Will the Pfizer / Merck KGaA Javelin Renal 101 trial go the distance in the face of heavy competition?

by Linda Zhao | Oct 22, 2018
Co-authored by Haris Vikis

While the 5-year survival rate for patients with locoregional renal cell carcinoma (RCC) is over 50%, many RCC patients with resectable disease will eventually progress to metastatic disease. In addition, about a third of RCC patients will present with de novo metastatic disease (2018 CancerMpact RCC US Report, Kantar Health).

Currently therapeutic options for metastatic RCC patients include a wide selection of targeted therapy agents, including two mTOR inhibitors ─ Afinitor® (everolimus, Novartis) and Torisel® (temsirolimus, Pfizer) ─ seven VEGF/VEGFR inhibitors ─ Avastin® (bevacizumab, Genentech / Roche / Chugai), Cabometyx® (cabozantinib, Exelixis / Ipsen), Inlyta® (Kisplyx® in Europe, axitinib, Pfizer), Lenvima® (lenvatinib, Eisai), Nexavar® (sorafenib, Amgen / Bayer), Sutent® (sunitinib, Pfizer), and Votrient® (pazopanib, Novartis). The latest additions are immune checkpoint inhibitors ─ Opdivo® (nivolumab, Bristol-Myers Squibb / Ono Pharmaceuticals) and Yervoy® (ipilimumab, BMS / Ono Pharmaceuticals).  With numerous treatments available it makes it possible for patients to receive multiple lines of therapy. However, even with these options, the outlook for advanced and metastatic RCC patients are quite poor with a 5-year survival rate of less than 10% (Ross, Clinical Science, 2017).

Historically, the median overall survival (mOS) for first-line patients treated with Sutent was slightly over two years (Motzer, N Engl J Med, 2013), but the recently approved immunotherapy combination regimen of Opdivo and Yervoy significantly raised the bar. The OS from the Opdivo and Yervoy combination in the CheckMate 214 study (NCT02231749) while having not been reached a median was significant (HR: 0.63, P<0.001) compared to Sutent in intermediate- and poor-risk patients (Motzer, N Engl J Med, 2018). The success of CheckMate 214 marked the entrance of immunotherapy into first-line treatment of advanced and metastatic RCC patients.

JAVELIN Renal 101 (NCT02684006) is global Phase III study investigating the combination of Bavencio® (avelumab, Pfizer / Merck KGaA), an anti-PD-L1 immunotherapy drug, with Inlyta, and compared to Sutent monotherapy as first-line treatment for advanced RCC. Bavencio is a human anti–PD-L1 IgG1 monoclonal antibody approved for the treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma for those who have progressed on platinum therapy. Inlyta is a VEGFR tyrosine kinase inhibitor (TKI) that is currently approved as a second line therapy for advanced RCC patients. Inlyta has shown to also exhibit immunomodulatory effects (Roland, PLoS One, 2009) and in the early phase JAVELIN Renal 100 study the combination of Inlyta with Bavencio exhibited an impressive 58% response rate (Choueiri TK, Lancet Oncol, 2018). 

On Sunday October 21, 2018, Dr. Robert Motzer from the Memorial Sloan Kettering Cancer Center (MSKCC) presented interim analysis data from JAVELIN Renal 101 at the Presidential Symposium of the 2018 ESMO conference in Munich, Germany (Motzer, LBA6-PR, ESMO 2018). Here, 886 treatment-naïve advanced / metastatic RCC patients with clear cell type were randomized 1:1 to receive Bavencio (N=442, 10 mg/kg, IV, every 2 weeks) plus Inlyta (5 mg PO BID) in a 6-week cycle or to receive Sutent (N= 444, 50 mg PO QD, schedule 4 weeks on / 2 weeks off).  Among these 886 patients, 560 patients are PD-L1 positive (63%), evenly distributed in both arms. The primary endpoints are PFS by RECIST v1.1 per independent review committee (IRC) in PD-L1 positive patients and OS in PD-L1 positive patients. Key secondary endpoints include PFS per IRC and OS in overall population.  The reported interim analysis by the IMDC was based on 253 PFS events.

The median PFS (mPFS) per IRC from the Bavencio plus Inlyta arm in PD-L1 positive patients was 13.8 months (N=270), which was significantly improved over the 7.2-month mPFS in the Sutent group (N=290; HR=0.61, P<0.0001). Similarly, the key secondary endpoint of PFS per IRC in the overall patient population was also met, with the mPFS from the Bavencio plus Inlyta arm at 13.8 months (N=442), compared to 8.4 months in the Sutent group (N=444; HR 0.69, P = 0.0001), suggesting efficacy is observed regardless of PD-L1 expression. Additionally, the PFS benefit favored the Bavencio plus Inlyta arm, whether patients had prior nephrectomy, and across risk status either by the IMDC or MSKCC risk criteria. The PFS results per investigator assessment matched well with the IRC assessment. In cross-trail comparisons the PFS observed in JAVELIN Renal 101 compares favorably to hazard ratios seen in Checkmate 214 (HR 0.82, intermediate-/poor-risk patients) and to Tecentriq plus Avastin (IMmotion151, HR 0.83, ITT; HR 0.74, PD-L1 positive) which was recently reported at ASCO GU (Motzer, Abs 578, ASCO GU 2018) with understanding that it can be difficult to reach conclusions based on such comparisons.

