the overall cohort. 10 patients (19%) developed grade 3 treatment-related adverse events (AEs), half of which were immune-related. There were no grade 4-5 AEs.
Conclusions: In this study, we show that therapy with atezolizumab and bevacizumab was safe and demonstrated anti-tumor activity in nccRCC and sccRCC. Further analyses will report ORR by histologic subtype and PD-L1 expression status. Analysis of tissue and blood-based biomarkers of response are ongoing. Clinical trial information: NCT02724878
Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. Thomas Powles, Elizabeth R. Plimack, Viktor Stus, et al.
Background: A phase 1b study of pembro (anti–PD-1) plus axi (VEGFR-TKI) showed promising antitumor activity and manageable safety in patients (pts) with previously untreated mRCC. The global, open-label, phase 3 KEYNOTE-426 study assessed the efficacy and safety of pembro + axi vs sunitinib as first-line therapy for mRCC (NCT02853331).
Methods: Eligible pts with clear-cell mRCC, no previous systemic therapy for mRCC, and KPS ≥70% were randomized 1:1 to pembro 200 mg IV Q3W for a maximum of 35 cycles plus axi 5 mg orally BID or sunitinib 50 mg orally QD (4-wk on/2-wk off schedule). Treatment was given until PD, intolerable toxicity, or pt/investigator decision. Randomization was stratified by IMDC risk group and geographic region. Primary end-points were OS and PFS (RECIST v1.1 by blinded, independent central review [BICR]). ORR was the key secondary endpoint. At the protocol-specified first interim analysis, the superiority thresholds were P = 0.0001 for OS, 0.0013 for PFS, and 0.025 for ORR (if OS and PFS were significant).
Results: 861 pts were randomized: 432 to pembro + axi, 429 to sunitinib. After a 12.8-mo median follow-up, 59.0% of pts in the pembro + axi arm and 43.1% in the sunitinib arm remained on treatment. Pembro + axi significantly improved OS (HR 0.53 [95% CI 0.38-0.74]; P< 0.0001; 12-mo rate 89.9% vs 78.3%), PFS (HR 0.69 [95% CI 0.57-0.84]; P = 0.0001; median 15.1 vs 11.1 mo), and ORR (59.3% vs 35.7%; P< 0.0001). Duration of response was prolonged with pembro + axi (median not reached vs 15.2 mo). The pembro + axi benefit was observed in all subgroups tested, including all IMDC risk and PD-L1 expression subgroups. Treatment-related AEs were grade 3-5 in 62.9% of pts in the pembro + axi arm vs 58.1% in the sunitinib arm and led to regimen discontinuation in 6.3% vs 10.1%.
Conclusions: Pembrolizumab + axitinib provided super-ior OS, PFS, and ORR compared with sunitinib and had manageable safety in pts with previously untreated, advanced or metastatic clear-cell RCC. These data suggest that pembrolizumab + axitinib should be a new standard of care for this population. Clinical trial information: NCT02853331
Subgroup analysis from JAVELIN Renal 101: Outcomes for avelumab plus axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Toni K. Choueiri, Robert J. Motzer, Matthew T. Campbell, et al.
Background: In the ongoing phase 3 JAVELIN Renal 101 trial, progression-free survival (PFS) was longer (median, 13.8 vs 8.4 mo; hazard ratio, 0.69; p=0.0001) and the objective response rate (ORR) was higher (51% vs 26%) with A + Ax vs S in patients with previously untreated aRCC. Here we report outcomes from an analysis of several pre-specified subgroups.
Methods: Patients were randomized 1:1 to receive A (10 mg/kg) IV every 2 weeks + Ax (5 mg) PO twice daily or S (50 mg) PO once daily for 4 wk (6-wk cycle). Primary and key secondary endpoints were PFS per independent review committee (IRC; RECIST v1.1) and OS in patients with PD-L1+ tumors (≥1% of immune cells) and in patients irrespective of PD-L1 expression; other secondary endpoints included OR per IRC (RECIST v1.1).
Results: A total of 886 patients were randomized; 560 (63%) had PD-L1+ tumors. At data cut-off (Jun 2018), median follow-up was 12.0 vs 11.5 mo for A + Ax vs S groups.
Conclusions: A + Ax demonstrated PFS and OR benefit across all prognostic risk groups and PD-L1 subgroups vs S in aRCC. Clinical trial information: NCT02684006
A phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO). Thomas Powles, James M. G. Larkin, Poulam Patel, et al
Methods: This single arm phase I/II trial explored durvalumab and savolitinib at starting doses of 1500mg Q4W and 600mg OD respectively, with a 4wk savolitinib run-in. Treatment naïve or previously treated patients with metastatic PRC were included. Response rate (RR) (RECIST v1.1) was the primary endpoint. Progression free survival (PFS), tolerability (CTCAE v4) and overall survival were secondary endpoints.
Results: Dose escalation work identified a dose of durvalumab of 1500mg Q4W and savolitinib 600mg OD to take forward to phase II. Between Jan 2017 and Jul 2018, 42 patients were enrolled at this dose. 1 patient did not receive study treatment. The following analyses were performed on the remaining 41 patients. 12% of patients did not receive the combination (3 PD, 1 death, 1 PS deterioration). The median follow up was 8.9 months (95% CI: 6.9-10.9 months). IMDC good, intermediate and poor risk disease occurred in 29% (n=12), 63% (n=26), and 7% (n=3) patients respectively. Overall RR was 27% (11/41), while median PFS was 3.3 months (95% CI: 1.5-NR months). RR and median PFS in the previously untreated cohort (N=28) were 29% (8/28) and 12.0 months (95% CI: 1.5-NR months) respectively. Grade 3/4 toxicity occurred in 15 patients.
Conclusions: The combination of savolitinib and durvalumab appears safe and associated with clinical activity in PRC. Clinical trial information: NCT02819596. KCJ