By: Len Kusdra, Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Senior Director, Clinical & Scientific Assessment, Kantar Health
The introduction of Herceptin® (trastuzumab, Roche/Genentech) over a decade ago turned HER2+ metastatic breast cancer (MBC) from what was once a patient population with poor prognosis to one with a vastly improved outlook and led the way for an influx of targeted therapies for this population. Now, the armamentarium against HER2+ MBC has expanded and includes several HER2-targeted agents: Tykerb® (lapatinib, GSK), Perjeta® (pertuzumab, Roche/Genentech) and Kadcyla® (ado-trastuzumab, Roche/Genentech). Updated overall survival (OS) data from the CLEOPATRA (NCT00567190) trial were presented at the Presidential Symposium at ESMO on September 28, 20141, and the results will serve to further solidify Roche as the dominant player in HER2-targeted treatment in MBC, if there was any doubt before now. The CLEOPATRA trial was designed to test whether the combination of Herceptin, Perjeta and docetaxel improved outcomes in first-line HER2+ MBC patients. The study randomized 808 patients to receive Hercpetin plus docetaxel plus either placebo or Perjeta. The primary endpoint was progression-free survival (PFS), and secondary endpoints included OS, PFS as assessed by the investigator, overall response rate and safety.
The initially published results2 in 2012 showed an improvement in PFS from 12.4 months in the control group to 18.5 months in the Perjeta group (HR=0.62; 95% confidence interval (CI), 0.51-0.75; P<0.001). The objective response rate was 69.3% in the control group and 80.2% in the Perjeta group (95% CI, 4.2-17.5; P = 0.001). These significant positive results led to FDA approval in 2012 and European approval in 2013 for Perjeta in combination with Herceptin and docetaxel as first-line treatment in HER2+ MBC. At the time, however, the data was not yet mature to determine OS, and many were left wondering whether the impressive improvement in the primary endpoint of PFS would translate into an equally significant improvement in OS.
Final results of CLEOPATRA did not disappoint. With a median follow-up of 50 months (range 0-70 months), addition of Perjeta to Herceptin plus docetaxel provided a 15.7-month improvement in OS compared with patients who received Herceptin, docetaxel and placebo (mOS: 56.5 months in the Perjeta arm vs. 40.8 months in the placebo arm; HR=0.68, 95% CI 0.56-0.84, p=0.0002). Updated PFS data were similar to what was published in 2012, with a slight increase in PFS in the Perjeta arm (18.7 months vs. 12.4 months, HR=0.68, p<0.0001). The toxicity profiles between the arms were similar and manageable, with the Perjeta arm experiencing a higher rate of Grade 3 febrile neutropenia (13.7% vs. 7.6%) and diarrhea (9.3% vs. 5.1%). The significant improvement in OS now solidifies Perjeta plus Herceptin and docetaxel as the new standard care in first-line MBC patients.
So what is next? According to Kantar Health’s CancerMPact® Treatment Architecture, Perjeta has already benefited from a significant penetration into the first line setting, with use in one-third of U.S. patients in the year after its launch.3 The question that arises is, can we improve even further on these results, and can we do it by eliminating chemotherapy altogether? One intriguing piece of data presented was the duration of study treatment: While the number of cycles of docetaxel remained the same at eight cycles (range: 1-42 cycles for the placebo arm and 1-52 cycles for the Perjeta arm), the duration of study treatment was extended with the addition of Perjeta from 11.4 months (range: 0.1-66.3 months) in the placebo arm to 17.4 months (range: 0.1-67.7 months) in the Perjeta arm, raising the possibility of prolonged Perjeta and Herceptin combination even after ending the docetaxel portion of the study treatment. The possibility of removing chemotherapy and replacing it with targeted therapy alone has been the Holy Grail in the oncology field ever since Herceptin revolutionized the way MBC is treated. In that vein, the MARIANNE (NCT01120184) study is looking to do just that by examining whether Perjeta and Kadcyla are more efficacious than Herceptin plus Perjeta and a taxane (paclitaxel or docetaxel). In essence, Kadcyla would provide both the targeted therapy and the microtubule-disrupting activity provided by taxanes. Results from this study would certainly provide further impetus for a paradigm shift of complete elimination of chemotherapy in first-line MBC. Results from MARIANNE are expected before the end of this year. Until then, the results from the CLEOPATRA trial provide great hope for patients in a disease that had few options over a decade ago and opens the door for the development of novel and more potent combination therapies in what was once an intractable disease. These are exciting times indeed.
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