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Patient-reported outcomes from IMvigor130: a global, randomised, partially blinded Phase III study of atezolizumab + platinum-based chemotherapy vs placebo + platinum-based chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma

IMvigor130 study is a phase 3 randomized placebo-controlled trial investigating the clinical efficacy of atezolizumab versus the combination atezolizumab and platinum chemotherapy versus chemotherapy alone as first-line treatment for advanced urothelial carcinoma. The study design is a follows:

It is the first immune checkpoint inhibitor study to demonstrate an improvement in PFS over standard of care for 1L mUC, with a HR of 0.82 (95% CI: 0.70, 0.96) for atezolizumab + plt/gem vs placebo + plt/gem in the ITT population. The safety profile of atezolizumab + plt/gem was consistent with that observed with the individual agents.

At ESMO 2020, the patient-reported outcomes in IMvigor130 was reported, which addresses the question of whether the addition of atezolizumab to standard-of-care plt/gem impact patients’ function and QoL.

Patients in both arms similarly reported nominal changes (either maintaining pre- treatment levels or improvements) in most symptom and function/QoL domains, suggesting an overall positive impact.

However, there was a trend towards a longer time to deterioration in favor of the combination across almost all scale metrics.

In conclusion, analyses of PROs show the addition of atezolizumab to plt/gem resulted in PFS improvement without compromising patients’ function or QoL. These PRO results, coupled with the prolonged PFS and satisfactory safety profile, support the favourable benefit-risk profile of atezolizumab + plt/gem as an important new treatment option for patients with untreated mUC.

IPATential150: efficacy and safety from the Phase III study of ipatasertib plus abiraterone vs placebo plus abiraterone in metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogenous disease. 40%-50% of mCRPCs have lost the AKT phosphatase PTEN, hyperactivating oncogenic PI3K/AKT signaling. PTEN loss in mCRPC is associated with worse prognosis and reduced benefit from androgen receptor (AR) blockade. The Phase III IPATential150 study (NCT03072238) was designed to evaluate the efficacy and safety of ipatasertib with abiraterone and prednisone in patients with previously untreated mCRPC.

In this primary endpoint analysis, ipatasertib plus abiraterone as a first-line treatment for mCRPC resulted in significantly superior rPFS and anti-tumour activity compared with placebo plus abiraterone in patients with PTEN-loss mCRPC.

In addition, Ipatasertib was associated with improved time to PSA progression and PSA response, as well as higher ORR in patients with measurable disease at baseline.

However, Improvement of rPFS in the ITT population was not statistically significant. In addition, overall survival remain immature and will require further follow-up.

In terms of safety, increased toxicity was also observed with the addition of ipatasertib to abiraterone, in line with prior observations in clinical studies, with a high proportion having dose alterations. Nevertheless, drug discontinuations may be avoided by instituting prophylactic loperamide and antihistamine for managing diarrhoea and cutaneous adverse events, respectively.

In conclusion, combined AR and AKT blockade with ipatasertib plus abiraterone improves clinical outcomes over AR blockade alone for PTEN-loss mCRPC, a poor-prognosis subset.

Cabozantinib in combination with atezolizumab as first-line therapy for advanced clear-cell renal cell carcinoma: results from the COSMIC-021 study

COSMIC-021 is a clinical trial platform testing the combination of the MET/VEGF/TAM kinase inhibitor cabozantinib in combination with the anti-PD-L1 drug atezolizumab, which demonstrated encouraging clinical activity in tumor types including renal cell carcinoma, urothelial carcinoma, prostate cancer, lung cancer, and hepatocellular carcinoma

At ESMO 2020, Dr. Pal shared data from a cohort of COSMIC-021 (NCT03170960) examining the efficacy and safety of this drug combination in previously untreated patients with advanced clear-cell renal cell carcinoma (ccRCC). The study design is as follows:

In terms of the efficacy findings, an ORR of 53% and median PFS of 19.5 months was observed for the 40 mg QD cabozantinib dose group. Interesting, an ORR of 58% and median PFS of 15.1 months for the 60 mg QD cabozantinib dose group.

Baseline PD-L1+ and high CD8 associate with greater tumor lesion reduction and overall response.

The safety profile of the combination was acceptable at both cabozantinib dose levels evaluated.

As such, it was concluded that the combination of cabozantinib and atezolizumab demonstrated encouraging clinical activity with reasonable safety profile in previously untreated advanced ccRCC patients. A phase 3 study (CONTACT-03) of cabozantinib with or without atezolizumab in RCC previously treated with immune checkpoint inhibitor therapy is currently ongoing.

Editor: Dr Tanujaa Rajasekaran

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