ASCO 2023: Pathologic Concordance Rate and Outcomes by Histologic Subtype in Advanced Papillary Renal Cell Carcinoma: An Analysis from the SWOG S1500 (PAPMET) Trial

( Dr. Abhishek Tripathi presents an analysis of the SWOG S1500 (PAPMET) trial, specifically assessing concordance rate and outcomes by histologic subtype in advanced papillary renal cell (pRCC) carcinoma.

He began by reviewing the PAPMET trial, which demonstrated significantly improved progression-free survival (PFS) with cabozantinib vs. sunitinib in advanced pRCC (median: 9.0 vs. 5.6 mos; hazard ratio (HR): 0.60; 95% CI 0.37–0.97). Until recently, pRCC was subclassified as type 1 vs. 2 based on histologic features. However, as he noted later, this subclassification has since been removed – but it was a stratification factor in the PAPMET trial.

The authors noted that during conception of the PAPMET study, they hypothesized that patients with type 1 pRCC will derive more benefit from cabozantinib compared to those with type 2 disease, given enrichment of MET alterations in the former. In this secondary analysis, they report the outcomes stratified by histologic subtype per central review.

In the trial, patients with advanced papillary RCC who had received up to 1 line of therapy were randomized to receive one of multiple agents, stratified by pRCC subtype (type 1, type 2 or not otherwise specified [NOS]).PAPMET study design
He notes that pathologic data from local pathology review was catalogued. They did obtain central pathology review, which was conducted by 3 expert genitourinary pathologists who independently reviewed tumor specimens.

Importantly, discordant opinions among these pathologists were individually arbitrated and a unified diagnosis was assigned.

The primary goal of the study was to compare clinical outcomes (objective response rate (ORR) and PFS) for patients with either papillary type 1 or 2 disease in the cabozantinib and sunitinib arms.

They identified 147 patients with available local and central pathology review. These were broken down into

  • Type 1: 17.7% (n=26) on local review, 29.3% (n=43) on central review
  • Type 2: 53% (n=78) on local review, 45.6% (n=67) on central review
  • NOS/Mixed: 29.3% (n=43) on local review, 25.2% (n=37 on central review.

As seen in the discrepancy of classification of above, individual cases were frequently reclassified (Table 1) and local pathology review demonstrated low sensitivity and PPV across subtypes (Table 2). During central review, complete agreement amongst the 3 pathologists was seen in only 33.3% (n=49) of cases and was highest in type 2 tumors (40%; n=27) (Table 3).

PAPMET tables

PAPMET histological subtypes
This data, taken in whole, indicates the significant difficulty in classifying papillary RCC as type 1 and type 2, which is one of the reasons such classification has since been removed.

Looking at outcomes, compared to sunitinib, cabozantinib demonstrated better ORR and PFS in both subgroups.suni and cabo table
Based on this, the authors concluded that designation of pRCC subtype by central review did not identify a subset of patients with greater clinical benefit from cabozantinib.

Clinical trial information: NCT02761057.

Presented by: Abhishek Tripathi, MD, City of Hope Comprehensive Cancer Center, Philadelphia, PA

Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Associate Professor of Urology, University of California, Davis, @tchandra_uromd @UCDavisUrology on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.