1. Goodwin, Peter M.

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MUNICH-A leading European oncologist acknowledged the impressive life-extending potential of new drug combinations for metastatic renal cell carcinoma discussed at the 2018 ESMO Annual Congress. Progress was reported with purely immunological approaches-using two different PD-L1 targeted immunotherapies together-and also with therapies combining immunotherapy with tyrosine kinase inhibitors (TKIs) of vascular endothelial growth factor (VEGF).

renal cell carcinoma... - Click to enlarge in new windowrenal cell carcinoma; ESMO 2018. renal cell carcinoma; ESMO 2018

Although such combinations had improved progression-free survival (PFS) and even promised prolongation of overall survival (OS), the lack of comparisons between them left clinicians with little guidance-other than toxicity profiles-upon which to individualize treatment for their patients.


"Unfortunately, we don't have good biomarkers that would help us selecting patients who would benefit either from immunotherapy alone, VEGF targeting agents alone, or the combination. So we have to look at the safety profiles of the combinations that we have right now-either the combinations with immunotherapies (alone) or the combination of a VEGF targeting agent and an anti PD-L1 drug-and see what would be the best for the patient that you have in front of you," said John B.A.G. Haanen, MD, PhD, Chief Scientific Officer Immunotherapy and Consultant Medical Oncologist in the Division of Medical Oncology and Immunotherapy at the Netherlands Cancer Institute in Amsterdam.


Haanen was impressed by recent progress in frontline therapy for metastatic renal cell cancer, noting that the only drugs available before 2005 had been interleukin-2 and interferon-alpha-neither of which had improved survival.

John B.A.G. Haanen, ... - Click to enlarge in new windowJohn B.A.G. Haanen, MD, PhD. John B.A.G. Haanen, MD, PhD

"As of 2005, VEGF targeting agents became available and they really changed the landscape for patients with metastatic renal cell cancer," he said.


When the anti-VEGF drug sunitinib had first been compared to interferon alpha-and had shown an improvement in PFS and OS-it had been approved very rapidly, Haanen noted. And currently there were more anti-VEGF agents-including axitinib, pazopanib, and cabozantinib-in addition to sunitinib. So, clinicians had a choice of TKI to target VEGF.


JAVELIN Study Results

Although individual TKIs had improved survival, there had been no cure for metastatic renal cell cancer. Haanen said this had led to questioning whether there could be further ways of improving outcomes of these patients.


The randomized phase III JAVELIN Renal 101 clinical trial (reported at 2018 ESMO) investigated whether immunotherapy targeting the immune checkpoint PD-L1 with avelumab could synergize with the TKI axitinib and prolong survival compared to sunitinib more either drug alone.


Haanen said it had been reasonable to choose axitinib as the TKI to partner with avelumab because it had fewer side effects-such as liver toxicity-than sunitinib or pazopanib.


Although the JAVELIN study reported a doubling of PFS in comparison with sunitinib, this had been at a relatively modest cost in terms of additional toxicity, he explained. "You do add some intolerance-because you have the toxicity of both drugs. But you didn't see additional toxicity on top of what we [usually] have from either drug. The new combination is highly tolerable.


"Combining a TKI with a checkpoint inhibitor may become the new standard of care," said Haanen, noting that there were new data coming out from the combination of another TKI and a checkpoint inhibitor also showing an improvement in OS and PFS. "So [JAVELIN] is not a stand-alone trial. There are other studies showing exactly the same."


With the dearth of predictive biomarkers, Haanen acknowledged the difficulties clinicians faced in trying to individualize clinical strategies when the efficacies of various new combinations for treating metastatic renal cell carcinoma were similar. Differences in the details of their tolerability were the only available criteria.


"We don't have any data on the comparison of, for example, the combination of ipilimumab plus nivolumab compared to this [JAVELIN] combination," he said. And there was also a lack of data on how improvements in PFS translated to OS. "So you have to discuss with the patient in front of you what the options are. And then-based on side effects-you can decide which combination you want to use."


When asked if he was confused by the proliferation of options because of the number of different PD-L1 agents and anti-VEGF agents available, Haanen said he was not. It was emerging that the VEGF and immunotherapy benefits were class effects.


"If you have the data showing that for the different TKIs and the different immune checkpoint inhibitors we see more or less the same results occurring, then we can say OK. The classes of TKIs and anti-PDL-1 drugs apparently can be combined. And then you have to choose the one you have most experience with-[and] most importantly a combination that has the least toxicity," he concluded.


Peter M. Goodwin is a contributing writer.