CHICAGO (FRONTLINE MEDICAL NEWS) – Artificially prolonging the platinum-free interval by introducing a non–platinum-based chemotherapy before re-treatment with platinum-based chemotherapy in patients with partially platinum-sensitive recurrent ovarian cancer did not improve efficacy, and actually worsened the outcomes in patients in the randomized, open-label, phase III Multicentre Italian Trials in Ovarian Cancer 8 (MITO8) trial.

Based on the findings, immediate re-treatment with platinum-based chemotherapy remains the standard treatment strategy in such patients, Dr. Sandro Pignata reported at the annual meeting of the American Society of Clinical Oncology.

The idea that a non-platinum therapy might artificially extend the platinum-free interval, thereby improving outcomes in ovarian cancer patients who experience recurrence between 6 and 12 months after responding to platinum-based therapy, was first proposed more than 20 years ago. Despite a lack of prospective data with respect to this non–platinum-therapy approach, the idea has been used successfully to market non-platinum chemotherapy agents such as paclitaxel, topotecan, pegylated liposomal doxorubicin (PLD), and more recently, PLD-trabectedin for use before reinitiating platinum chemotherapy, explained Dr. Pignata of S.C. Oncologia Medica Ginecologica, Istituto Nazionale Tumori, Napoli.

In fact, a 2007 retrospective analysis ( SOCRATES ) showed that 35% of patients with recurrence at 6-12 months after platinum-based therapy were treated with a non-platinum single agent before re-treatment with a platinum-based therapy, and that the approach has been used as the control arm in multiple phase III trials that included patients with a platinum-free interval of 6-12 months. The findings indicate that the unproven hypothesis has been adapted into clinical practice, but the investigators were unable to demonstrate an advantage with the approach and concluded that further investigation was warranted.

MITO8, a multi-organization collaborative effort, was designed to test whether artificial prolongation of the platinum-free interval with a single-agent non-platinum treatment would improve overall survival in recurrent partially platinum-sensitive ovarian cancer patients.

In 107 such patients randomized to the experimental arm – receiving a non–platinum-based chemotherapy first to prolong the platinum-free interval, followed by platinum-based chemotherapy after progression – the median time from previous platinum to randomization was 8 months, and from randomization to platinum, 7.8 months. Median overall survival, the primary endpoint of the study, was 21.8 months.

In 108 patients randomized to immediate standard therapy with platinum-based chemotherapy followed by non-platinum therapy, median time from previous platinum to randomization was 8 months, and overall survival was 24.5 months (hazard ratio favoring platinum chemotherapy, 1.38), Dr. Pignata said, noting that the difference in overall survival approached but did not reach statistical significance.

A secondary endpoint of progression-free survival after the second treatment was 12.8 months in the experimental arm, vs. 16.4 months in the platinum-based chemotherapy arm (adjusted HR, 1.41). This difference was statistically significant.

No differences with respect to safety or toxicity were seen between the groups.

MITO8 subjects were women with ovarian cancer recurring between 6 and 12 months after previous platinum-based chemotherapy. The patients had received no more than two prior lines of chemotherapy, had good performance status, and had normal organ function.

Non–platinum-based therapy used in the study included pegylated liposomal doxorubicin, except during a period of the study when the agent was in short supply and other single agents were used, including gemcitabine and topotecan. Most patients, however, received PLD.

Platinum-based therapy was carboplatin plus paclitaxel or, in patients with neurotoxicity at baseline, carboplatin plus gemcitabine.

The shortage of PLD was just one of numerous challenges encountered during the course of the beleaguered study. Enrollment began in 2009, but was temporarily suspended in 2011 because of the PLD shortage. In 2012, the amendment to allow other non–platinum-based chemotherapies to be used was approved at most sites and enrollment resumed. However, accrual slowed and enrollment was closed in 2015. The study was stopped early, and the final analysis was conducted in March 2016 when events plateaued. The investigators, in conjunction with the independent data monitoring committee, determined that the results “still had to be presented early because they still may affect clinical practice.”

Dr. Pignata said that the hypothesis “was based on the fact that there were more responses in the patients treated with a platinum after a non-platinum, but this was not the case … Responses were more frequent in the patients who received platinum first and then non-platinum later,” he said. The response rates for the experimental vs. standard approaches, respectively, were 43% vs. 56% among RECIST responders, and 70% vs. 75% among CA125 responders.

The findings of MITO8, one of the first clinical trials in ovarian cancer to evaluate two different sequences of chemotherapy, send “a strong message that even in the presence of a very nice hypothesis, we have to await the results of prospective clinical trials before changing clinical practice,” he said.

Dr. Maurie Markman of Cancer Treatment Centers of America in Boca Raton, Fla., the invited discussant, praised the work of Dr. Pignata and his colleagues, calling their study “elegant,” and “an extraordinary effort.”

“In this unbelievably important analysis, the hypothesis was flat-out wrong,” he said.

The study is an example of “a simple, provocative, and potentially highly clinically relevant hypothesis that should be able to be quickly tested in either a cooperative group setting, in multiple institutions interested in gynecologic malignancies … when or very shortly after it is initially proposed,” he said.

Waiting 20 years is unacceptable, he said, adding: “This is tragic, this length of time to get an answer. And I must ask … how many ovarian cancer patients over this many-year period have received second-line chemotherapy based on this conceptual approach, and may have actually been harmed?”

To prevent such outcomes in the future, Dr. Markman proposed heavier reliance on “nonrandomized population-based studies including real-world patients managed by a variety of approaches with securely privacy-protected data included within a public database,” to test noninvestigational approaches to disease management.

“And for this database, I would propose ASCO’s CancerLinq ,” he said.

Dr. Pignata reported receiving honoraria from, and serving as a consultant or adviser for AstraZeneca, PharmaMar, and Roche, and receiving research funding from Roche. Dr. Markman is a consultant or advisor for Amgen, Celgene, CritiTech, and Pfizer; is on the speakers bureau for AstraZeneca and Genentech/Roche, and has provided expert testimony for several entities


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