Staff Writer

Genitourinary cancers — particularly urothelial cancer – saw activity with the combination of Cabometyx (cabozantinib) and Opdivo (nivolumab), with or without Yervoy (ipilimumab), according to a preliminary clinical study.

Almost a third of 43 patients responded to the combination therapy, including three complete responses. More than half of the patients had stable disease, as only seven patients had progressive disease as a best response.

The study population included patients with rare cancers for no standard therapy currently exists, and they also benefited from treatment with combination treatments with two or three drugs, as reported at the 2017 Genitourinary Cancers Symposium in Orlando, FL.

“Both combinations are safe and well tolerated,” Andrea Apolo, M.D., head of the bladder cancer section at the Center for Cancer Research of the National Cancer Institute, and coinvestigators concluded in a poster session. “Larger cohorts of metastatic urothelial carcinoma and rare genitourinary tumors are ongoing.”

Cabometyx primarily inhibits the VEGFR2 and MET pathways. At the 2017 ASCO meeting, Apolo and her colleagues reported that Cabometyx demonstrated activity in refractory metastatic urothelial carcinoma. In a previous study, the investigators showed that Cabometyx treatment of urothelial carcinoma led to a decrease in T-regulatory cells (T-regs) among CD4-positive T cells, increased PD-1 expression in T-regs, and decreased CTLA-4 expression in T-regs.

The anti-PD-1 agent Opdivo received FDA approval February. 2, 2017 for treatment of metastatic urothelial carcinoma. Combining checkpoint inhibitors, such as Opdivo and Yervoy, with other active agents that enhance the immune system might improve response in urothelial and other genitourinary cancers.

“We hypothesized that cabozantinib has immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rational for combining cabozantinib with nivolumab,” the investigators stated.

To test the hypothesis, investigators enrolled patients with metastatic genitourinary cancers that had not responded to one or more prior lines of therapy. A total of 30 patients received Cabometyx and Opdivo, a clinical experience that identified 40 mg Cabometyx and 3 mg/kg Opdivo as the phase 2 dose, which will be evaluated in an expansion cohort of patients with urothelial and renal cell carcinoma (RCC).

An additional 18 patients received Cabometyx, Opdivo and Yervoy at three dose levels. All 48 patients were evaluable for toxicity, and 43 were evaluable for response.

The study population comprised 19 patients with urothelial carcinoma; nine with castration-resistant prostate cancer (CRPC); four each with urachal adenocarcinoma, germ-cell tumor and penile cancer; two each with squamous cell carcinoma of the bladder or urethra, clear-cell RCC and sarcomatoid RCC; and one each with trophoblastic disease and Sertoli cell carcinoma.

The 43 evaluable patients (26 treated with two drugs, 17 with three drugs) had an objective response rate (ORR) of 30 percent, as three patients achieved complete responses and 10 achieved partial responses. More than half of the 43 patients had some degree of tumor shrinkage with the combination regimens.

Two of the complete responses occurred in patients with urothelial cancer and the third in a patient with squamous cell carcinoma of the bladder. Partial responses were observed in four patients with urothelial cancer, two with penile cancer and one each with squamous cell carcinoma of the bladder, CRPC and sarcomatoid RCC.

The response summary showed that 10 of 26 (38 percent) patients treated with Cabometyx and Opdivo had ORRs and three out of 17 treated with Yervoy combination. Additionally, 12 patients treated with each combination had stable disease.

The most common adverse events (AEs; any grade) with Cabometyx and Opdivo were fatigue (19 patients); diarrhea (18); hypothyroidism (17); elevated liver enzyme (AST, 15); anorexia (14); hoarseness, mucositis, and hypocalcemia (12 each); and hyponatremia, hypophosphatemia, hand-foot syndrome, and thrombocytopenia (11 each). The most common grade 3/4 AEs were hypophosphatemia (four patients) and neutropenia (five patients).

The most common AEs with the Yervoy regimen were fatigue (13 patients), diarrhea (11), and anorexia (11). The most common grade 3/4 AEs were hypophosphatemia and hypertension (three patients each); and fatigue, hyponatremia and elevated lipase (two each).

Articles

Cabometyx combinations showed activity in patients with GU cancers, according to a preliminary clinical study.

Combination Regimen Benefits Genitourinary Cancers

According to a recent international patient survey, patients who have myeloproliferative disorders have a high symptom burden that affects their emotional status, quality of life and functional ability.

The survey showed that 90 percent of patients reported one or more symptoms within the past 12 months, the most common symptom being fatigue/tiredness. A substantial proportion of patients with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) reported multiple troubling symptoms, which often were rated as 6 or higher on a severity scale of 0-10.

