Immunotherapy Anti-PD-1 Antibody Nivolumab on Patients with Ovarian Cancer

Ovarian cancer remains a significant cause of cancer morbidity and mortality, even with the use of standard treatments with cytoreductive surgery integrated with platinum-based chemotherapy. Therapy with the monoclonal antibody nivolumab may be an additional type of treatment to which this disease will respond, and this paper reports on the literature concerning nivolumab for various cancers. To date, two studies have been conducted on nivolumab that include ovarian cancer, and these are included in the data set that was taken from the literature review. These data can be found in Table 2.

In Table 2 it can be seen that there are a total of 1683 patients for whom nivolumab was attempted as a type of therapy for various cancers. Of these 1683 patients, 443 exhibited an objective response to the therapy, indicating that there was a measurable decrease in tumor size that was attributable to the therapy. An additional 349 patients maintained stable disease on this therapy, meaning that their tumor(s) was neither shrinking nor growing. Based upon these data, slightly more than 26% of patients responded to the nivolumab therapy with a tumor shrinkage, 20.7% maintained stable disease that was not growing, and this means that a total of 47 percent of patients did not have progressive disease during the time period when nivolumab therapy was being conducted.

These are overall data for many types of tumors, and it is instructive to assess the results of nivolumab for ovarian cancer only. The studies by Brahmer et al. (2012) and Hamanishi et al. (2015) both included patients with ovarian cancer. Hamanishi et al. (2015) included 20 patients, while Brahmer et al. (2012) included 17. Three of the patients in the Hamanishi et al. (2015) study had an objective response, while 1 of the Brahmer et al. (2012) patients had an objective response, for a total objective response by ovarian cancers of 8.1%. Six of the patients in the Hamanishi et al. (2015) study had stable disease and none of the Brahmer et al. (2012) did, for a total of 16.2%. This means that of the ovarian cancer patients studied, 27% did not have progressive disease during the time period when nivolumab therapy was being conducted.

Table 2 redacted for preview. Available with document download.

Dosages

This study was interested in the most efficacious dosage of nivolumab for ovarian cancer, but the data are very limited. The Brahmer et al. (2012) study that included ovarian cancer used an escalating dose over a 14 week time period that went from 0.3 to 10 mg per kilogram of body weight. The Hamanishi et al. (2015) study of only ovarian cancer used up to 24 doses of nivolumab, with half of the cohort taking a dose of 1 mg per kilogram of body weight and the other half taking a dose of 3 mg per kilogram of body weight. Other studies of different cancer types also varied greatly in the dosages that were used, and thus it is difficult to determine what dose would be most effective for ovarian cancer from these data. For the purposes of this paper, since Hamanishi et al (2015) had the largest study that focused solely on ovarian cancer, their data will be used to determine an appropriate dosage, and they found that the best response occurred with the 3 mg per kg body weight dosage.

Limitations

The present study has at least three important limitations. The first is that this is a descriptive study, based upon a literature review, and thus it includes no statistical analysis of its own. The researcher performed this study by conducting a PubMed literature search on the published research of clinical trials that included nivolumab as a therapy for any cancer tumor type. There are thus likely nuances concerning the type of cancer, whether it has been treated prior, length of prior treatment, and other factors that are not included in this result. Along those lines, the dosage and length of treatment varied between studies, and this was not taken into account for the present study.

The second important limitation of this study is that there were very few cases of ovarian cancer included. As mentioned previously, only two studies to date have included ovarian cancer cases in their research protocol, and one of the two only included ovarian cancer cases as a subset of all tumor types studied. Because each type of cancer is different and responds differently to treatment, the results from these two studies are important, but the sample size is relatively small (37 individuals total between the two studies).  Extrapolations have been made about ovarian cancer based upon the data from the other tumors, but these are broad and should by no means be taken as absolute pronouncements on the ability of nivolumab to help shrink an ovarian tumor or even maintain stable disease.

