ESMO 2018: Invited Discussant - IMmotion151 and ATLAS Trial Results

Munich, Germany ( Manuela Schmidinger, MD provided a discussion of both of the following abstracts: Molecular Correlates Differentiate Response to Atezolizumab plus Bevacizumab vs Sunitinib: Results From a Phase III Study IMmotion151 in Untreated mRCC and Axitinib vs. Placebo in Patients at High Risk of Recurrent Renal Cell Carcinoma (RCC): ATLAS Trial Results

First, Dr. Schmidinger discussed the role of biomarkers in RCC. The last decade of RCC management have yielded some important lessons:

1) Targeted agents (TTs) – work well in mRCC based on ORR and PFS, they were the 1st breakthrough in RCC management
2) Immune checkpoint inhibitors (ICIs) – work well in mRCC, highest complete response (CR) rates ever; improved overall survival, which was 2nd breakthrough
3) TT+ICI vs. ICI-ICI combos – appear to work even better; TTs provide an immune permissive microenvironment for ICIs

As a result, there are numerous ongoing combination phase III trials – including InMotion151, which assesses bevacizumab+atezolizumab (BA) versus sunitinib alone. This is the study was presented by Dr. Rini.  Most of these trials have met their primary endpoint – but the trials also demonstrate that the results vary. There are extremes of benefits with ICI – some patients that benefit a lot while others that have no benefit. Additionally, there are some patients that still do well with the comparator arm (usually sunitinib). This highlights the importance of predictive biomarkers – and PDL1 is not enough.

The first lesson is whether or not these unique signatures (angiogenesis, pre-existing immune response, inflammation) are appropriate markers. She feels that they are – because they reflect the tumor and disease biology, but also the mechanism of action of the different treatment strategies.

Dr. Schmidinger's key take-home points from Dr. Rini’s talk are below:

Across treatment arms (AB vs. SUN) and within the SUN arm –

  • SUN should be given in patients with Ang-high tumors but not Ang-low (PFS HR 0.59)
  • AB > SUN in Ang-low patients (PFS HR 0.68)
  • AB > SUN in T-eff high (PD-L1+) patients (PFS HR 0.86) – but not in T-eff low patients
Across different biologic subgroups:

  • Favorable risk patients: show more frequently Ang-high signature than intermediate/poor risk (74% vs 26%)
  • Intermediate/poor risk: show more frequently T-eff high signature and PD-L1+ than favorable risk (64% vs. 36%)
  • Sarcomatoid RCCs: show more frequently Ang-high signature and more frequently T-eff high/PD-L1+ than non-sarcomatoid tumors
Based on this:

- There are specific patients that may benefit from either sunitinib or ICIs.
- Her pictograms help define which patients benefit from sunitinib vs. those who benefit from ICI combos.

Sunitinib: Favorable risk (74% are Ang-high and only 36% are T-eff high) and non-sarcomatoid

In contrast, patients who should receive ICI are:

  • Intermediate/poor risk patients because they are
    • More likely to be Ang-low than favorable risk
    • Higher chance to be T-eff high or PD-L1+
  • Sarcomatoid features
    • High chance to be Ang-low (66%)
    • Higher chance of being T-eff high / PD-L1 positive
Yet, by no means are these perfect. None of those percentages are 100%! There are numerous patients that don’t fit the profile perfectly. As such, they need to be assessed in each individual patient in clinical practice, rather than broadly applied.

UroToday ESMO2018 LBA31

While this is the first identification of useful biomarkers in RCC, there are other markers that may be utilized to improve the predictive ability. Additionally, PFS may not always correlate to CR rates, and biomarkers may need to be linked to CR for better utility.

Next, she went on to focus on the ATLAS trial and its implications on adjuvant therapy for RCC.

Again, to date 3 RCTs have been completed in this disease space. The 3 trials in this disease space are the ASSURE (Haas NB et al. Lancet 2016), S-TRAC (Ravaud A et al. NEJM 2016) and PROTECT trials (Motzer RJ et al. JCO 2017) – only S-TRAC was positive for DFS benefit. Based on this, sunitinib has been FDA approved for adjuvant therapy, though uptake has been minimal.

There is a biologic rationale for VEGF targeting in the adjuvant setting, as VEGF has been implicated in multiple steps along the metastases pathogenesis in RCC. 

UroToday ESMO2018 ATLAS

Each of the 2 prior negative trials had criticisms regarding why they were negative or positive.

  • ASSURE – 21% were not clear cell RCC, the starting dose was reduced, a dose reduction to 25 mg allowed
  • PROTECT – pT2 allowed, 600 mg dose reduction may have limited efficacy
As a result, the thought and hope were that with the appropriate starting dose, appropriate dose maintenance and right patient population (clear cell, high-risk), VEGF inhibitors may improve DFS.

Additionally, as axitinib is slightly different, there was hope it may have an effect where the others didn’t –

1) Higher bioavailability than sunitinib, sorafenib, and pazopanib
2) Better relative potency
3) 3-years of duration in ATLAS

But, at the end of the day, ~40% of the ATLAS population was not high-risk and many patients did not get 3 years duration (only 20% did).

So, it ended up being a negative trial, but there are some lessons to take home:

  • Axitinib is not different than the other agents in the adjuvant setting
  • While VEGF may be involved in most steps of metastasis pathogenesis, even those inhibitors with pharmacokinetic advantages have little or no benefit
  • Adjuvant treatment with VEGFR-inhibitors is very unconvincing – even if accounting for risk profile, drug potency, dose maintenance, only 1 of 4 trials was marginally positive
  • So far there has been no hint of OS benefit
Dr. Schmidinger feels we need to move on past VEGF targeted therapies to other adjuvant treatment strategies.

Presented by: Manuela Schmidinger, MD, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria

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

Further Related Content:
Axitinib vs. Placebo in Patients at High Risk of Recurrent Renal Cell Carcinoma (RCC): ATLAS Trial Results
Molecular Correlates Differentiate Response to Atezolizumab plus Bevacizumab vs Sunitinib: Results From a Phase III Study IMmotion151 in Untreated mRCC

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