A dozen types of symptoms affected a fourth or more of the 699 survey participants, Claire N. Harrison, D.M., deputy clinical director of cancer and hematology at Guy’s and St. Thomas’ Hospital in London, reported at the American Society of Hematology meeting in San Diego.

“The findings from this international survey indicate that many patients with myeloproliferative neoplasms (MPNs) experience a high disease burden, including a high prevalence of symptoms and reduction in emotional wellbeing, quality of life, activities of daily living, and ability to work,” Harrison and colleagues concluded in a poster presentation.

“When patients with myeloproliferative neoplasms are treated, care should be taken in trying to manage patient disease burden to minimize the impact on patients’ daily lives.”

The findings came from the global MPN LANDMARK survey, conducted in Australia, Canada, Germany, Italy, Japan and the United Kingdom. Patients in those countries completed comprehensive surveys designed to assess the impact of MPNs on symptoms, quality of life, and normal activities.

This global survey involved 174 patients with MF, 223 with PV, and 302 with ET. Geographic distribution consisted of 10 patients from Australia, 64 from Canada, 149 from Germany, 106 from Italy, 84 from Japan and 286 from the UK. Patients were recruited by clinical practices and patient support groups.

The survey consisted of 63 questions, some of which had multiple items. Patients completed the questionnaire online, and the survey required 25 to 30 minutes to complete. Physicians completed a companion survey, results of which will be reported at a later date, according to Harrison.

Fatigue or tiredness was the single most common symptom, reported by 64 percent, 54 percent, and 45 percent of patients with ET, MF, and PV, respectively. The types of symptoms and symptom burden varied by MPN type:

MF—Abdominal discomfort (30 percent), shortness of breath (29 percent), night sweats (29 percent) and difficulty sleeping (27 percent)

PV—Pruritus (28 percent), loss of concentration (27 percent), night sweats (25 percent) and dizziness (25 percent)

ET—Dizziness (33 percent), night sweats (31 percent), bruising (30 percent) and difficulty sleeping (28 percent)

Similarly, fatigue ranked at the top of the list of “most severe symptoms” for patients with all three types of MPNs. The mean severity scores for fatigue (scale of 0-10) were 6.68 for MF, 6.53 for PV, and 6.44 for ET. “Inactivity” followed, with mean scores of 6.7 for MF, 5.97 for ET and 5.54 for PV. Patients with ET had a mean severity score of 7.89 for “other symptoms not listed” and 6.92 for blood clots.

Overall, more than 25 different symptoms had mean severity scores exceeding 5.

Asked whether MPN symptoms affected quality of life, three-fourths of the patients agreed strongly (29 percent) or somewhat (47 percent). The proportion of agreement was similar across the 3 types of MPN.

A fourth of all the patients said their disease frequently caused emotional hardship, and 29 percent said they frequently felt anxious or worried.

An 8-item assessment of MPNs’ effect on quality of life showed generally similar responses across patients with the 3 types of conditions. A test for statistical significance showed that patients with MF had higher mean scores for feeling anxious or worried, physical hardship, and emotional hardship.

About half (48 percent) of the patients said they frequently felt satisfied with their ability to cope with their disease. Harrison and colleagues found that 33 percent, 24 percent and 23 percent of patients with MF, PV and ET, respectively, said their condition caused emotional hardship. Additionally, 34 percent, 29 percent and 26 percent of patients with MF, PV and ET reported feeling anxious or worried about their disease.

Twenty-seven percent of patients felt their condition had a high impact on them or their caregivers. Other evidence of interference with activities of daily living included pain-limiting activities (24 percent), interference with family or social life (26 percent) and interference with daily activities (26 percent). Two-thirds of patients with PV or ET reported never needing a caregiver, as compared with 42 percent of patients with MF.

The survey also revealed that 20 percent of patients had to reduce hours at work because of their disease. Overall, almost 7 percent reported increased absenteeism from work because of MPNs, 31 percent worked while sick and 35 percent felt their condition impaired their ability to work. Employed patients with MF reported missing an average of 4.8 hours from work the previous seven days, followed by 3.3 hours among patients with PV, and 2.6 hours among those with ET.

Finally, 37.8 percent, 35.5 percent, and 33.4 percent of patients with MF, PV, and ET, respectively, reported work impairment as a result of their condition. Additionally, 44.9 percent, 39.9 percent, and 38.1 percent of patients with MF, PV, and ET reported impairment in their overall activity.