The third limitation of this study is that it is difficult to say anything definitive about dosage of nivolumab necessary for successful treatment (if success is defined as either an objective response or stable disease). The Brahmer et al. (2012) study that included ovarian cancer used an escalating dose over a 14 week time period that went from 0.3 to 10 mg per kilogram of body weight. The Hamanishi et al. (2015) study of only ovarian cancer used up to 24 doses of nivolumab, with half of the cohort taking a dose of 1 mg per kilogram of body weight and the other half taking a dose of 3 mg per kilogram of body weight. Other studies had varying dosages and lengths of treatment, and so it is difficult to ascertain for ovarian cancer from these data which was the most effective dose. For the purposes of this paper, the data from Hamanishi et al. (2015) were used, because they had the largest study of ovarian cancer patients that focused only upon ovarian cancer. It should be noted that the ovarian cancer cohort of the Brahmer et al. (2012) study was nearly as large, however.

Use and Application of Findings

The use and application of the findings from this report are subject to the limitations described above in the sections on limitations. Although these findings are primarily aimed at individuals suffering from ovarian cancer, the results of the studies reviewed here indicate that more than one fourth of patients with various types of cancer tumors experienced shrinkage. Further, when patients who experienced shrinkage of tumors are combined with those who experienced stable disease, meaning that their cancer tumors did not progress, the success rate of nivolumab rises to 47% of patients, which is nearly half. These results strongly suggest that trials with nivolumab and other similar immunological based therapies should continue for patients with ovarian and other types of cancers. Three recommendations will be discussed next: that for more trials with nivolumab, that for an earlier initiation of nivolumab therapy, and that for combination of nivolumab with other types of therapies.

Recommendation 1

Ovarian cancer is a significant cause of morbidity and mortality among women in the world, and despite treatment with the standard methods, most patients experience significant morbidity and mortality from the disease (Mittica et al., 2016). New therapeutic strategies are urgently needed, because every year there are approximately 20,000 women in the United States alone who are diagnosed with ovarian cancer, and more than 14,000 women who die from the disease (CDC, 2016). Even with this urgent need for new therapeutic strategies aimed at ovarian cancer, this literature review found only two trials of a promising new therapy, nivolumab, that have included women with ovarian cancer in them. Further, of these two trials, only one was focused solely upon ovarian cancer. One of the recommendations of this study is therefore that there be more clinical controlled trials on nivolumab as a therapy for ovarian cancer.

Recommendation 2

The second recommendation of this paper is that trials with nivolumab for ovarian cancer begin earlier in the cancer process, for instance upon initial diagnosis of the cancer. Unfortunately, in the two trials in which nivolumab was tested, the cancers had already been treated with the standard platinum based therapy and had been resistant to it. The researchers in the Hamanishi et al. (2015) trial found that nivolumab had good safety and clinical efficacy relative to other types of treatment, with a median progression-free time of survival of 3.5 months and median overall survival time of 20.0 months at the time of the termination of the study. These results suggest that nivolumab may be of use in treatment of ovarian cancers before they reach a more advanced state after platinum therapy has been attempted.

Recommendation 3

The third recommendation is that, in addition to attempting nivolumab therapy earlier in the disease process, as recommended above, it should also be attempted to use nivolumab in combination with other therapies. Larkin et al. (2015) found that a combination of nivolumab and ipilimumab resulted in a significantly increased progression-free survival than did ipilimumab alone. In patients with certain types of tumors there was also longer progression-free survival with the combination than with nivolumab alone. These results suggest that combination therapy may be more effective than single therapy.

Conclusion

This descriptive research project found that there is a limited amount of evidence on nivolumab immuno-editing therapy for ovarian cancer. The report thus broadened to include various other types of cancers for which clinical trials have been conducted with nivolumab. It was learned that among all of these different cancer types, most of which had been refractory to other sorts of treatments, nivolumab therapy resulted in total objective response rate of 26.2%, and a stable disease rate of 20.7% -- indicating that a total of 47 percent of patients did not have progressive disease during the time period when nivolumab therapy was being conducted.

These results are not overwhelming, but they do trend in a positive direction and suggest that more research should be conducted in nivolumab and other immunotherapies for cancers in general, and for ovarian cancer in particular. It was also recommended that trials with nivolumab for ovarian cancer begin earlier in the cancer process, rather than after the tumor has had time to progress, as happens when other therapies are tried first. Along these lines, it was suggested that combining nivolumab with other therapies earlier in the process may lead to better patient outcomes. Overall, the recommendation of this paper is for more cancer trials with nivolumab.

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