In Managing Ovarian Cancer, Precision Medicine Is a Work in Progress


Get Permission

Steven B. Newman, MD

The biology of these tumors is different enough that any one [targeted agent] for any one target is probably going to be limited in scope. At the end of the day, this is going to lead to a cavalcade of drugs that may be useful in a specific tumor, but not overall, the way paclitaxel and carboplatin are?

—Steven B. Newman, MD

Precision medicine in the management of ovarian cancer “is a work in progress, to be sure,” Steven B.
Newman, MD
, noted in wrapping up the session on gynecologic cancer at the recent Best of ASCO meeting in Chicago. “A list of different histologic types of ovarian cancer and potential targets are currently being looked at,” he said, but much work needs to be done in matching specific genetic sequences, defects, and therapeutic agents. Dr. Newman is Associate Professor of Clinical Medicine-Hematology/Oncology at Northwestern University, Feinberg School of Medicine, Chicago.

“Progress in extending the lives of women with recurrent ovarian cancer has hit a therapeutic ceiling. A lot of that has to do with the fact that the best therapy, which is given upfront, is really the only good therapy we have. While these molecular targets may in fact have added value going forward, the targets are going to have to be considerably more precise than they are now,” Dr. Newman continued.

“The biology of these tumors is different enough that any one compound for any one target is probably going to be limited in scope. At the end of the day, this is going to lead to a cavalcade of drugs that may be useful in a specific tumor, but not overall, the way paclitaxel and carboplatin are,” he added.

MUC1 Dendritic Cell Vaccine Immunotherapy Targets Mucin

The phase II open-label CAN-003 trial of, a targeted therapy known as CVac (made by culturing autologous dendritic cells with a mucin 1 fusion protein), was among the gynecologic cancer studies summarized at Best of ASCO. An autologous cellular therapy intended to elicit a killer T-cell response specific to mucin 1–overexpressing ovarian cancer cells, CVac produced a significant improvement in progression-free survival over observational standard of care in patients with epithelial ovarian cancer who had obtained a complete response after second-line chemotherapy.1

Mucin 1 is overexpressed in several cancers, including 83% of ovarian cancers, and “should in theory be a reasonable target,” Dr. Newman observed.

Among the 56 patients in the intent-to-treat population, 29 were randomly assigned to 10 doses of CVac over 56 weeks and 27 to observational standard of care. All patients had stage III or IV epithelial ovarian cancer, and 42 had achieved a complete response to standard first-line chemotherapy, while 21 had achieved a complete response to second-line chemotherapy.

Progression-free survival was significantly improved in 20 patients in second-line complete response receiving CVac compared to standard of care. In the second-line complete responders, the median progression-free survival was 4.94 months for patients receiving observational standard of care, but for patients receiving CVac, the median progression-free survival was not reached but greater than 12.91 months (P = .04). Progression-free survival was not improved among patients with a complete response to first-line chemotherapy receiving CVac (hazard ratio [HR] = 1.8; P = .69). The overall median progression-free survival was 8.64 months with observational standard of care and 12.89 with CVac.

Nine serious adverse events occurred. None were unexpected, and only one (small bowel obstruction) was classified as “unlikely–related to CVac,” the researchers reported.

CVac therapy is “feasible and doable,” Dr. Newman said. Many questions remain about overall survival, but “I think the important thing to take home here is that there is a target,” he added.

Predicting Benefit From Bevacizumab

Following the identification of an immune molecular subgroup of high-grade serous ovarian cancer with superior survival, researchers from the United Kingdom hypothesized that since this subgroup had repressed angiogenesis-related gene expression, these patients would benefit less from bevacizumab (Avastin). A 63-gene expression signature was generated to prospectively identify this subgroup and validated as prognostic for overall survival.

The gene signature was then applied to translational research samples from the ICON 7 study of paclitaxel/carboplatin with and without concomitant and maintenance bevacizumab for first-line treatment of ovarian cancer. The assay showed that for patients in the immune molecular subgroup (41% of cases), the addition of bevacizumab resulted in worse progression-free survival (HR = 1.73, 95% confidence interval [CI] = 1.12–2.68) and overall survival (HR = 2.00, 95% CI = 1.11–3.61) compared to chemotherapy alone.

Two other subgroups identified had angiogenic gene upregulation, and among patients in the proangiogenic subgroups, there was a nonsignificant trend to improved progression-free survival with the addition of bevacizumab (median, 17.4 vs 12.3 months), the researchers noted in their ASCO Annual Meeting abstract.2 “These data suggest a mechanism for stratification of [bevacizumab] therapy and should be validated in additional datasets,” the authors concluded.