The researchers noted that additional analyses of clinician—patient interaction, differences by country, and treatment patterns are planned, they added.

A recent study examined the symptoms and impairments for patients with MPNs. 

Examining Symptom Burden for Patients With MPNs

Lynparza (olaparib) demonstrated improved progression-free survival (PFS) compared to the placebo arm for patients with ovarian cancer, according to findings from the phase 3 SOLO-2 trial. The single-agent PARP inhibitor was tested in the maintenance setting for patients with advanced 

Although specific data from the trial are not yet available, AstraZeneca, the manufacturer of Lynparza, reported that the median PFS with Lynparza was significantly higher than in the Lynparza arm of the phase 2 Study 19 in a similar population. The safety profile for the PARP inhibitor was consistent with results reported from previous trials.

“We are pleased with the robust improvement in progression-free survival demonstrated by Lynparza in the SOLO-2 trial. We will work with regulatory authorities to make Lynparza tablets available as quickly as possible to patients with ovarian cancer. We remain committed to investigating the full potential of Lynparza, both as monotherapy and in combinations, and to identifying all patients who may benefit from this important medicine,” Sean Bohen, M.D., Ph.D., executive vice president, Global Medicines Development, and Chief Medical Officer at AstraZeneca, said in a statement.

The multicenter phase 3 SOLO-2 trial included 295 patients with platinum-sensitive, relapsed/recurrent, 

-positive ovarian cancer who had received two or more prior lines of platinum-based chemotherapy. Patients were randomized to receive either Lynparza at 300 mg twice daily or placebo until disease progression.

The latest data from the phase 2 Study 19, which were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that in patients with platinum-sensitive relapsed serous ovarian cancer, Lynparza increased overall survival (OS) when given as maintenance therapy.

Results of the study's extension showed that the PARP inhibitor demonstrated the greatest OS advantage in women who had a 

 mutation, according to lead author Jonathan Ledermann, M.D., professor of Medical Oncology at the University College London Cancer Institute and director of the Cancer Research UK & UCL Cancer Trials Centre, who presented the results at ASCO.

Additional key findings were that both time to first subsequent therapy or death (TFST) and time to second subsequent therapy or death (TSST) were substantially prolonged in patients taking Lynparza; again, the greatest benefit was seen in those with a 

mutation. Additionally, the unprecedented long-term exposure meant that 13 percent of all trial patients (15 percent of 

-mutated patients) received maintenance Lynparza for at least five years. In three years of follow-up since the 2012 analysis, there were no new safety findings.

Study 19 assessed patients with platinum-sensitive, recurrent high-grade serous ovarian cancer (265 patients). They had received two or more prior regimens of platinum-based chemotherapy and experienced complete response or partial response to their most recent regimen. In a double-blind, one-to-one randomization, half the patients received Lynparza 400 mg capsules twice daily as maintenance therapy (136 patients) and half received placebo capsules twice daily (129 patients).

 testing occurred for all patients in the form of case reports that contained the results of previous local germline 

 testing. The division between patients was nearly even between those 

 mutations (136 patients) and those with wild-type 

 findings (118 patients), meaning that they either did not have a detected 

In Study 19, the median PFS for patients taking maintenance Lynparza was 8.4 months, compared to 4.8 months for the control group. The difference in the 

 mutation subgroup was even more pronounced: 11.2 months with Lynparza and 4.3 months with placebo.

The third data analysis of Study 19, with data cutoff at Sept. 30, 2015, was performed with data at 77 percent maturity, OS in the overall study population (265 patients) was a median 29.8 months in the Lynparza group and 27.8 months in the placebo. In the 

 mutation group (136 patients), where the data were at 70 percent maturity, median OS was 34.9 months for the Lynparza group and 30.2 months for placebo.

With a median follow-up interval of 5.9 years, 15 patients (11 percent) were still receiving Lynparza (eight with 

-mutated patient was still receiving placebo. Twelve percent of 

 wild-type patients on Lynparza achieved median follow-up of between five and six years.

In the overall study population, 59 patients (43 percent) experienced an adverse event (AE) of grade 3 or above, while only 28 (22 percent) of those on placebo did. Those percentages remained fairly consistent among patients who remained on trial for two years or more: 15 (47 percent) in the Lynparza arm and one (20 percent) in the control arm.

Likewise, the percentages of dose reductions due to AEs were consistent over time, and there were few treatment discontinuations due to AEs: eight active and two control patients overall and three Lynparza patients from the long-term treatment group. No patients from the long-term placebo group discontinued treatment due to AEs.

