In a plenary presentation at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Morris presented the first results of the VISION trial, a phase III study assessing lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer.
The VISION trial is an international, randomized, open-label phase III study evaluating 177Lu-PSMA-617 in men with PSMA-positive mCRPC who had previously received treatment with next-generation androgen receptor signaling inhibition (abiraterone, enzalutamide, etc) and one or two prior lines of taxane chemotherapy (NCT03511664). Additionally, patients must have had an ECOG performance status of 0-2 and life expectancy of at least 6 months.
Importantly, patients must have had PSMA-positive disease on the basis of a central review of 68Ga-PSMA-11 staging scans. PSMA positivity was defined as uptake greater in metastatic lesions than in the liver. Further, they could have no PSMA-negative metastatic lesions.
Following enrollment, patients were randomized in a 2:1 fashion to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks x 6 cycles) plus standard of care (SOC) or SOC alone. SOC treatments were at the discretion of the treating investigator; however, cytotoxic chemotherapy, immunotherapy, and radium-223 were explicitly excluded. Most patients received alternative androgen-directed therapies while others received palliative radiotherapy and glucocorticoids.
The authors assessed two alternate primary endpoints: radiographic progression-free survival (rPFS) using PCWG3 criteria by independent central review (ICR) and overall survival (OS). To inform their sample size calculations, the study was designed on the premise of a median rPFS of 4 months without 177Lu-PSMA-617 and 6 months with 177Lu-PSMA-617 (hazard ratio 0.67). Thus, for rPFS, this design allows an 84% power for this hazard ratio with 364 events in 557 patients. Accordingly, rPFS was allocated a one-sided alpha of 0.004. Similarly, with respect to overall survival, the authors assumed a median OS of 10 months without 177Lu-PSMA-617 and 13.7 months with 177Lu-PSMA-617 (hazard ratio 0.7306). Thus, 508 deaths in 814 patients would allow a 90% power to detect a difference with the HR of 0.7306 with allocation of a one-sided alpha of 0.021.
In addition to these two primary endpoints, they also assessed key secondary endpoints of objective response rate (ORR; RECIST v1.1), disease control rate (DCR), and time to first symptomatic skeletal event (SSE) as well as other secondary endpoints including safety and tolerability, biomarkers including PSA, and health-related quality of life and pain
Among 1179 screened patients, the VISION trial enrolled 831 patients between 4 June 2018 and 23 October 2019. In keeping with the 2:1 randomization schema, 551 patients were allocated to 177Lu-PSMA-617 + SOC and 280 were allocated to SOC only.
Dr. Morris emphasized that early in the study accrual, there was a very high rate of drop-out from the SOC alone arm (56%). The trial group then reinforced the importance of trial conduct and subsequent drop-out from the SOC arm was lower moving forward. As a result, on the basis of discussion with the FDA, the rPFS analysis focused on patients accrued after March 2019.
As expected in the randomization design, demographic characteristics and baseline features were well balanced between the two treatment groups.
Further, pre-randomization treatment was well balanced. In both the rPFS analysis set and among all randomized patients, between 45-50% of patients had received more than one androgen receptor pathway inhibitor and 41-48% of patients had received more than one taxane regime.
Dr. Morris then presented the primary results of the VISION trial assessing overall survival. Over a median study follow-up of 20.9 month (as of a data cut-off of 27 January 2021), treatment with 177Lu-PSMA-617 + SOC significantly improved overall survival by a median of 4.0 months (median OS, 15.3 vs 11.3 months; HR, 0.62 [95% CI: 0.52, 0.74]; p < 0.001, one-sided), compared to SOC alone, in the overall cohort of all randomized patients (n=831).
The authors further assessed overall survival in the rPFS analysis subset (n=581), showing that treatment with 177Lu-PSMA-617 + SOC significantly improved overall survival by a median of 4.2 months (median OS, 14.6 vs 10.4 months; HR, 0.63 [95% CI: 0.51, 0.7]), compared to SOC alone. The authors further performed a number of subgroup analyses showing a relative consistent benefit of 177Lu-PSMA-617 + SOC across categories defined by the SOC used, disease characteristics, and demographic characteristics though many of these subgroup analyses were very small and are difficult to interpret.
Dr. Morris then provided the results of the second, alternate primary endpoint showing that treatment with 177Lu-PSMA-617 + SOC significantly improved rPFS by a median 5.3 months (median rPFS, 8.7 vs 3.4 months; HR, 0.40 [99.2% CI: 0.29, 0.57]; p < 0.001, one-sided).
As they had done looking at overall survival, the authors then considered the effect of 177Lu-PSMA-617 + SOC in the whole randomized cohort (n=831) showing that rPFS was significantly improved by a median 5.2 months (median rPFS, 8.8 vs 3.6 months; HR, 0.42 [99.2% CI: 0.32, 0.58]). Again similar to overall survival, subgroup analyses demonstrated a generally consistent effect, though conclusions were limited in many subgroups due to small numbers.
In addition to these primary endpoints, the addition of 177Lu-PSMA-617 to SOC statistically significantly improved all key secondary endpoints, including ICR-determined ORR (29.8% vs 1.7%), ICR-determined DCR (89.0% vs 66.7%) and time to first SSE (median time, 11.5 vs 6.8 months; HR, 0.50). Further, PSA responses (whether defined as a 50% decrease or an 80% decrease) were significantly more common among those treated with 177Lu-PSMA-617 + SOC.
Dr. Morris emphasized that patients in the 177Lu-PSMA-617 + SOC arm had much longer durations of therapy: among those in the 177Lu-PSMA-617 + SOC arm, median duration of standard of care was 7.56 months (range 0.3-31.3 months) compared with 2.07 months (range 0.0-26.0 months) in the SOC alone arm.
Further, he emphasizes that post-protocol treatment could not explain the observed survival benefits seen in the 177Lu-PSMA-617 arm as there was a somewhat higher use of chemotherapy and radiotherapy among patients randomized to the SOC alone arm. Further, use of radiopharmaceuticals was uncommon in both arms following protocol treatments.
While a higher rate of high-grade (grade 3-5) treatment-emergent adverse events was observed with 177Lu-PSMA-617 (28.4% vs 3.9%), overall therapy was well tolerated. However, it bears note that there were 5 deaths attributable to 177Lu-PSMA-617 treatment. In terms of specific adverse events, treatment with 177Lu-PSMA-617 + SOC was associated with increased rates of bone marrow suppression, xerostomia, and nausea and vomiting.
Dr. Morris then concluded that the VISION trial demonstrates that 177Lu-PSMA-617 can be safely added to SOC treatment and improves rPFS and prolongs OS compared with SOC alone in men with advanced-stage PSMA-positive mCRPC, supporting its adoption as a standard of care.
Presented by: Michael Morris, MD, Medical Oncologist Clinical Director, Genitourinary Medical Oncology Service & Prostate Cancer Section Head, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021