Hannah Slater

Rubraca (Rucaparib) improved progression-free survival compared with chemotherapy in patients whose ovarian cancer tumors harbor BRCA mutations and who had had two or more prior lines of chemotherapy, researchers say. The findings are from the ARIEL4 study, which was recently completed but is not yet published.

Women who test positive for BRCA mutations are at higher risk of developing breast or ovarian cancer compared with those who do not have this genetic mutation.

“The ARIEL4 study (results) verified that women with relapsed, BRCA mutation-positive advanced ovarian cancer, including those who are platinum-sensitive or (platinum)-resistant, received benefit with (Rubraca) treatment when compared to chemotherapy,” Dr. Amit M. Oza, head of the Division of Medical Oncology and Hematology at University of Toronto in Canada and coordinating researcher on the ARIEL4 study, said in a news release. “These results underscore the importance of (Rubraca) as a treatment option for women with BRCA-mutant advanced ovarian cancer.”

The phase 3 study evaluated 600 milligrams of Rubraca twice per day versus chemotherapy in patients with a BRCA mutation and platinum-sensitive, partially platinum-sensitive or platinum-resistant relapsed ovarian, fallopian tube or primary peritoneal cancers who have received two or more prior lines of chemotherapy. Patients who are platinum sensitive are those who responded to a platinum-based chemotherapy and had the cancer recur in six or more months, whereas those who are platinum resistant had recurrent disease within six months. Overall, 349 women were enrolled in the trial across North America, South America, Europe and Israel.

The primary end point of the study was progression-free survival, or the time since treatment when the disease does not worsen. Other outcome measures include overall survival (time a patient is alive after receiving a diagnosis or the start of treatment), objective response rate (the number of patients whose tumor size was reduced for a particular period of time), duration of response (the time when a tumor responds to treatment), patient-reported outcomes, and safety and tolerability of Rubraca versus chemotherapy.

For one analysis of progression-free survival, therapy with Rubraca (220 patients) was significantly better than chemotherapy (105 patients). The median progression-free survival was 7.4 months with Rubraca compared with 5.7 months for chemotherapy alone.

Additionally, in another analysis with 349 patients, the researcher-assessed progression-free survival in the Rubraca group (233 patients) was statistically better than the chemotherapy group (116 patients). The medians were 7.4 months versus 5.7 months, respectively.

Minimal benefit with Rubraca was noted in the 7% of patients who had a BRCA reversion mutation, or when a mutation reverts back to its original state.

Results also revealed a trend toward an overall survival advantage in the chemotherapy arm; however, this was driven by the high rate (64%) of crossover to Rubraca following disease progression with chemotherapy. When comparing patients who received Rubraca at any point on the trial with those who did not, Rubraca showed a trend toward an overall survival advantage; although numerically different, it was not statistically significant.

Regarding safety, side effects were found to be consistent with the known safety profiles of Rubraca and chemotherapy. The most common serious side effects occurring in more than 5% of all patients who received Rubraca in the ARIEL4 study were anemia (low red blood cell count; 22%), neutropenia (low count of white blood cells called neutrophils; 10%), fatigue (8%), thrombocytopenia (decreased platelets; 8%) and increased alanine transaminase/aspartate transaminase (liver enzymes that may indicate injury to the liver by the drug; 8%).

“We are pleased with these topline results from the ARIEL4 trial, which confirm the clinical benefit of Rubraca versus chemotherapy, including platinum-based chemotherapy, as a treatment for women with BRCA mutation- positive advanced ovarian cancer, including patients who are platinum resistant,” Patrick J. Mahaffy, president and CEO of Clovis Oncology, said in the news release. “We look forward to sharing comprehensive results at an upcoming medical meeting.”

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The phase 3 ARIEL4 trial evaluated Rubraca (rucaparib) versus chemotherapy in patients with ovarian cancer and a BRCA mutation who did not respond to two or more lines of chemotherapy.

Rubraca May Prolong Progression-Free Survival in Patients With Ovarian Cancer With BRCA Mutations, Preliminary Results Show

Strategies for shortening the time from diagnosis until surgery for Black patients are essential for reducing racial disparities in melanoma outcomes, according to results published in the 

Journal of the American Academy of Dermatology

In the study, Black patients with melanoma waited longer to receive surgery than non-Hispanic white patients. Racial differences persisted after categorizing patients by insurance type and melanoma stage.

“We already knew that Black patients with melanoma have a worse prognosis and that longer time to treatment is associated with worse survival, but we didn’t fully under- stand the relationship between race and time to treatment after controlling for various other factors,” first author Raghav Tripathi, a medical student at the Case Western Reserve School of Medicine in Cleveland and a researcher at University Hospitals Cleveland Medical Center, said in a press release. “A more thorough understanding of the factors associated with worse outcomes for Black patients is critical in reducing racial disparities in melanoma outcomes.”

Using the National Cancer Database from 2004 to 2015, researchers retrospectively reviewed 233,982 cases of patients with melanoma, 1,221 (0.52%) of which occurred in Black patients. According to Tripathi, using a large health care database and a sample size of this magnitude allowed researchers to include enough Black patients to investigate racial disparities in skin cancers.

