At that same meeting at ASCO the fly in the ointment was presented. That was GOG protocol 132. This study was done while we were waiting for the data on GOG 111 to mature. This randomized patients with large volume advanced disease to either cisplatin, Taxol or a combination of Taxol plus cisplatin, with the Taxol given as a 24 hour infusion. Again, each regimen was given every three weeks for a total of six cycles.
While we thought we knew what the results of this study would be before we started, and what we found out was that there is no significant different difference in overall survival. The Taxol single agent arm gave a lower response rate and a shorter progression-free survival, but overall survival was exactly the same. You might ask yourself, “Why did this study differ from OV10 and GOG111?” Well the circumstances were quite different. When GOG111 and OV10 were done Taxol was not available for salvage therapy in those countries. In the U.S. for 111 and in Canada and Europe for OV10. So patients who were assigned a Cytoxan/cisplatin did not get salvage Taxol. On the other hand, when this study was done, Taxol was commercially available and in fact what happened was that at the end of six cycles of therapy if patients had any residual disease left, they immediately got salvage therapy.
Patients assigned to the cisplatin arm got Taxol and patients assigned to the Taxol arm got cisplatin.
Patients assigned to the combination arm got a whole hodgepodge of different things, most of which probably did absolutely nothing or even harmed the patient.
So as a result, half the patients got some form of salvage therapy and we believe the crossover to the opposite drug accounts for the blunting of the survival differences that you see in the study. Also this was not merely salvage therapy. This was immediate use of the other drug without waiting for disease progression to take place. So in effect what we were really studying here was sequential cisplatin for six cycles followed by Taxol for 6-12 cycles or Taxol for six cycles followed by cisplatin for six cycles, or concurrent therapy. We proved something here that I think is going to turn out to be very useful for us. We’ve proved that you can give drugs concurrently or sequentially and achieve the same results. That sort of approach is going to be applied in trying to introduce additional active new agents to up front therapy, that is, sequential doublets will probably be used in that experimental approach.
Now the most recent study to be completed was ICON-3, the International Collaborators on Ovarian Neoplasms study number 3. This study was conducted in the United Kingdom and Italy. About 70% of the patients came from the United Kingdom, about 30% from Italy. Patients here were randomized to the experimental arm of Taxol/carboplatin, Taxol given as a three hour infusion followed by carboplatin. Or to one of two control arms. Each institution had to select which control arm the institution would use; either carboplatin alone or a three drug combination of Cytoxan, Adriamycin and cisplatin.
All stages of the disease were allowed onto this study. So this study includes stage I, stage II, stage III and stage IV patients. One-third of the patients in the study on the control arm also received salvage Taxol. So there will be some blunting of any survival differences as you would expect, because of the salvage therapy. Seventy percent of the control patients received single agent carboplatin as a control, 30% received a three drug combination. Now I should tell you that there was an ICON study, ICON-2, that showed no difference between the three drug combination and carboplatin so it’s reasonable to lump the control arms. Now if you attended ASCO and attended the GYN session you know that the ICON investigators presented the following data; in terms of progression-free survival, no difference between the two arms.
In terms of overall survival, no difference between the two arms. What they did not present was presented by Dr. McGuire in his discussion and was obtained from one of the ICON collaborators and that is a more detailed breakdown of the data. And this is a very important subset analysis; 622 of the patients had stage I disease. Only 83 events had occurred in that subset. Too few events to allow any meaningful conclusions to be drawn. But 1,452 of the patients had either stage III or stage IV disease and among those 1,452 there had been 544 events, enough events to allow valid conclusions to be drawn. In this subset, which is the same subset studied in OV10 and a similar subset to GOG111, hazard ratio was 0.82 and that is statistically significant at a P value of 0.03. So in the same population of patients studies in OV10 and GOG111 you see the same result, a benefit from concurrent Taxol, platinum administration. If you put all four of these trials on the same slide you will note that three of the four, GOG111, OV10 and ICON-3, show a clear value for the Taxol/platinum combination. One, GOG132, shows no difference but is accounted for the immediate rather than the salvage use of the opposite drug. The weight of evidence in these four studies speaks to the standard of care as being a combination of Taxol and platinum. And if you are asked that on the Boards, that’s what your answer is.