Asco-GU – Ambiguous renal readout clouds Tecentriq and Avastin roles
A partial phase III success for Tecentriq in first-line renal cancer could open up a new indication for the Roche anti-PD-L1 drug, as well as adding relevance to the company’s blockbuster Avastin in the face of approaching biosimilars.
However the results from the Immotion-151 study, being presented this week at the Asco-GU symposium, are highly ambiguous, and a key discrepancy between investigator-assessed and centrally reviewed survival data is a major red flag. Moreover, a separate battle is raging in first-line renal cancer between Bristol-Myers Squibb’s Opdivo and Exelixis’s Cabometyx.
That battle centres on patients’ prognosis status and level of PD-L1 expression. Bristol’s Checkmate-214 trial showed a strong effect for Opdivo plus Yervoy in intermediate/poor-risk patients who were PD-L1 positive, while in Exelixis’s Cabosun study Cabometyx extended progression-free survival in all-comers, but only recruited intermediate/poor-prognosis subjects.
The Immotion-151 trial of Tecentriq plus Avastin has shown the combo to extend progression-free survival (PFS) significantly in PD-L1-high subjects, and a strong numerical PFS benefit in all-comers too; all three studies use as active comparator the first-line standard of care, Pfizer’s Sutent.
However, Roche did not split out how its combo fared in good-prognosis patients – those who did so badly relative to Sutent in Checkmate-214 (Esmo 2017 – Renal cancer battlefront moves to the front line, September 11, 2017). The only clue was that the PFS benefit seen in Immotion-151 was “consistent across subgroups including MSKCC risk”, a measure of disease prognosis.
Opdivo is the only anti-PD-(L)1 drug to have renal cancer on its label, but in second-line use. Cabometyx received a US FDA approval last December in the first-line setting.
There are other reasons why investors and doctors should seek more clarity before deciding on the real value of the Immotion-151 readout.
In presenting the data at an Asco-GU press briefing yesterday Dr Robert Motzer, of the Memorial Sloan Kettering Cancer Center, stressed that the primary PFS endpoint was by investigator assessment. Independent review – a more stringent measure – showed a much smaller benefit, with loss of statistical significance, and Dr Motzer said analyses were under way to find out why.
|Immotion-151 study in first-line renal cancer patients|
|Tecentriq + Avastin||Sutent||Tecentriq + Avastin||Sutent|
|mPFS (investigator-assessed)||11.2 mth||8.4 mth|
|Stats||HR=0.83, p=0.02 (not stat sig)|
|mPFS (independent review)||8.9 mth||7.2 mth||9.6 mth||8.3 mth|
|Stats||HR=0.93, p>0.05||HR=0.88, p>0.05|
|mOS||Not reached||23.3 mth|
|Note: *co-primary endpoint. Trial ID NCT02420821|
For a more obvious positive sign Dr Motzer pointed to the fact that there were fewer high-grade or more severe adverse events with Tecentriq plus Avastin versus Sutent, and he said this was one of the main benefits of the Roche combo.
There was no significant difference in overall survival, though this was an early interim analysis.
Moderating the session, the Asco expert Dr Sumanta Pal agreed that tolerability was an important piece of the Immotion-151 data, adding: “The side-effect profile also compares favourably to ... Opdivo and Yervoy, [where] nearly 60% of patients required steroids for management of side effects, versus 16% in the current trial.”
As far as Avastin goes, maintaining relevance of this franchise is important for Roche given that the drug generates some $7bn of annual sales, but could face biosimilars in 2020. If there really is an additive effect for Tecentriq and Avastin in renal cancer, and the drugs can be bundled together, this could help Roche defend itself against the biosimilar threat.
A similar analogy exists in first-line lung cancer (All to play for in first-line lung cancer, Roche insists, February 2, 2018). Mechanistically the rationale in both first-line settings is that adding Avastin into the mix might help make a tumour immunogenic, and allow an immune approach to work despite the cancer being PD-L1 negative.
Indeed, in Immotion-151’s all-comer population the Tecentriq plus Avastin combo beat Sutent in terms of progression-free survival, though the p value was not statistically significant, presumably given the need to adjust it for multiplicity, and of course the numerical benefit fell away when progression was assessed independently.
The surprisingly large discrepancy between investigator assessment and independent review is a major red flag over the Immotion-151 readout.
If the discrepancy can be clarified, with no deleterious effect on the ostensibly positive Immotion-151 readout, the focus will fall on the relevance of patients’ PD-L1 expression. In turn, if Immotion-151 clearly shows an added benefit for Tecentriq and Avastin in all-comers this could reduce the focus on PD-L1 expression.
The added boost to the Avastin franchise would be significant, though more data are needed to know for sure, and for now these are two big ifs.