**3.6 Case 6**

Another case of very rapidly growing advanced cancer showing complete remission following ingestion of 200 mg/day oral mifepristone was an 80-year-old woman with a history of chronic lymphocytic leukemia who developed sudden onset respiratory failure with a po2 of 72 mmHg. Chest X-ray revealed many lung lesions with a radiographic diagnosis of probable advanced lung cancer with multiple metastatic lesions. Her serum sodium was 118 mmol/L. She refused a surgical diagnosis or chemotherapy based on the presumptive clinical diagnosis of small cell lung cancer with the syndrome of inappropriate anti-diuretic hormone (SIADH) and the bleak prognosis, even with chemotherapy [42].

She sought an alternative treatment and agreed to mifepristone therapy 200 mg orally daily. Within 1 month her po2 returned to 99-100 mmHg without supplemental oxygen. Her serum sodium increased to normal at 145 mmol/L. Her CT-scans showed complete disappearance of all lung lesions even 5 years after initial diagnosis. There did remain, however, a ground glass appearance in the lungs. She died 5½ years later at the age of 85.5 from an acute myocardial infarction, not from lung cancer [42].

Interestingly, though we know that PIBF is secreted by leukemia cell lines and is suppressed by mifepristone, this woman's CLL slowly progressed while her rapidly growing presumed small cell lung cancer had a complete remission [19]. This could suggest that mifepristone acts better on rapidly growing cells than slowly growing cancers. Of course, it is possible that the mifepristone helped keep the CLL slow growing, but that could simply be related to the normal situation of slow progression with CLL even without treatment. It should be noted that lung cancer, whether small cell or non-small cell (which is still possibly the type of cancer this woman had though small cell was more likely because of the clinical picture) is not known to be associated with nuclear P receptors.

Many cancer therapies are ineffective for brain metastases or primary brain cancers because they cannot cross the blood-brain barrier. There is anecdotal evidence that mifepristone can cross the blood brain barrier and provide palliative benefits for primary brain cancer and brain metastases.

*Progesterone and Glucocorticoid Receptor Modulator Mifepristone (RU-486) as Treatment… DOI: http://dx.doi.org/10.5772/intechopen.93545*

## **3.7 Case 7**

A 43-year-old male with a 3-week history of severe protracted headaches was found to have a large glioblastoma multiforme grade IV that originated in the temporal lobe but involved also the frontal, parietal and temporal lobes and metastases to the spinal cord. Despite surgery, radio and chemotherapy, the tumor rapidly progressed. He was not considered a candidate for any other therapy. At the time of starting mifepristone therapy, he was paralyzed from the neck down and his hands were fixed in the clenched position. He slept most of the day, and when awake, was not able to carry out conversations [43].

Within 2 weeks of treatment with 200 mg oral mifepristone daily, he became much more alert and was able to carry out intelligent conversations. He was now able to open his clenched fists and move his hands. He continued treatment for 3 months and remained alert. However, his paralysis slowly progressed to the point where he was having trouble breathing and swallowing. The mifepristone was stopped, and he died 2 weeks later [43].

### **3.8 Case 8**

Another case demonstrating that mifepristone can cross the blood brain barrier to thwart brain metastases from progressing is a case of a 68 year old male with stage IV metastatic non-small cell adenocarcinoma lung cancer with brain metastases who was referred by his oncologist for mifepristone therapy [44]. Based on the experimental data with efficacy of mifepristone inhibiting growth of cancer cell lines, the beneficial effect in controlled various murine carcinomas, and the anecdotal benefits in individual causes with various advanced cancers following single agent mifepristone therapy the FDA approved our investigator imitated study entitled "A phase II study of treatment with oral mifepristone as salvage therapy in patients who have failed two or more previous chemotherapy regimens" (www.clinicaltrials.gov).

