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ESMO 2018

ESMO 2018: Invited Discussant - mCRPC with High Tumor Mutational Burden and a Phase I Dose-Escalation Study of 177Lu-PSMA-617 for mCRPC

Munich, Germany (UroToday.com) Aristotelis Bamias, MD discussed the following two studies:

  1. 798PD - In-depth assessment of metastatic prostate cancer with the high tumor mutational burden – Niven Mehra et al.
  2. 799PD - Phase I dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration-resistant prostate cancer (mCRPC) – Scott Tagawa et al.
The bone metastatic disease is the most frequent prostate metastatic disease with a significant impact on the patient’s quality of life. PSMA is highly expressed in the prostate, roughly a hundred times greater than in most other tissues. In some prostate cancers, PSMA is the second-most upregulated gene product, with an 8- to 12-fold increase over levels in noncancerous prostate cells. The radioligand PSMA is internalized into prostate cancer cells and causes low bone marrow toxicity. The small molecule of PSMA has been used for imaging, as it has good tolerance and encouraging efficacy.

We are currently entering an age of theranostics where the use of a compound can be for both diagnosis and treatment. For imaging, Galium-68 PSMA is used, while for treatment, Lutetium 177 is used. Lutetium 177 is the ideal radionuclide for targeted therapy. It is persistent, short range and powerful. It also emits low levels of Gamma radiation, making it suitable for imaging as well. It is possible to use it in high doses with less marrow toxicity.Its physical properties make it optimal for curability in small tumors (1-3 mm). No formal dose escalation study has ever been performed with a radiolabeled PSMA peptide/ligand. 

The first study discussed by Dr. Bamias was the 799PD - Phase I dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration-resistant prostate cancer (mCRPC) – Scott Tagawa et al. The entry criteria for this trial included patients with progressive mCRPC according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Patients needed to have adequate bone marrow and organ function, with a good performance status. The also needed to demonstrate progression after potent androgen receptor signaling/CYP 17 inhibitor therapy, and progression after therapy with chemotherapy (or refuse chemotherapy or be unfit for chemotherapy).

All patients were treated with a single cycle of a fractionated dose of Lu-PSMA-617, which is a small PSMA ligand, that binds viable PSMA+ cells, is rapidly internalized and may be conjugated. Overall, 29 patients were included in this study. The results demonstrated that the patients accrued were all typical CRPC patients with 100% of them demonstratingPSMA uptake on imaging. The median age was 70, with a median PSA of 98.91 ng/dl, and 93% of them had bone metastasis. A total of 45% of the patients were treated with more than one androgen receptor inhibitor, with 52% being treated in the past with chemotherapy and 17% of them with a history of being treated with Radium 223. As this was a phase 1 study, safety was the primary concern, demonstrating only two patients have a grade 3 complication, with the most adverse effect being of grade 1. No maximum tolerated dose was achieved in this study, and the recommended phase 2 dose was 22.2 GBq (600 mCi) per fractionated cycle. 

In conclusion, dose-escalation of LU-PSMA-617 is safe to 22.2 GBq, in a single cycle with fractionated dosing. This study shows promising early efficacy signals. While most patients had mild toxicity (the most common being reversible low-grade xerostomia [dry mouth]), severe toxicity was very rare. Currently, the enrollment to the phase 2 portion of the study continues, to provide additional efficacy and toxicity data (NCT03042468). It is not clear how this novel treatment will fit in the current treatment paradigm, which patients would be the best candidates (asymptomatic mCRPC patients? Or mCRPC patients following docetaxel treatment?). Only one single cycle was given in this study, and the implications of additional cycles are not clear either.

The next and last study discussed was the 798PD - In-depth assessment of metastatic prostate cancer subtypes by whole genome sequencing and multiplex immunohistochemistry – Niven Mehra et al.

PD-1/PD-L1 immune checkpoint blockade benefits 10% of patients with mCRPC. Selecting patients by PD-L1 expression alone is insufficient to enrich for responsiveness to immune checkpoint blockade, and the search for other biomarkers is needed. Tumor mutational burden is a potential biomarker that can be used. It has been shown that overall survival had improved in patients with a high tumor mutational burden, in addition to high PD-L1 expression.

In this study, 197 metastatic tissue biopsies were whole-genome sequenced (selected patients were treated with nivolumab or pembrolizumab). Furthermore, select tumors with a high tumor mutational burden were further evaluated with:

  1. Mismatch repair (MMR) protein expression
  2. Multiplex intra-tumoral immune cell phenotyping (VECTRA)
  3. Eight color flow cytometry blood immune cell phenotyping with high tumor mutational burden patients compared with low tumor mutational burden patients.
The results demonstrated that up to 25% of mCRPC patients show an immunogenic molecular signature for immune checkpoint blockade inhibitor monotherapy or combination therapy (PARP inhibitor and immune checkpoint inhibitor). A total of 7.7% of patients had a high tumor mutational burden (>10 mutations/Mb). 6.7% of patients had CDK12 bi-allelic inactivation and tandem duplication signature, and lastly, 12% of patients had BRCA mutations. The VECTRA multiplex intra-tumoral immune cell phenotyping results demonstrated that a relationship was found between tumor mutational burden and CD8 T-lymphocytes, particularly with intra-tumoral cytotoxic T-cells. Enrichment of frameshift mutations in immune suppressive genes was identified in patients with high tumor mutational burden, together with high infiltration of immunosuppressive regulatory T-cells.

In summary, whole genome sequencing identifies approximately 25% of mCRPC patients with a putative immunogenic signature, of which ~15% have a high neoantigen burden. Multiplex immunohistochemistry paired with whole genome sequencing appears complementary to select for patients with immunogenic signatures. Lastly, patients with a high tumor mutational burden tumors progress within one year following initiation of treatment, possibly due to clonal heterogeneity, enrichment of mutations in immune suppressive genes, and presence of an immune suppressive intra-tumoral micro-environment.

Presented by: Aristotelis Bamias, MD, Athens, GR

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter: @GoldbergHanan at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany