New data from the GOG 0213 ovarian cancer trial has shown that the addition of the antiangiogenic agent bevacizumab (Avastin, Genentech/Roche) to combination chemotherapy resulted in a "clinically meaningful" improvement in overall survival (OS), although it just missed achieving statistical significance.
Previous data from clinical trials in ovarian cancer have shown significant improvement in progression-free survival, which led to approval for this indication, but they did not show differences in OS. However, these previous trials did not have OS as the main endpoint, whereas the GOG 0213 did.
"It used to be that if you had a patient who was diagnosed with any recurrence of ovarian cancer, whether it was platinum-sensitive or platinum-resistant, you would have to say, 'You're looking at a year to two,' " commented Shannon Westin, MD, from the University of Texas MD Anderson Cancer Center, in Houston.
"Now, with these new regimens, patients are getting out to nearly 4 years, which I think is very reassuring," she added. Even patients in the control group (which did not receive bevacizumab) are living for a median of 3 years, she noted.
"And while we'd love to cure this disease, we have made incremental improvements over time," Dr Westin told Medscape Medical News.
The new results come from the GOG 0213 study and were presented at the Society of Gynecologic Oncology's (SGO's) annual meeting on women's cancer. Dr Westin acts as a spokesperson for the society, and was approached to comment on the news.
What is important about the GOG 0213 study is that it almost achieved a statistically significant OS benefit in favor of additional bevacizumab, Dr Westin said. She also pointed out that women who received additional bevacizumab enjoyed a significantly prolonged interval before the disease progressed, compared with standard chemotherapy alone.
"What I think is remarkable about this study was that we're starting to see these extremely long overall survivorship expectations," principal investigator Robert Coleman, MD, of the University of Texas MD Anderson Cancer Center, Texas, told Medscape Medical News.
"In this trial, we're now breaching past 40 months in overall survival, and that's just a really impressive migration in expectation of survivorship in this patient population."
Details of the Results
The GOG 0213 study was a large phase 3 trial that included 748 women with platinum-sensitive, recurrent ovarian, peritoneal primary, and fallopian tube cancer. The median age of the cohort was 60 years, and the predominant histology was serous.
The patients were randomly assigned to receive combination chemotherapy (paclitaxel plus carboplatin) with or without the addition of bevacizumab (15 mg/kg).
At the meeting, Dr Coleman and colleagues reported that compared with the standard platinum-based doublet arm, the hazard ratio (HR) for death was 18.6% in favor of the those assigned to receive additional bevacizumab.
This corresponds to a median OS of 42.2 months for the bevacizumab-containing arm compared with a median of 37.3 months for the standard chemotherapy arm (HR, 0.827; 95% CI, 0.683 - 1.005; P = .056).
As with previous trials, this trial showed a significant improvement in progression-free survival, which was 13.8 months with the addition of bevacizumab compared with 10.4 months for women receiving standard chemotherapy alone.
"However," Dr Coleman said, "that median PFS interval of 3.5 months in favor of bevacizumab really undermines the true benefit of the drug, which is better measured by the hazard ratio."
With an HR for PFS of 0.614 (95% CI, 0.522 - 0.722; P < .0001), "this means that there is nearly a 40% reduction in the hazard for progression across all time points of exposure to bevacizumab," Dr Coleman added.
"And if you look across the board at trials that have evaluated this class of drugs, we see changes in PFS in all of them that are pretty consistent."
Addition of Bevacizumab Adds Toxicity
As expected, the addition of bevacizumab to standard chemotherapy was associated with more toxicity than standard chemotherapy alone.
Reassuringly, Dr Coleman observed, "none of the safety signals we saw in this trial were new, which is important."
| Toxicity (Grade 3+) | Standard Chemotherapy | Standard Chemotherapy Plus Bevacizumab | P-value |
| GI perforations, necrosis, fistula (any grade) | 4% | 14.8% | <0 .001="" td=""> |
| GI perforations, necrosis, fistula | 1% | 1.85 | 0.5 |
| Infections | 5.8% | 13.0% | 0.002 |
| Joint pain | 4.6% | 15.1% | <0 .001="" td=""> |
| Proteinuria | 0% | 8.1% | <0 .001="" td=""> |
| Venous thrombosis | 1.2% | 3.9% | 0.046 |
| Febrile neutropenia | 2.7% | 6.1% | 0.06 |
"Understanding how to manage these adverse events is probably the most important aspect of mitigating them," Dr Coleman commented. "We've probably treated about 4000 patients with bevacizumab chemotherapy-based trials over the years, and we've learned you need to be very aggressive with hypertension when it occurs, and we've learned how to mitigate issues with proteinuria when it occurs."
FDA Approval of Bevacizumab
The US Food and Drug Administration (FDA) approved bevacizumab for the treatment of recurrent ovarian cancer in November 2014.
The agency made its decision on the basis of results of the phase 3 AURELIA study, which demonstrated a 62% reduction in the risk for progression in the additional bevacizumab arm at 6.8 months compared with standard chemotherapy at 3.4 months at an HR of 0.38 (95% CI, 0.38 - 0.49; P < .0001).
There was, however, no statistically significant difference in OS between the two treatment arms, at a median OS of 16.6 months with additional bevacizumab compared with 13.3 months for the standard chemotherapy arm.
It is noteworthy that the AURELIA study was carried out in platinum-resistant ovarian cancer.
Similarly, another phase 3 trial, known as the OCEANS study, demonstrated that the addition of bevacizumab following chemotherapy — in this study, carboplatin and gemcitabine — until disease progression provided a clinically meaningful benefit in recurrent ovarian cancer, reducing the risk for disease progression by 52% compared with standard chemotherapy alone.
At the time the OCEANS study was reported, OS data were still immature, but more recent reports indicate there was no difference in OS between the two arms.
The GOG 0213 study was funded by the National Cancer Institute. Neither Dr Coleman nor Dr Westin have declared any relevant financial relationships.
SGO 2015. Abstract 3. Presented March 28, 2015.
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