He had no tumor markers that could provide him targeted therapy. His cancer progressed despite 3 rounds of multi-agent chemotherapy including carboplatin/ avastin/docetaxel, pemetrexed, and gemcitabine. In October of 2015 he had a seizure and magnetic resonance imaging indicated a 1 cm right frontal lobe metastatic lesion. He received palliative stereotactic radiotherapy to the brain lesion which was completed in November 2015.

With deteriorating symptoms, for example, dyspnea on exertion and fatigue and with no other treatment options available (PD-L1 marker was negative and checkpoint inhibitors were not approved for PD-L1 negative patients at this time), he was referred for our FDA study.

In all previous cases, the 200 mg mifepristone tablets were obtained from Danco Inc. at a cost of about \$500 per month. For the FDA approved investigator-initiated study, we decided to use mifepristone 300 mg tablets daily because the company Corcept, Inc. which manufactures the 300 mg tablet for treatment of Cushing's syndrome (though the dosage is generally much higher than 300 mg to block the glucocorticoid receptor) was willing to provide the drug free to approved patients.

His clinical symptoms improved significantly within 1 month of treatment with single agent oral mifepristone 300 mg daily. He was ECOG 1 at the start of therapy and after 1 month was ECOG zero. He remains ECOG zero after 4.8 years of treatment, and for the majority of visits, he answers his 43 questions on the quality of life evaluation as "not at all" (the best answer that could be given). There has been no evidence of growth of his previous brain metastases or any new lesions by MRI testing.

One additional important piece of information that his case provides. His metastatic lesions remained stable for 1.5 years. But after 1½ years, some lesions began to grow slowly. His oncologist, based on his experience with other anticancer agents, thought that once disease progression began, it usually accelerates rapidly. He thus suggested to the patient that he stop the mifepristone, and consider nivolumab or pembrolizumab, which had at this time been tried on some patients who were PD-L1 negative, or consider another biopsy to determine if a new tumor marker could be found that would allow targeted therapy. The patient feeling so good on mifepristone therapy and feeling so poorly on all of his previous chemotherapy regimens, opted to take our advice and continue on the mifepristone therapy. Now 3.5 years later and still feeling great, he is very satisfied with his decision not to stop mifepristone therapy [44].

This case exemplifies the mistakes, from lack of experience, that we alluded to in some of the previous case reports, that is, one should not stop the drug if there is the start of tumor progression. There is still a good chance the drug will provide continued extension of a good quality life. Naturally, if a new therapy is likely to be more effective than the mifepristone therapy, then it would make sense to try the new agent. But it makes no sense to try a completely new experimental drug with unknown side effects, as tried by some of the previous described cases. Furthermore, experience suggests that mifepristone inhibits metastases, but cessation of therapy results in rapid spread. This progression can be so rapid that it could be too late to resume mifepristone therapy if the new anticancer therapy is not working.

Therapy with mifepristone could be considered hormonal therapy, but because its hypothesized mechanism is that it removed a block (i.e., PIBF), and thus allows the cellular immune system (especially NK cells) to attack cancer cells, it could also be considered a form of immunotherapy. The question arises as to whether the drug would be effective in cancers positive for the programmed cell death protein ligand 1 (PD-L1) marker where there was initial response to immunotherapy with a checkpoint inhibitor but where the tumor was now showing resistance.

#### **3.9 Case 9**

We did describe a case of a 66-year-old woman with stage IV non-small cell lung cancer, who not only had the PD-L1 marker, but also her cancer was positive for the epidermal growth factor receptor (EGFR). When her cancer began progressing following chemotherapy with carboplatin, pemetrexed and bevacizumab regimen and the carboplatin and docetaxel regimen, she was started on a targeted therapy for the EGFR marker, erlotinib [45]. At that time, there was only first-generation tyrosine kinase inhibitors.

When her cancer progressed despite erlotinib, she was treated with 11 cycles of the check-point inhibitor nivolumab. It was stopped after 11 months because it was apparent the drug was no longer inhibiting her cancer progression. She qualified for the investigator-initiated study, and thus she was treated with the 300 mg oral daily dose of mifepristone [45].