“This is a really important paper,” Dr. Newman commented. “We’re talking about the administration of an extremely expensive compound” that in many cases has, at best, only marginal survival benefit to patients. “There does appear to be a group of patients for which the addition of bevacizumab not only doesn’t help,” Dr. Newman said, but can actually be associated with less favorable outcomes. By identifying patients most likely to benefit from a drug, studies such as this may drive discussions about the value of a specific drug, Dr. Newman noted.

First-Line Standard of Care

A Japanese Gynecologic Oncology Group (JGOG)/Gynecologic Cancer Intergroup (GCIG) phase III trial compared paclitaxel/carboplatin to cisplatin/irinotecan as first-line chemotherapy in patients with clear cell carcinoma of the ovary. A histologic subtype of epithelial ovarian cancer, clear cell carcinoma represents 19% of ovarian cancers in Japan, but only 6% in the United States.

“[Clear cell carcinoma] has become well known for its resistance to current standard chemotherapy [paclitaxel/carboplatin]. Our previous trial demonstrated the potential benefit of [cisplatin/irinotecan] regimen on [clear cell carcinoma],” wrote the Japanese researchers in their ASCO abstract.3 In the current trial, however, progression-free survival, the primary endpoint, was not significantly different between the two study arms.

“Sometimes good intentions go unrewarded, and this is one of those situations,” Dr. Newman said. “Carboplatin/paclitaxel remains the standard of care.” He noted that over the years, “there has certainly been no shortage of randomized trials comparing other agents to carboplatin/paclitaxel.”

At 44.3 months’ median follow-up, 2-year progression-free survival among the 314 evaluable patients in the cisplatin/irinotecan arm was 73.0% (95% CI = 67.7–77.5) vs 77.6% (95% CI = 72.4–81.9) among the 305 evaluable patients in the paclitaxel/carboplatin arm (HR = 1.171, 95% CI = 0.867–1.581, P = .303). The 2-year overall survival rates were 85.5% in the cisplatin/irinotecan arm (95% CI = 81.1–89.0) and 87.4% in the paclitaxel/carboplatin arm (95% CI = 83.1–90.7; HR = 1.133, 95% CI = 0.796–1.613, P = .486).

“In the early stage of the disease, there is absolutely no difference whatsoever,” Dr. Newman said. “In the later stages, there is some difference. It does not approach statistical significance, but there appears to be some advantage to the [cisplatin/irinotecan] regimen.”

Grade 3/4 leukopenia, neutropenia, thrombocytopenia, peripheral sensory neuropathy, and joint pain occurred more frequently in the paclitaxel/carboplatin arm (P < .05), whereas grade 3/4 anorexia, diarrhea, nausea, vomiting, and febrile neutropenia occurred more frequently in the cisplatin/irinotecan arm (P < .05).

“Since both regimens were well tolerated and the toxicity profiles were different, CPT-P can be an alternative regimen for [clear cell carcinoma],” the study’s authors stated.

Previously Reported Studies

Dr. Newman also reviewed two other ovarian cancer studies presented at the 2014 ASCO Annual Meeting. A phase II trial, reported in detail in the June 25, 2014, issue of The ASCO Post, found that the oral investigational agents olaparib and cediranib nearly doubled progression-free survival in women with platinum-sensitive recurrent ovarian cancer.4 A phase III trial, described in the same issue of The ASCO Post, suggested that neoadjuvant chemotherapy followed by interval debulking surgery may be a better strategy for the initial treatment of advanced ovarian cancer.

Disclosure: Dr. Newman reported no potential conflicts of interest.

References

1. Gray HJ, Gargosky SE: Progression-free survival in ovarian cancer patients in second remission with mucin-1 autologous dendritic cell therapy. ASCO Annual Meeting. Abstract 5504. Presented May 31, 2014.

2. Gourley C, McCavigan A, Perren T, et al: Molecular subgroup of high-grade serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab. ASCO Annual Meeting. Abstract 5502. Presented May 31, 2014.

3. Okamoto A, Sugiyama T, Hamano T, et al: Randomized phase III trial of paclitaxel/carboplatin (PC) versus cisplatin/irinotecan (CPT-P) as first line chemotherapy in patient with clear cell carcinoma (CCC) of the ovary. ASCO Annual Meeting. Abstract 5507. Presented May 31, 2014.

4. Liu J, Barry WT, Birrer, MJ, et al: A randomized phase 2 trial comparing efficacy of the combination of the PARP-inhibitor olaparib and the anti-angiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. ASCO Annual Meeting. Abstract 5500. Presented May 31, 2014.

5. Onda T, Yoshikawa H, Shibata T, et al: Comparison of treatment invasiveness between upfront debulking surgery versus neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in phase III randomized trial. ASCO Annual Meeting. Abstract 5508. Presented May 31, 2014.

 



Advertisement

Advertisement



Advertisement