Toni Choueiri: New insights from the JAVELIN Renal 101 trial in RCC in Cancer Discovery

Toni Choueiri, Professor of Medicine at Harvard Medical School and Director of the Lank Center for Genitourinary Oncology at the Dana–Farber Cancer Institute, shared a post on X/Twitter:

“JUST IN: New insights from the JAVELIN Renal 101 trial in RCC in Cancer Discovery. We delve into integrative biomarkers of PDL1 inhibitor avelumab + TKI axitinib (A+Ax) vs. TKI sunitinib (Sun).

As a reminder, the phase 3 JR101 trial showed improved PFS for aRCC patients treated with A+Ax vs. Sun. Final OS pending –last update ESMO Open with John Haanen The Netherlands Cancer Institute leading

In a previous report in Nature Medicine led by Robert Motzer, we examined immune + angiogenic gene expression signatures, as well as somatic alterations. We highlighted the role of NK-mediated cytotoxicity + prognostic implications of double mutants.

In this work, we present the results of COMPREHENSIVE analyses of the JR101 data (circulating proteins, cell populations, and TCR repertoires…). We evaluated the association with patient outcomes in light of pretreatment tumor attributes, such as the occurrence of tumor-infiltrating leukocytes and tumor genotype.

Different peripheral cell populations were associated with PFS in each arm: High PFS was associated with high lymphocyte (w/ Sun) and low monocytes (w/ A+Ax) Moreover, blood cell levels exhibited little change during A+Ax treatment, but fluctuated with Sun dosing schedule.

Baseline T-cell quantity and repertoire in peripheral blood correlated with longer PFS w/ Sun, not A+Ax. While expanded peripheral T-cells were seen w/ Sun, A+Ax showed greater TCR repertoire modulation.

Double mutant (DM) tumors had a mutation in ≥2/10 genes associated with PFS. DM tumors had high PFS vs. WT/S in pts treated w/ A+Ax, but not Sun. A revised classification (rDM), taking into consideration somatic vs. germline mutations, even showed a low PFS with Sun

rDM tumors displayed unique circulating and tumor-infiltrating immunologic profiles, highlighting the role of non-T cell, non-NK mediated immunity in these tumors.

Lastly, minimal variation in T-cell metrics were observed among molecular subgroups, but notably longer PFS was seen in WT/S patients with high baseline T-cell fractions when treated with A+Ax, but not in rDM.

Our work helps shed light on the different immunomodulatory mechanisms in patients according to treatment type (A+Ax vs. Sun) and tumor molecular subtypes, marking a further step toward more effective, personalized aRCC treatment strategies.

by the way, gratitude from the phenomenal Cancer Discovery Ex. Editor Elizabeth McKenna who was present and guide all along the process.

Finally, huge thanks to all the investigators who took part in this project and to our patients and their families, to whom we dedicate all our efforts!–Fin!”

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Source: Toni Choueiri/X