Avelumab is an anti-PDL1 immune checkpoint inhibitor that has demonstrated single-agent activity in aRCC and has been approved for other solid organ malignancies. Axitinib is a potent VEGF-receptor TKI that is approved as second-line treatment for aRCC. In a phase 1b study, the combination had an objective response rate (ORR) of 58% and a favorable safety profile. What is the biologic rationale for combining these two agents? Axitinib mediated VEGF-R blockade has immunomodulatory effects (increased immune cell tumor infiltration, decreased immune suppressor cells). In addition, preclinical models support a synergistic effect of the combination.
The basic study protocol is as follows
Treatment-naïve aRCC with clear cell histology and >= 1 measurable lesion (defined by RECIST) in good performace status are randomized 1:1 to either sunitinib (standard of care) vs. A+Av, with doses as noted above. Both axitinib and sunitinib were allowed dose adjustments as formally recommended in prior studies.
Primary objectives were two-fold: PFS by RECIST criteria by independent review committee (IRC) in patients with PD-L1+ tumors and OS in the same group.
Secondary objectives were PFS and OS in the unselected overall population.
Investigator-assessed PFS were also assessed as secondary endpoints, as was ORR and safety.
886 patients were enrolled, of which 560 (63%) had PD-L1+ primary tumors. Independent DMRB occurred on August 2018 to review interim analysis when 253 PFS events had occurred (statistical design had expected 336 events).
The baseline characteristics of the groups (PDL1+ and overall) are shown below, and are pretty well matched.
Most patients had cytoreductive nephrectomy. Most patients were IMDC and MSKCC intermediate/poor risk.
Moving on to outcomes –
- PFS in PDL1+ patients by IRC:
- HR 0.61, p < 0.001
- PFS in unselected patients by IRC
- HR 0.69, p < 0.001
- Overall survival in the overall population
- HR 0.78, p = 0.06 (trend favoring A+Av)
- This data is not yet mature
- PFS in PDL1+ patients by investigator review:
- HR 0.51, p < 0.001
- PFS in unselected patients by investigator review
- HR 0.64, p < 0.001
- Confirmed ORR
- 4% so far with CR
- In the unselected population, it was 51% in the A+Av arm vs. 26% in the SUN arm
- Many patients have an ongoing response still
- The median duration of response has NOT YET BEEN REACHED in either treatment arm in both groups
ORR summary slide below:
Looking at key subgroups, PFS by IRC favored A+Av in all analyses – however, the HR was insignificant due to low number of events in certain categories:
1) No prior nephrectomy – HR 0.75, p > 0.05
2) MSKCC favorable risk – HR 0.65, p > 0.05
In terms of tolerability, as expected, there were a high rate of Grade 3-5 toxicity (51% in A+Av arm and 48% in SUN arm), but no significant difference. There was less drug discontinuation due to TRAEs in the A+Av arm. Special attention should be noted for the following TRAEs, which were lower than expected for the combination:
Based on these results, the authors conclude that:
1) A+Av have a longer PFS and higher ORR than SUN alone for patients with aRCC
2) PFS benefit was seen regardless of PD-L1 status or risk category
3) The study continues to follow-up for OS, as this data is immature
4) A+Av had a favorable safety profile
They feel that this should be first line therapy for patients with aRCC.
Dr. Grunwald followed Dr. Motzer with a brief discussion of the results and made the following important points.
First, single-agent therapy has been the standard of care for a long time in the setting of aRCC. This just changed recently with the use of Ipi/Nivo combination ICI in the setting of intermediate/poor risk disease – and it has become the new standard of care, along with cabozantinib for this population. However, single-agent therapy remains the standard for favorable risk disease.
Next, he noted that depth of response is associated with prognosis. While complete response (CR) is associated with the best prognosis, even patients with partial response (PR) have improved outcomes over those with stable disease (SD) or progression. So, the question becomes – do we chase the holy grail of CRs (associated with long-term response and increased treatment free survival by combining multiple agents)? Or do we continue to stick with sequential therapies (aim for tumor control but is associated with chronic toxicity)?
He then briefly reviewed the data presented by Dr. Motzer.
1) Even in unselected patients, there was a 56% ORR with a 3% CR rate. In PD-L1+ patients, this was even higher – 62% ORR with 4% CR (by investigator review rather than IRC)
2) He does not feel PD-L1 is an optimal marker for this combination therapy as it appears to have a strong response regardless of PD-L1 status
3) He notes that good-risk aRCC appears to be TKI sensitive while intermediate/poor risk appears to be ICI sensitive – hence the combination appears to work well for all risk categories
4) Overall the combination appeared well tolerated with relatively low discontinuation rates from either agent (13.8% avelumab, 6.9% axitinib).
However, he notes the data that makes this study incomplete – OS benefit and/or HRQOL benefit. With more mature data from both aspects (TRAE’s and OS), perhaps its utilization will be more convincing.
Yet, let us not forget that other studies in this population are already ongoing and will even report soon – Merck/Pfizer study KEYNOTE-426 of pembrolizumab/axitinib will be reporting soon as well. They have hinted that they demonstrate not only PFS benefit, but also OS benefit. So, this may become a crowded space.
Presented by: Robert J. Motzer, MD, Memorial Sloan Kettering Cancer Center, New York, US
Invited Discussant: Victor Grünwald, MD Prof, Clinic for Hematology, Hemostasis, Oncology and Stem Cell Transplantation, University Hospital Essen, UK Essen, Hannover, Germany
Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, twitter: @tchandra_uromd, @TjuUrology at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23, 2018, Munich Germany