The confirmed objective response rates (ORR) per IRC from the Bavencio plus Inlyta arm were 55%, almost double that of the Sutent control arm (26%) in the PD-L1 positive patients, and the same trend was true in the overall population (51% versus 26%, Bavencio plus Inlyta versus Sutent). The complete response (CR) rate was largely similar (4% Bavencio plus Inlyta, 2% Sutent) in the PD-L1 positive group.  Again, similar ORR trends were observed per investigator assessment.  By the time of the interim analysis, 73% (108 out of 149 patients in the Bavencio plus Inlyta arm) with PD-L1 positive disease had ongoing responses. The OS data in the overall population were not mature in either arm, even though the OS curves started to separate with a HR ratio of 0.78 (P = 0.0679). Follow up of OS data will be closely monitored.

Surprisingly, treatment related Grade 3/4 AEs in the Bavencio plus Inlyta arm (51%) were similar to the Sutent arm (48%) with no new TRAEs observed, and no differences in discontinuation rate (4% versus 8%). The top Grade 3/4 TRAEs in the Bavencio plus Inlyta versus Sutent arms were hypertension (24% versus 15%), hand-foot syndrome (6% versus 4%), and diarrhea (5% versus 3%) and there were no unexpected immune-related AEs. This is very encouraging as early phase studies in RCC of other combinations including Keytruda plus Votrient (Chowdhury, J Clin Oncol, Abs 4506, ASCO 2017) and Opdivo plus Sutent or Votrient (Amin, J Clin Oncol, Abs 5010, 2014) yielded significant hepatic toxicities. Hence which TKI is chosen as the combination partner with an immunotherapy may influence the toxicity profile of the combination. Dr. Robert Motzer concluded that the Javelin Renal 101 trial results support Bavencio plus Inlyta to be a new standard of care for first-line treatment of advanced RCC patients. This is exciting for the strategy of combining immunotherapy and targeted therapy, after several setbacks with such combination strategy in early phase trials in RCC trials. 

The abstract discussant, Professor Viktor Grünwald from the West-German Cancer Center in Essen Germany, praised the high response rates observed in JAVELIN Renal 101, citing that the depth of response correlates well with better outcomes. Historically, first-line RCC patients are managed by TKI monotherapy, and the combination strategies revealed are very promising and practice changing.  However, what is the trade-off in using a combination regimen in first line compared to sequencing the two monotherapy agents? To answer this question, Dr. Grünwald argued that the OS benefit from the combination regimen needs to be compared to the combined OS benefit from sequencing an immunotherapy and targeted agent, and furthermore argued that quality of life (QoL) measures should also be a determinant.

JAVELIN Renal 101 is the first positive Phase III study combining an immune checkpoint blocker with a TKI compared to TKI alone in the first line treatment of advanced RCC. However, the excitement for the Bavencio plus Inlyta combination was dampened recently as the KEYNOTE-426 trial of Keytruda plus Inlyta reportedly met both PFS and OS primary endpoints as first-line treatment (Merck press release, October 18, 2018).  This puts into question which combination will get the FDA nod first.  But more importantly will Bavencio plus Inlyta now have to wait for mature OS to obtain a regulatory decision, since both KEYNOTE-426 has demonstrated OS benefit as has the recently approved Opdivo plus Yervoy combination in poor- and intermediate-risk patients?

Bavencio plus Inlyta will additionally need to compete with several other immunotherapy combinations in pivotal development including Keytruda plus Lenvima (Study 307), and Tecentriq plus Avastin (IMmotion151), the latter which recently reported a PFS benefit (Motzer, Abs 578, ASCO GU 2018), in addition to recent non-immunotherapy entrants to the first line market including Cabometyx. Nevertheless, Dr. Grünwald does believe that Bavencio plus Inlyta with carve a niche in favorable risk patients and with Breakthrough Therapy Designation by the FDA in hand, this should accelerate the approval process.  Still, other immunotherapy combinations might already be ahead of the curve, and ultimately the heated competition for first-line management of advanced RCC patients is a welcomed benefit to both physicians and patients.



  1. 2018 CancerMpact RCC US Report, Kantar Health
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