What's in the Molecular Enrichment Tool Box?

(UroToday.com) As part of the ASCO 2020 Virtual Education Program, David McConkey, PhD, chaired a session on molecular enrichment strategies in genitourinary cancer, specifically highlighting in his talk what exactly is in the molecular enrichment toolbox. Indeed, the landscape is rapidly changing for advanced disease, including (i) the vascular endothelial growth factor (VEGF) pathway and immune checkpoint inhibitors in renal cell carcinoma, and (ii) cisplatin-based combination chemotherapy, immunotherapy, FGFR inhibitors, and antibody-drug conjugates in bladder urothelial carcinoma. However, the new therapies are expensive, benefit a minority of patients, and can produce significant toxicities, thus, there is a great need for predictive biomarkers for treatment selection.

Biomarkers for immune checkpoint blockade have general features across solid tumors. These include high PDL1 count in the cancer and stroma, high tumor mutational burden, and effector T-cell infiltration. The first part of Dr. McConkey’s talk discussed biomarkers and renal cell carcinoma (RCC). The CheckMate-214 trial assessed nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma (RCC),1 showing that progression-free survival, overall survival and objective response rates were all significantly greater in the combined immune checkpoint blockade arm. In an exploratory analysis, patients with PDL1 positive tumors (>1% staining) had higher objective response rates and longer progression-free and overall survival with combined checkpoint blockade compared to sunitinib.

IMmotion150 and IMmotion1512-3 assessed atezolizumab plus bevacizumab versus atezolizumab monotherapy versus sunitinib in treatment-naïve patients with metastatic RCC. Unfortunately, neither atezolizumab-containing arm outperformed sunitinib in the intention-to-treat population, but there was a trend toward increased benefit with atezolizumab plus bevacizumab in the PDL1 positive population. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with progression-free survival, however angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments:4

GeneSignature_ASCO2020.png

JAVELIN 1015 and KEYNOTE-4266 were phase III trials of avelumab or pembrolizumab plus axitinib in patients with metastatic RCC. Objective response rates, progression-free survival, and overall survival were greater in the axitinib plus anti-PD(L)1 arms of both trials, but the benefit was not associated with PDL1 expression in either trial. According to Dr. McConkey, with regards to RCC, tumor mutational burden is out as a biomarker, CD31 (immunohistochemistry) and angiogenesis gene expression signatures are in for sunitinib, but single-agent sunitinib is less likely to be used much longer for advanced disease. Furthermore, PDL1 may be somewhat useful for nivolumab plus ipilimumab and atezolizumab plus bevacizumab, but has been somewhat disappointing as a biomarker. In his opinion, the myeloid gene expression signatures may be the next biomarker to have significant impact.

Dr. McConkey then discussed candidate biomarkers for bladder urothelial carcinoma. These include (i) basal and luminal molecular subtypes, (ii) DNA damage response mutations, (iii) PDL1, tumor mutational burden, T effector gene expression signatures (sensitivity), and (iv) TGFbeta, cancer-associated fibroblast gene expression (resistance). With regards to subtypes and chemotherapy, “p53-like” (infiltrated) tumors were resistant to downstaging, whereas basal tumors were associated with the most survival benefit with chemotherapy. The S1314 (“CoXEN”) trial was designed to randomize patients with stage cT2-T4aN0M0 urothelial carcinoma planning for a cystectomy to Arm 1 gemcitabine plus cisplatin versus Arm 2 dose-dense MVAC. Importantly, prior to receiving chemotherapy, each participant must provide tissue for analysis. The schema is as follows:

CoXENTrialSchema.png

The primary objective will be CoXEN analysis, but will also include micro RNA profiling, molecular subtyping, DDR mutational analysis, and SNPs associated with drug metabolism.

Although 25-50% of patients may derive a pathological response benefit from neoadjuvant chemotherapy, predictive biomarkers are necessary to predict response. Plimack and colleagues found that an alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (87% sensitivity, 100% specificity; p<0.001) and better overall survival (p=0.007) compared to those with genetic alterations [7]. Work from Dr. McConkey’s group that is yet published, assessed the accuracy of post-neoadjuvant chemotherapy transurethral resection tissue for the presence/absence of DDR mutations for predicting efficacy. Unfortunately, their results revealed no correlation with downstaging on final pathological stage.

Molecular subtypes and immunotherapy have also been assessed in bladder urothelial carcinoma. The IMvigor-210 trial assessed atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy.8 This study showed that luminal infiltrated tumors were sensitivity to immunotherapy, whereas luminal papillary tumors were resistant. Unfortunately, subsequent analyses have failed to robustly reproduce these results. Instead, the small subset of TCGA 2017 “neuroendocrine” tumors were sensitive to treatment and tumors enriched with TGFbeta and fibroblasts were resistant. Enfortumab vedotin also recently showed strong single-agent activity in advanced disease,9 as well as having improved response rates when combined with immunotherapy. Enfortumab vedotin targets nectin-4, which is broadly-expressed but may be enriched in luminal bladder tumors.

Dr. McConkey concluded the bladder cancer section of his talk by noting that molecular subtypes are no longer optimal for assessing downstaging/response, but are still usable for estimating survival. Additionally, molecular subtypes are still useful for neuroendocrine tumors with regards to predicting immunotherapy response, but TGFbeta and fibroblasts are likely more promising. In his opinion, tumor mutational burden, PDL1, and IFN are all still useful for immunotherapy biomarkers.

Presented by: David J. McConkey, PhD, Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, Maryland, USA 

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, USA, Twitter: @zklaassen_md, at the ASCO20 Virtual Education Program, #ASCO20, August 8-10, 2020

References:
  1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carinoma. N Engl J Med 2018;378(14):1277-1290.
  2. Atkins MB, McDermott DF, Powles T, et al. IMmotion150: A phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). J Clin Oncol 2017;35(15 Suppl 1).
  3. Motzer RJ, Powles T, Atkins MB, et al. IMmotion 151: A randomized Phase III Study of Atezolizumab plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). J Clin Oncol 2018;36(suppl 6S; abstr 578).
  4. McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018 Jun;24(6):749-757.
  5. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1103-1115.
  6. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1116-1127.
  7. Plimack ER Dunbrack RL, Brennan TA, et al. Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive bladder cancer. Eur Urol 2015;68:959-967.
  8. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 2016;387(10031):1909-1920.
  9. Rosenberg J, Sridhar SS, Zhang J, et al. EV-101: A Phase I study of single-agent enfortumab vedotin in patients with nectin-4-positive solid tumors, including metastatic urothelial carcinoma. J Clin Oncol 2020 Apr 1;38(10):1041-1049.
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