ESMO 2018: Efficacy and Safety of Axitinib in Metastatic Papillary Renal Carcinoma: Results of GETUG, a Multicenter Phase II Trial

Munich, Germany ( The majority of renal cell carcinomas (RCCs) are clear cell histology, and therefore, the brunt of the effort in drug and therapy development focused on this histology. Yet papillary RCC (pRCC) is not an insignificant histologic subset of RCC - pRCC represents 10-15% of renal carcinomas. In the metastatic setting, there is no standard treatment for pRCC. Few trials were conducted with sunitinib, everolimus and more recently savolitinib, with disappointing response rates. Axitinib, an inhibitor of VEGF receptors, currently indicated as 2nd line treatment in advanced renal cell carcinoma, was investigated.

This was a phase 2 trial assessing the safety and efficacy of axinitib (AXT) in the 1st line for patients with pRCC. The primary endpoint was 24-week progression free survival (PFS), while secondary endpoints included safety, PFS in each histologic subtype of pRCC, OS and best response rate and duration of response.

This was a small study. Inclusion criteria included adult patients (pts) with measurable disease, ECOG PS 0 or 1, no previous treatment, no brain metastases, and adequate organ functions. 56 patients were approached for enrollment, 55 were enrolled. Interestingly, 5 patients were actually excluded after central path review – as they did not have pRCC histology! Ultimately of the 50 eligible patients, 44 were confirmed for inclusion and treated with AXT 5 mg twice daily.  Of these 44, 12 had papillary type 1 and 30 had papillary 2. The remaining two patients had either mixed and undetermined papillary histology was enrolled. Basic demographics were: median age was 65 (27-82), 84% pts were males, 23.8% were in the good, 45.2% in the intermediate and 31% pts in the poor IMDC prognostic groups.

In terms of outcomes, PFS at 24 weeks is 45.2% for all-comers, but 46.2% and 42.9% in type 1 and 2 pRCC, respectively; best response rate is 26.2% (11/42) with 1 PR and 10 PR in type 1 and 2 respectively. Median PFS is 23.8 weeks for the entire cohort, similar for both subgroups (21.0 for Type 1 and 23.8 for Type 2). Median OS is 18.9 months for the entire cohort, NR for Type 1 and 17.4 for Type 2.

Treatment-related all grade toxicity was as expected with fatigue 73%, hypertension 61%, dysphonia 55%, diarrhea 52%, loss of appetite 30%, hand-foot syndrome 23%; grade 3-4 events were hypertension 27.3%, digestive symptoms 9.1% and PS decrease 5%.

In this first trial of axitinib in mPRC, it shows encouraging efficacy, especially in type 2 pRCC Toxicity was manageable. Axitinib appears as a good candidate to combine with immunotherapy for future trials in mPRC.

Invited Discussant

Dr. Suarez made the following points when addressing this poster presentation.
  1. This study highlights the importance of pathology review. 5/55 patients (~10%) of patients referred with pRCC were found to not have papillary histology!
  2. papillary RCC trials group Type 1 and Type 2 together, and separate them out as an afterthought. However, these are two distinct disease processes, with different mutational profiles, different driver mutations (cMET in pRCC Type 1 and fumarate hydratase in pRCC Type 2), and different clinical presentations.
  3. Prior studies looking at therapies for pRCC have had similar outcomes
- Amongst TKI’s, sunitinib had the best median PFS of 8.3 months (ASPEN), but everolimus has trial data as well
- MET inhibitors have had more promise, particularly in MET (+) tumors, with ORR’s approaching 50%

  1. There are numerous ongoing clinical trials with ICI’s in this disease space
In her opinion, in patients who have pRCC with metastatic disease, the current treatment algorithm should be:
1) Treat on a clinical trial if possible
2) If no clinical trial available, then base the decision on MET status
            - MET positive – MET-inhibitor should be used
            - MET negative – sunitinib or AXT

However, she again emphasized that we need to stop putting Type 1 and Type 2 pRCC patients in one category for clinical trials!

Presented by: S. Negrier, The University of Lyon, Lyon, France
Invited Discussant: Dr. Cristina Suarez, Spain

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