PracticeUpdate: Haematology & Oncology

ESMO 2016 27

etoposide carboplatin. So, it’s certainly possible that etoposide carboplatin isn’t enough to engender benefit in the neoadjuvant setting for small-cell tumours of the bladder, and perhaps with more patients treated with a more aggressive regimen, maybe they would have seen a different result. Dr Pal: I’ve seen phenomenal responses with this regimen of Adriamycin ifosfamide followed by cisplatin etoposide, concurrent with what you’ve just outlined. With all the buzz around immuno-oncology, the question that frequently comes up in our clinic is whether or not these agents are applicable to patients with rare histologies. So if I see a patient with a mix of transitional cell and small-cell, a mix of transitional cell and adenocarcinoma, is it reasonable to potentially apply I-O in that setting? Dr Siefker-Radtke: Well, the way we’re thinking about bladder cancer is definitely changing. In the past, all of our trials would exclude patients with a predominant non- urothelial component. So if we saw predominantly small-cell tumours, predominantly adenocarcinomas, microcapillary, or sarcomatoid, we would typically exclude those patients from the trial, but as we start understanding more about the biology, I think this is going to have to change, and I would argue we should start including these patients because the biology might actually predict the benefit with specific agents. For instance, when we look at microcapillary tumours, we see enrichment for perhaps HER2 signatures in that group of patients. And even when Bogdan Czerniak and Charles Guo in our group did some subtyping work in microcapillary, where they would isolate the microcapillary component, and then an adjacent urothelial component that did not have microcapillary features and what they found is that by gene expression profiling they essentially overlap. They appear biologically to be the same tumour, so even if there’s a less than 50% component of microcapillary those tumours may behave in a microcapillary fashion, and if we exclude them from our clinical trials, then we might actually miss groups of patients who would benefit from a specific targeted treatment.

Improvement in progression-free survival with ribociclib + letrozole may represent a paradigm shift in advanced breast cancer Adding the CDK4/6 inhibitor ribociclib to letrozole therapy significantly improved progression-free survival in postmenopausal women with hormone receptor-positive advanced breast cancer, finds the first interim analysis of data from the randomised, placebo- controlled, double-blind MONALEESA2. A s reported by Gabriel Hortobagyi, MD, of the University of Texas MD Anderson Cancer Center, the combination of ribociclib + letrozole Houston led to a 44% improvement in progression-free survival when used as a first-line treatment combination. He noted, “This was the definitive study to demonstrate the superiority of the combination of ribociclib + letrozole over letrozole alone.” A total of 668 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, who had not undergone prior systemic treatment, were randomised to ribociclib (600 mg daily, 3 weeks on/1 week off) + letrozole (2.5 mg daily, continuous), or letrozole + placebo. A 44% improvement was observed in the primary objective of progression-free survival versus placebo in patients taking ribociclib (hazard ratio 0.556, P = 0.00000329). Median progression- free survival was 14.7 months in patients taking placebo but was not reached in those taking ribociclib at data cutoff. “The results represent compelling proof of principle,” saidDr Hortobagyi, “and suggest a paradigm shift in metastatic, hormone receptor-positive breast cancer. They also suggest that testing combinations of ribociclib with other inhibitors of various signalling pathways might lead to additional progress in the management of several subtypes of breast cancer.” Patients who demonstrated measurable disease at baseline exhibited a significantly higher objective response rate to ribociclib + letrozole than to letrozole alone (53% vs 37%; P = 0.00028), as well as a better rate of clinical benefit rate (80% vs 72%, P = 0.02). Serious adverse events were reported by fewer than 5% of patients in both groups. Other adverse events were significantly more common in patients taking ribociclib. Fifty-nine percent of patients in the ribociclib arm suffered from neutropenia versus 1% in the placebo arm. Leukopenia occurred in 21% versus 1%, lymphopenia in 7% versus 1%, respectively. Patients who received ribociclib exhibited higher incidences of elevated alanine aminotransferase and aspartate aminotransferase. Too few patients in the study died to enable a reliable analysis of the impact of ribociclib therapy on overall survival. Dr Hortobagyi concluded that the combination of ribociclib and letrozole prolonged progression- free survival significantly and was well tolerated versus letrozole alone in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer who had received no prior therapy for advanced breast cancer. Giuseppe Curigliano, MD, of the European Institute of Oncology, Milan, Italy, commented, “I believe the results of this study are significant because now we have a new CDK4/6 inhibitor for patients with oestrogen receptor-positive metastatic breast cancer, in addition to palbociclib (already FDA approved) and abemaciclib (under development).” He added, “The addition of ribociclib to letrozole raises the rate of toxicity, but overall, if we evaluate the magnitude of clinical benefit, adding ribociclib is clearly beneficial.” Dr Curigliano said, “Further studies of ribociclib should examine biomarkers to better identify patients who would respond to the addition of the drug to letrozole.”

DECEMBER 2016