After 18 months of oral 300 mg single agent mifepristone therapy, there had been no cancer progression based on lung CT scans performed every 2 months. In fact, some lesions were actually smaller. She was considered ECOG 1 at the start of mifepristone therapy. At the end of 1 year, she was still ECOG 1 with a good quality of life and normal physical activity.

After 1 year, her pre-existing severe chronic obstructive pulmonary disease (COPD) worsened and she required supplemental oxygen to keep her po2 above 80 mmHg. Based on her COPD, but not her cancer which still had not progressed, at *Progesterone and Glucocorticoid Receptor Modulator Mifepristone (RU-486) as Treatment… DOI: http://dx.doi.org/10.5772/intechopen.93545*

18 months from initiation of treatment, she was an ECOG 3. She died 2 months later from pneumonia.

Thus, this patient not only showed that mifepristone can prolong life and provide a good quality of life not only in a patient whose lung cancer is positive for the PD-L1 marker, but a person who also has the EGFR mutation [45].

Anecdotal cases are important, but more influential to other physicians would be a larger series. Even better would be a controlled trial with sufficient power, and the very best, a study that has all these qualifications, but is also multi-centered. The FDA approved the aforementioned investigator-initiated study for 40 patients. It is not considered ethical to have patients with such severe disease and subject them to placebo controls. Thus, the study was to evaluate in a larger series the efficacy of mifepristone therapy for advanced lung cancer and compare outcome to historical controls, that is, from quality of life to life expectancy, when dealing with a similar group of patients with lung cancer that has stage IV and failed at least two chemo or immunotherapy regimens.

We were allowed two principal investigators. However, as an investigatorinitiated study with no funds provided to the principal investigator by a pharmacological company or a grant, we could not find a principal investigator who treats a larger population of patients with lung cancer. Thus, we became, by default, the only principal investigator. Unfortunately, it is not totally clear to us as to the reasons, but despite our efforts we have only recruited the two aforementioned patients that were treated in this investigator-initiated study. Perhaps some of the fault lies in making the criteria for registering too harsh, but most of the problem is that we have not been referred very many patients to even screen for the study. Even the physician who referred us our first case who still is doing so well after almost 5 years of single agent mifepristone therapy, plus years with no side effects, has not referred us another patient [44]. We asked him if he had more patients and he stated that he could send us 40 patients in 1 year, but patients do not want to travel 100 miles every month to receive the medication. This seem unbelievable but this was also related to us by an oncologist whose research with us involving PIBF helped him get into medical school, where the patients would only have to travel only 15 miles. He was supposed to be our first principal investigator, but his associates objected. Even our own well renowned cancer facility at our institution turned down the opportunity to be a principal investigator and has never referred one patient for treating cancer whether they had lung cancer for this investigatorinitiated study, or for compassionate use for other cancers. From what we have ascertained, they refer the patients to hospice when they are at the stage eligible for our study. Yet they kindly refer to us many patients to consider oocyte freezing or embryo banking before potential ovary damaging therapy.

#### **3.10 Cases 10 and 11**

Actually, there were two patients with lung cancer that we screened that would have qualified for the investigator-initiated study. They both had stage IV non-small cell lung cancer positive for the EGFR mutation that were at the end of targeted therapy (erlotinib, afatinib, and osimertinib) because the lesions were progressing. They both responded very well to single agent mifepristone. Their case reports were accepted for presentation at the 2020 American Association for Cancer Research ("Improvement in quality and length of life following treatment with mifepristone in women with stage IV non-small cell lung cancer positive for the EGFR mutation that previously progressed on targeted therapy"). Because our study was not recruiting very well, we advised these two patients to try compassionate use 200 mg mifepristone, where the drug can be shipped to their

homes, rather than travel thousands of miles monthly to receive the medication gratis as required by the study design.
