Immunotherapy for Consolidation Treatment of Ovarian Cancer—Is This the One?

Abstract & Commentary

Synopsis: Consolidation therapy with oregovomab did not significantly improve TTR overall. A set of confirmatory phase III studies has been initiated to determine whether the SFLT population derives benefit from oregovomab treatment.

Source: Berek JS, et al. J Clin Oncol. 2004;22: 3507-3516.

It has been well described and consistently reported that more than half of advanced ovarian cancer patients achieving complete clinical remission (CCR) following primary surgery and chemotherapy will ultimately recur—the majority within 3 years of treatment completion. This observation has prompted many clinicians and researchers to evaluate alternative treatment strategies to improve, in the short term, the duration of remission—in the long term, overall survival. Berek and colleagues evaluated a novel immunotherapeutic agent, oregovomab (Ovarex™), in this setting with the primary objective of improving time-to-treatment relapse (TTR).

The study methodology was a randomized, double-blinded, placebo controlled trial where patients who had undergone a maximal effort at surgery and chemotherapy and who had achieved CCR were offered participation. The agent, oregovomab, is a murine-derived monoclonal antibody with high affinity for CA-125—the tumor-associated antigen present in more than 90% of non-mucinous epithelial ovarian cancers. Oregovomab, or placebo, was administered to patients at baseline, 4 weeks and 8 weeks after enrollment and then every 12 weeks to 2 years in the absence of tumor progression or toxicity. Tumor recurrence was documented by CT imagery, as the effect of CA-125 immunotherapy on endogenous CA-125 values was not known. Although collected, these values were blinded to Berek as well. Enrollment goals were powered to detect a 50% improvement in TTR with oregovomab. Stratification variables as well as quality-of-life (QOL) parameters were assessed. Overall, the therapy was well tolerated, with few severe adverse events recorded. Likewise, QOL parameters were seemingly unaffected by treatment compared to placebo. Unfortunately, the primary end points were not achieved—no improvement in TTR was detected with oregovomab therapy (13.3 mos vs 10.3 mos; P = 0.71).

Survival data were immature and not presented. In the evaluation of risks for relapse, performance status, CA-125 values before the third cycle of chemotherapy, and baseline CA-125 values were identified as prognostic. Subgroup analysis taking these factors into account identified a population that may benefit from oregovomab therapy, demonstrating more than twice the median TTR in treated patients vs controls. Berek et al concluded that while this consolidation strategy did not significantly improve TTR, the exploratory, hypothesis-generating subgroup analysis provided information to support planned and ongoing clinical trials in selected patients.

Comment by Robert L. Coleman, MD

One of the more difficult aspects of ovarian cancer management is making a solid and convincing recommendation regarding "what to do next" following initial successful therapy. At our disposal are a smorgasbord of options including surgery, observation and additional therapy. Currently, while surgery predominately represents another diagnostic modality for treatment planning, the "second-look" or "reassessment" operation itself is generally not considered standard therapy because we have yet to clearly document that doing the procedure actually improves survival. Indeed, even among those patients deemed in complete remission by pathological assessment, approximately 40-50% will ultimately recur. This event occurs principally from growth of undocumented foci of microscopic or small-volume residual disease. In this regard, additional or consolidation therapy is aimed at addressing this (likely present) disease. Informed counseling involves explaining these clinical facts, providing some estimation of their personal recurrence risk (based on previous findings at surgery, response to therapy by direct or surrogate measures and current disease status) and reviewing the clinical data of trials that have been conducted in this arena. All of these are a challenge to do, but the latter can also be confusing and frustrating to patients who naturally want to maximize their odds of cure.

The confusion stems from the plethora of phase II and III trials that have been conducted in this setting, including hormones, vitamins, radiation, chemotherapy (standard and high dose), radioimmunoconjugates, immune therapy, vaccines, gene therapy, biologics, complementary medicines, and holistic approaches. The delivery is local, regional or systemic and may be relatively invasive and toxic. The frustration (for patients and health care providers) stems from the lack of clear benefit (survival), particularly when one of these "promising" strategies or modalities fails to achieve its anticipated effect when evaluated in formal randomized investigation. To date, the only randomized trial that has demonstrated a clear survival, albeit progression-free survival, advantage has been the GOG/SWOG 178 trial, which found significant improvement in this end point after an additional year of paclitaxel chemotherapy. Of note, 24% of patients randomized to the 12-cycle arm experienced clinical relevant neurotoxicity (grade II/III). The median gain to patients was 7 months and, as discussed in an earlier edition of OB/GYN Clinical Alert,1 some authors have raised the question as to whether similar survival may be achieved by simply adopting a "wait and treat" policy.

The current trial with oregovomab seems to follow suit with most other agents evaluated in this setting.2-4 While unique and interesting in its mechanism of action, the primary objective was not reached. However, all is not lost in that, as is often the case, good clinical design has allowed for preliminary evaluation of other exploratory hypotheses. In the current trial, two important observations were discussed: mounting of individual human anti-mouse antibody (HAMA) titers and subgroup patient selection. In both of these cases, interesting findings have ushered development of follow-up protocols, which may allow this immuno-targeted strategy to succeed in the treatment of advanced ovarian cancer.

References

1. Coleman R. OB/GYN Clinical Alert. 2004;21(8):61-62.

2. Alberts DS, et al. Int J Gyn Can. 2004:14:224-228.

3. De Placido S, et al. J Clin Oncol. 2004; 22:2635-2642.

4. Markman M, et al. J Clin Oncol. 2003;21:2460-2465.

Robert L. Coleman, MD, Associate Professor, University of Texas; M.D, Anderson Cancer Center, Houston Texas, is Associate Editor for OB/GYN Clinical Alert.