Black patients were found to have longer waits for surgery in stages 1 through 3 melanoma and also a greater amount of time between diagnosis and receiving immunotherapy. They did not wait longer than white patients for chemotherapy, nor did Black patients with stage 4 melanoma wait longer for surgery. After controlling for gender, age, median household income and insurance type, Black patients were found to have more than twice the odds of waiting from 41 to 60 days for surgery, more than triple the odds of waiting 61 to 90 days, and more than five times the odds of waiting over 90 days. On average, the time until surgery for melanoma was 23.4 days for Black patients compared with 11.7 days for non-Hispanic white patients.

Patients with Medicaid had the longest wait (a mean of 60.4 days), whereas those with private insurance had the shortest (44.6 days). Racial differences remained within each insurance type, indicating that insurance status does not fully account for such disparities.

According to the researchers, difference in disease characteristics by race may affect the wait for surgery in patients with melanoma. For instance, Black patients more often have acral lentiginous melanoma, which typically appears on the soles of the feet or under the nails. They also tend to have a greater Breslow depth and stage — measures of the tumor’s invasion &mdash; when they receive diagnoses of other melanoma subtypes, which generally predicts a worse prognosis. These cancers require more complex surgeries that take longer to arrange.

“Our data suggest that increased TTDS (time to definitive surgery) in Black patients with melanoma may be an independent explanatory factor for racial differences in melanoma survival, alongside factors such as later stage at presentation, biological differences in melanoma characteristics and differences in health care utilization,” the authors wrote.

Tripathi added that Black Americans often have limited awareness about skin cancer because it is relatively rare in that population.

Nevertheless, the authors highlighted the need to better understand the precise nature of the association between wait for surgery and race, as well as the various components underlying worse outcomes for Black patients with melanoma.

“Ultimately, we hope this study will draw attention to the importance of further understanding the various components of TTDS and worse outcomes for Black patients with melanoma,” Tripathi said. “Additionally, this study suggests that targeted approaches to improve TTDS for Black patients with melanoma are integral in reducing racial disparities in melanoma outcomes.”

Investigating a Health Gap in Skin Cancer

(pembrolizumab) demonstrated favorable effectiveness and safety in patients with advanced rare cancers, suggesting a much- needed option for this patient population. The findings from an interim analysis in a phase 2 study support further evaluation of the drug for these patients, the researchers concluded.

The ongoing study is testing Keytruda in patients with squamous cell carcinoma of the skin; two types of cancer that arise in the adrenal glands above the kidneys, adrenocortical carcinoma and paraganglioma-pheochro-mocytoma; and carcinoma of unknown primary, which can affect various organs. The interim findings were published in the 

“Studies such as this one are key, since rare cancers collectively accounted for 13% of all new cancer diagnoses and 25% of all cancer-related deaths in adults in 2017,” Dr. Aung Naing, associate professor of investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center in Houston, said in a press release.

“The five-year survival rate is 15% to 20% lower than for more common cancers. The poor outcomes associated with rare cancers have been attributed to difficulty or delay in diagnosis, a dearth of clinical trial data, limited access to centers with expertise such as MD Anderson and limited therapeutic options.”

Between Aug. 15, 2016 and July 27, 2018, the researchers administered IV Keytruda to 127 individuals whose tumors had progressed on standard therapies within the previous six months. The patients, who received 200 mg of IV Keytruda every 21 days, were enrolled in nine tumor- specific groups and a 10th that included those with other rare histologies.

The researchers aimed to measure the non-progression rate at 27 weeks, which was the study’s primary goal. Secondary goals included measuring safety and tolerability; objective response rate, or the percentage of patients whose tumors shrank by a prespecified amount; and clinical benefit rate, or the percentage of patients with an objective response or stable disease.

At 27 weeks, 28% of patients had no disease progression. An objective response was noted in 15 of 110 evaluable patients (14%); one experienced a complete response, with no detectable evidence of remaining cancer, and the other 14 had a partial response. The clinical benefit rate, or the percent of patients who responded or had no disease progression for at least 24 weeks, was 38% (42 people).

Treatment continued for 11 of the 15 responders. Among patients with squamous cell carcinoma, the non-progression rate at 27 weeks was 36%, the objective response rate was 31%, and the clinical benefit rate was 38%. The 27-week non-progression rate, objective response rate and clinical benefit rate were 31%, 15% and 54%, respectively, for those with adrenocortical carcinoma; 33%, 23% and 54% for patients with carcinoma of unknown primary; and 43%, 0% and 75% in the paraganglioma-pheochromo-cytoma group.

Treatment-related side effects occurred in 66 of the 127 patients (52%) and were serious in 12 (9%). The most common side effects were fatigue and rash. Six participants died, five from progressive disease and one due to kidney injury from sepsis. Keytruda’s safety in these patient groups is consistent with that reported for patients with common cancers, such as melanoma and non-small cell lung cancer.