In June 2014, the FDA’s Oncologic Drugs Advisory Committee voted 11-2 against the accelerated approval of Lynparza as a maintenance therapy for women with platinum-sensitive relapsed ovarian cancer with germline 

 mutations. By voting no, the committee recommended waiting for results from the SOLO-2 trial before approving Lynparza in this setting.

Following this vote, AstraZeneca submitted an amendment to Lynparza’s new drug application upon the FDA’s request, which led to the drug’s eventual approval in December 2014 for the treatment of women with 

-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy.

Lynparza imrpoved progresion-free survival (PFS) when compared to the placebo group in a phase 3 ovarian cancer trial.

PARP Inhibitor Shows Benefit in Ovarian Cancer

Because of low response, the first trial evaluating the efficacy of Zytiga (abiraterone) for patients who have ovarian cancer has been halted, according to results from the CORAL phase 2 trial, which were presented at the European Society for Medical Oncology Congress Annual Meeting.

At 12 weeks, the response rate was 2.4 percent in the overall study cohort and 3.4 percent in patients expressing the androgen receptor (AR). However, one patient achieved complete response (CR) when treated with Zytiga and continues to remain on this treatment. A total of 11 patients showed clinical benefit at 12 weeks, which was prolonged to 24 weeks for four patients.

"Abiraterone is a CYP17 inhibitor of androgen biosynthesis that has been approved by the FDA for the treatment of prostate cancer. Androgens bind to the androgen receptor, which is reported to be expressed in up to 90 percent of epithelial ovarian cancer cases," said Susanna Banerjee, Ph.D., medical oncologist at Royal Marsden NHS Foundation Trust, London, UK. "The efficacy of anti-androgens tested so far in ovarian cancer is limited, although abiraterone has been successfully developed in prostate cancer and there are studies in breast cancer," she continued, "There is a rationale for evaluating anti-androgen approaches in ovarian cancer.”

“There is an urgent need to develop smarter treatment options for women with recurrent epithelial ovarian cancer,” she said.

Banerjee and colleagues conducted the CORAL phase 2 trial in 42 patients with a median age of 64 (Range, 34-85) years with epithelial ovarian cancer who had progressed within 12 months of the last systemic therapy; of these, 88 percent had high-grade serous histology. The patients had not received prior hormonal anticancer agents, but 47 percent had received three or more previous lines of therapy. The median time from diagnosis was 2.8 years. All patients were administered Zytiga acetate at 1,000 mg plus 5 mg prednisone daily until disease progression or end of study.

The primary endpoint was the overall response rate (ORR) according to combined RECIST/Gynecological Cancer Intergroup criteria at 12 weeks and the secondary endpoint was the clinical benefit rate (CBR) at 12 weeks.

Tissue and blood samples were obtained to determine hormone receptor status; at baseline, 29 (69 percent) patients were positive for AR expression, 35 (83.3 percent) were positive for the estrogen receptor (ER), and 25 (59.5 percent) patients were positive for the progesterone receptor (PgR).

“For some patients, abiraterone showed activity in ovarian cancer,” Banerjee added. “One patient developed a response, a patient with low-grade serous histology, a subtype that is known to be difficult to treat. Further work on the significance of androgen receptor pathway in epithelial ovarian cancer may warrant further investigation, perhaps in low-grade serous histology.” This patient was AR positive had low-grade serous histology, and achieved a CR that lasted for 47 weeks.

“The clinical benefit was not limited to androgen receptor positive disease only,” Dr. Banerjee noted. The CBR was 26 percent in the intent-to-treat population and 28 percent in AR positive patients. Four AR positive patients achieved stable disease lasting for at least 6 months.

Treatment emergent adverse events (TEAEs) Grade 3/4 included hypertension, which occurred in 29 percent of patients, and hypokalemia in 10 percent. Dose delays were required in 23 percent of patients lasting for an average of 7.6 days.

Treatment discontinuation due to disease progression was reported for 78 percent of patients, three patients also choose to discontinue treatment, and three discontinuations occurred for other reasons.

“This is the first trial of abiraterone in ovarian cancer,” Banerjee said. “The desired level of activity was not observed, leading to early trial closure. But, 42 patients were recruited, and hopefully we will be able to derive more information on why some of the patients had clinical benefit by looking at their tumor and blood samples,” Banerjee said.

A trial testing Zytiga's effectiveness in ovarian cancer was recently halted.

Staff Writer

Combination Regimen Benefits Genitourinary Cancers

Examining Symptom Burden for Patients With MPNs

PARP Inhibitor Shows Benefit in Ovarian Cancer

Ovarian Cancer Trial Stopped Due to Low Response

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