Background:

There is consensus that combination therapy will be key to cure cancer or stabilize tumors in a durable way. Combining radiation therapy with dual checkpoint inhibition, CTLA-4 and PD-(L)1, improves survival in different mouse models and is currently being tested in a clinical trial in gynecological cancer. However, the price of novel anticancer drugs, including checkpoint inhibitors, routinely exceeds 100 000 USD per year of treatment. This financial toxicity brings the affordability of cancer care at stake for both patients and national healthcare services.

Radiotherapy activates antigen presenting cells and provides antigens through immunogenic cell death. Checkpoint inhibitors unleash the brakes of tumor specific T cells. We hypothesized that additional modulation of the tumor microenvironment by targeting myeloid derived suppressor cells, regulatory T cells, acidity, vasculature and inflammation could potentially further improve the efficacy of PD-1 inhibition and radiotherapy. This PRIMMO trial (NCT03192059) aims to achieve this without further increasing the financial toxicity.

Brief Methods:

Treatment consists of daily intake of 3 low-cost repurposed drugs (vitamin D, lansoprazole and aspirin), metronomic chemotherapy (cyclophosphamide) and a food supplement (curcumin), starting 2 weeks before the first pembrolizumab dose of 6 cycles. Stereotactic radiation (3 x 8Gy, 48h apart) starts on the same day as the first pembrolizumab dose.

The safety run-in consists of 6 patients. In total, this phase 2 study will recruit respectively 18 and 25 evaluable recurrent/refractory cervical and endometrial carcinoma patients in 2 separate cohorts. Uterine sarcoma patients are recruited in a separate cohort, but due to the rarity of the disease we do not expect a sufficient number of patients for statistical considerations.

Price calculation of the 5 immunomodulators in Belgium was based on the Belgian center for pharmacotherapeutic information (www.bcfi.be) on January 2018. Cost mentioned for the Netherlands is according to Zorginstituut Nederland (www.medicijnkosten.nl).

Results:

Currently 16 out of 18 cervical cancer patients and 18 out of 25 endometrial cancer patients are recruited. The primary endpoint is objective response rate at week 26 according to immune related response criteria. As secondary endpoints we will assess safety, objective response rate at week 26 according to Response Evaluation Criteria in Solid Tumors, best overall response, progression-free survival, overall survival and quality of life. Based on the official public prices, 25 weeks of treatment with the 5 immunomodulators added to PD-1 blockade and radiotherapy costs 698,62 euro in Belgium and 625,61 euro in the Netherlands, thus significantly lower than the launch price of new drugs.

Conclusion:

If encouraging results are found, it would be a more affordable way to increase the response rate to the expensive PD-1 blockade and radiotherapy than combination with novel anticancer drugs. Moreover, since repurposed drugs are already-approved for a non-oncology primary purpose, they are widely available and can be brought faster to patients. Therefore, the PRIMMO trial can inspire others to run investigator driven trials that explore the potential of combination treatments with drug repurposing to limit financial toxicity.

Funding:

This trial is supported by Kom Op Tegen Kanker and the Anticancer Fund.

Read more on the PRIMMO trial here.