“Findings from our study support further investigation to confirm the clinical activity of pembrolizumab in advanced rare cancers and to identify immune signatures predictive of response to treatment,” Naing said.

The researchers noted some limitations to their findings. Given the small sample size of the tumor-specific groups, the researchers could not apply their findings to all rare cancers.

Additionally, the site in the body from which the tissue was obtained for evaluation, and whether the sample came from a primary or metastatic tumor, could have influenced measurements of response, the researchers reported. Even so, the results shed much-needed light onto potential treatments, they said.

Immunotherapy with Keytruda shows promise in advanced uncommon cancers in which new treatment options are needed.
 

Good News For Rare Cancer Treatment, Keytruda Can Help

Results of the phase 3 KEYNOTE-177 trial demonstrated that front-line therapy with the immune checkpoint inhibitor Keytruda (pembrolizumab) doubled progression-free survival vs. standard of care chemotherapy in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC).

The randomized, open-label trial, which was presented during a 2020 ASCO Virtual Scientific Program press briefing, is the first in which Keytruda has been shown to benefit these patients when used as a front-line therapy.

“These long-awaited trial results will change clinical practice,” lead study author Dr. Thierry André, of the Sorbonne Université and Hôpital Saint Antoine in Paris, said in an ASCO-issued press release. “Pembrolizumab works in non-randomized studies in this group of patients with advanced disease. This randomized study demonstrates a huge benefit in first line with pembrolizumab and should be the new standard of care.”

Overall, patients with MSI-H CRC represent 5% of all patients with mCRC. The presence of MSI-H or dMMR tumors is generally associated with decreased survival rates, and patients with MSI-H or dMMR metastatic disease also tend to be less responsive to conventional chemotherapy.

In phase 2 studies, Keytruda demonstrated durable antitumor activity with an acceptable safety profile in previously treated MSI-H mCRC. Keytruda works by blocking the activity of PD-1 receptors, allowing the immune system to attack cancer cells.

As of February 19, 2020, the time of data cutoff for this interim analysis, the phase 3 trial included 307 patients with MSI-H or dMMR mCRC. Patients were randomly assigned to receive either first line Keytruda for up to two years or, the investigator’s choice of six different standard of care chemotherapy regimens, selected prior to randomization. The investigators had their choice of:

mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin)

FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan)

Progression-free survival (PFS), or time from random assignment in a clinical trial to disease progression or death from any cause, and overall survival (OS) were the primary endpoints for the trial. Additional endpoints included overall response rate (ORR) and safety.

At 12- and 24-months follow up, PFS was 55.3% and 48.3%, respectively, with Keytruda vs. 37.3% and 18.6% with chemotherapy. The ORR was also better with Keytruda as well, with 43.8% of patients seeing a reduction in tumor size compared with 33.1% for chemotherapy.

Moreover, 11% of patients receiving Keytruda had a complete response, 32.7% had a partial response, and 30.9% had stable disease. In comparison, 3.9%, 29.2% and 42.2% of patients, respectively, receiving chemotherapy had complete response, partial response, and stable disease. Response with study drug was also longer lasting, with 83% of patients having a response longer than two years, compared with 35% of patients receiving chemotherapy.

“Immunotherapies like pembrolizumab have proved to be effective as second-line treatments for advanced disease,” said ASCO&#8239;President Dr. Howard A. Burris III in the release. “Now, in studies like this one, we are starting to see significant efficacy for immunotherapies as first-line treatment for advanced cancers with specific genetic signatures, in this case metastatic colorectal carcinoma with microsatellite instability high/mismatch repair deficient mutations. The data presented have the potential to change the standard of care.”

Severe treatment-related side effects were also less common with Keytruda than chemotherapy (22% vs 66%). However, the profile of toxicities was very different between both groups, with immune-mediated adverse events observed with Keytruda (colitis and hepatitis). The most frequent toxicities observed with standard of care chemotherapy were diarrhea, neutropenia, fatigue, nausea and vomiting, stomatitis, alopecia, and neurotoxicity.

Patients could cross over at progression from the chemotherapy group to the Keytruda group. The study will continue to evaluate OS.

“In the past, no medical treatment has shown such a difference in terms of improved PFS in metastatic colorectal cancer,” André said in a pre-recorded presentation of the data. “These data represent another step forward for biomarker driven studies and will help bring this approach to target MSI-high tumor into the adjuvant and neoadjuvant setting.”

During the press briefing, André indicated that it likely will not be long before Keytruda is approved in the United States for use in this space.

“These long-awaited trial results will change clinical practice,” lead study author Dr. Thierry André, of the Sorbonne Université and Hôpital Saint Antoine in Paris, said in an ASCO-issued press release.

Hannah Slater

Rubraca May Prolong Progression-Free Survival in Patients With Ovarian Cancer With BRCA Mutations, Preliminary Results Show

Investigating a Health Gap in Skin Cancer

Good News For Rare Cancer Treatment, Keytruda Can Help

Keytruda 'Should Be New Standard of Care' in First-Line Setting in Certain Patients with Metastatic Colorectal Cancer

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