Mixed Findings Show Dose-Dense Therapy Noninferior to IP Treatment in Ovarian Cancer

Paul Sabbatini, MD

Phase III findings of the ICON8 trial demonstrated that patients with ovarian cancer can safely undergo a 3-week dosing schedule of chemotherapy with paclitaxel versus a weekly dose-dense regimen, as neither approach was found to have a benefit in progression-free survival (PFS).¹

The European study, which was presented at the 2017 ESMO Congress, randomized 1566 patients to receive 6 cycles of standard carboplatin AUC 5/6 and paclitaxel at 175 mg/m2 at the standard 3-week dosing regimen (arm 1) or to 2 other regimens, which included once-weekly dose-dense paclitaxel—carboplatin AUC 5/6 with weekly paclitaxel at 80 mg/m2 (arm 2)—or carboplatin AUC2 plus paclitaxel at 80 mg/m2 weekly (arm 3).

Results showed no benefit to either of the once-weekly regimens. Additionally, PFS was 24.4 months with standard dosing versus 24.9 and 25.3 months in arms 2 and 3, respectively.

These results differ from similar previous studies done, including the GOG-252, GOG-262, and the Japanese JGOG3016 trial, which did showcase a 10-month PFS advantage, as well as an OS benefit, with dose-dense weekly paclitaxel versus a standard 3-week schedule.²

OncLive^®: Please provide an overview of your presentation on IP therapy.

What were the data presented at the 2017 ESMO Congress?

Paul Sabbatini, MD, deputy physician-in-chief for clinical research at Memorial Sloan Kettering Cancer Center, discussed the recent data surrounding IP and dose-dense therapy and the next steps for both treatment approaches in ovarian cancer. Sabbatini also highlighted the topic during the 2017 OncLive^® State of the Science Summit™ on Treatment Options in Ovarian Cancer.Sabbatini: There has been a series of clinical trials in the last few years, which have really created some confusion about which modalities to offer people up front in ovarian cancer treatment. For example, the use of IP therapy or not, the use of bevacizumab (Avastin) or not, or the use of dose-dense therapy or not. More recently, additional trials have been done. A trial was reported at the 2017 ESMO Congress, which clarifies a lot of this for us going forward. One question that has been relatively long-standing in upfront therapy for ovarian cancer is whether or not IP therapy should be used. There were some studies in the past that suggested that there were overall survival [OS] and PFS advantages for the use of IP treatment. Probably the best conducted study, GOG-252, just answers the question and says that IP therapy with either cisplatin or carboplatin does not offer any advantage over dose-dense therapy, and that we can be sure of.

One confounding factor in that clinical trial was that bevacizumab was used in all arms, but the take-home point, at least from that trial, is that dose-dense therapy provides the same benefit as IP therapy.

If you fast forward a little bit, the GOG-262 trial asked the question of whether dos-dense therapy was as good as the more standard chemotherapy approach. In this trial, about 84% of patients received bevacizumab. If you look at the group that did not receive bevacizumab, it appears that the dose-dense therapy confers a slight advantage over the standard schedule. It was in the order of magnitude of about 4 months, so that followed a study by the Japanese Gynecologic Oncology Group, which also evaluated dose-dense therapy versus a standard (every 3 weeks) approach. These results demonstrated a much larger PFS advantage of about 10 months, suggesting that dose-dense therapy did, in fact, conferred an advantage.

Then, at the 2017 ESMO Congress, an abstract of the results of ICON8 was presented, which also asked the weekly versus 3-weekly treatment question. In that study, they showed no benefit for dose-dense therapy over a 3-weekly treatment. When you look at that together, you have varying benefit of using dose-dense therapy over standard therapy. There was about a 10-month PFS advantage in the Japanese trial, an approximate 4-month advantage in the GOG-252 trial, and approximately no benefit in the ICON8 trial.

We have to start to think about how we might explain that. One, there is a pharmacogenetic question in the Japanese patient population—very homogenous—and we’ve seen this with drug development with other drugs in that population. Drug metabolism can be different and pharmacogenetics can be different, so maybe there is some pharma conjunction and a difference in the Japanese study versus the European study or US study. If you look at the US study and then the ICON8 study, you get this 4-month to zero benefit.

The take-home message from all of this is that, for now, based on the recent 2017 ESMO Congress data, as well as the past GOG-252 and GOG-262 data, there is really no reason to offer patients primary therapy with an IP approach [over] a dose-dense approach. Again, more information has to come from the ICON8 trial. Most of the information suggests that dose-dense therapy and perhaps the every-3-week regimen has the same benefit.

Finally, why that is important is that it is really time for us to decide on a primary regimen and move beyond. If you look beyond the new drugs we have—PARP inhibitors, other anti-vascular agents beyond bevacizumab—we need to be able to integrate those into frontline therapy. It is very hard to integrate that into an IP platinum approach because of the toxicity, and much easier to integrate it into the more weekly approaches.

Can we take any next steps or novel approaches that we can try with IP therapy or dose-dense therapy?

Is IP therapy used in other gynecologic malignancies or just in ovarian cancer?

One final comment is that if one looks at the OS of the subsequent studies that have been reported—for example, in GOG-252—it looks like it will be markedly longer than traditional studies. If this is the case, it tells us we’re getting better despite the fact that we may not have achieved what we wanted in a primary therapy setting—probably implying that recurrent therapy has been effective. There is. The benefit of just saying now that we can use dose-dense therapy or every-3-week therapy allows us to do a lot of additional combinations in the primary therapy setting. Therefore, whether we add a PARP inhibitor, which is being done, and looking at maintenance therapy, whether we add other anti-vascular agents, anti— vascular-disrupting agents, or other novel compounds, or whether we consider immune strategies for maintenance or immune combination strategies, these can all be done with a dose-dense or every- 3-week schedule. It would be very difficult to try and incorporate those into an IP with cisplatin question. That is what this information has given us. IP therapy has been traditionally used in the gynecologic world just in ovarian cancer. It has been used in other gynecologic malignancies with other agents, as well. In terms of endometrial or cervical cancer treatment, because of the pattern of spread of those diseases, you wouldn’t use the IP approach.

There was certainly growing enthusiasm behind dose-dense therapy, and the ICON8 results are a bit unexpected. They are so new and only presented at the one meeting, and, before we make a statement, it’s worth that we look at those results more thoroughly. Clearly, there is an order-of-magnitude difference in what the Japanese showed in their dose-dense therapy study and what the GOG-252 and GOG-262 showed and then, of course, with ICON8 not showing a benefit. Probably somewhere in there is the truth, but certainly not the benefit that we had expected from the Japanese study in all patients.

References

1. Clamp AR, McNeish I, Dean A, et al. ICON 8: a GCIG phase III randomised trial evaluating weekly dose- dense chemotherapy integration in first-line epithelial ovarian/ fallopian tube/ primary peritoneal carcinoma (EOC) treatment: results of primary progression-free survival (PFS) analysis. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 929O_PR.
2. Katsumata M, Yasuda M, Isonishi S, et al; Japanese Gynecologic Oncology Group. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol. 2013;14(10):1020-1026. doi: 10.1016/S1470-2045(13)70363-2.