Audrey Sternberg

Patients with relapsed ovarian cancer that harbors a deleterious BRCA1/2 mutation and is sensitive to platinum-based therapy lived longer without their disease progressing (an outcome referred to as progression-free survival) when treated with Rubraca (rucaparib) compared to chemotherapy, according to updated findings from the phase 3 ARIEL4 clinical trial.

Of note, overall survival — time from treatment until death of any cause — was similar between the two treatment groups.

Findings, which were presented at the 2022 European Society for Medical Oncology Congress, showed that median overall survival favored the chemotherapy group with medians of 19.4 months in the Rubraca group, compared with 25.4 months in the chemotherapy group.

The researchers noted that the difference in overall survival was driven by the subgroup of patients with platinum-resistant disease (cancer that comes back within six months of being treated with a platinum-based chemotherapy agent), with medians of 14.2 months and 22.2 months with Rubraca and chemotherapy, respectively.

In the patients with platinum-sensitive ovarian cancer — meaning that their disease responds to platinum-based therapy — the median overall survival was 29.4 months with Rubraca and 27.6 months with chemotherapy.

“The overall survival (results were) confounded by the high rate of crossover from chemotherapy to (Rubraca) which was built in (to the trial and resulted in) 90% of patients receiving (Rubraca),” Dr. Amit Oza, head of the Division of Medical Oncology & Hematology and medical director of the Cancer Clinical Research Unit at Princess Margaret (PM) Cancer Centre in Toronto, Canada, as well as co-leader of the Ovarian Cancer Translational Research Initiative, said during a presentation of the results. “Additionally, 42% of patients in the (Rubraca treatment group) did not receive subsequent anticancer treatment, and we need to understand this pattern.”

In March 2021, preliminary findings from the ARIEL4 trial showed that 

 progression-free survival versus chemotherapy.

Then, The initial read-out of the trial that was published in 

 earlier this year showed that median progression-free survival was significantly improved with Rubraca compared with chemotherapy in the efficacy population, or those harboring deleterious BRCA1/2 mutations without reversion mutations, at 7.4 months versus 5.7 months, respectively. Similar progression-free survival effect was noted in the overall study population (7.4 versus 5.7 months).

Patients were eligible for the trial if they had high-grade relapsed epithelial ovarian, fallopian tube or primary peritoneal cancer; two or more prior chemotherapy regimens, one of which had to be platinum based; a deleterious germline or somatic BRCA1/2 mutation; and no prior experience with either a PARP inhibitor or single-agent paclitaxel.

Notably, 313 of 349 patients treated on the trial received Rubraca at some point, either at first randomization or at crossover (patients were allowed to cross from the chemotherapy group to the Rubraca group if their disease progressed), which may have affected the overall survival results. In total, 80 patients (69%) in the chemotherapy group did crossover to receive Rubraca.

At the data cutoff of April 10, 2022, 6% of patients in the Rubraca group and zero in the chemotherapy group had ongoing treatment with the assigned study regimen.

Average duration on treatment tended to be longer for those given Rubraca compared to those given chemotherapy across those with platinum resistance (5.6 months versus 4.4 months), partial platinum sensitivity (7.6 months versus 4.5 months) and full platinum sensitivity (13.7 months versus 3.4 months).

Subsequent anticancer treatment of any kind was more common in the chemotherapy group compared to Rubraca group in those with platinum resistance (76.3% versus 57.5%, respectively), partial platinum sensitivity (83.9% versus 61.5%) and full platinum sensitivity (84.6% versus 54.2%).

“A significant proportion of patients who were in the (Rubraca) group did not receive subsequent anticancer treatment (and those who) received crossover (Rubraca) largely stayed on treatment for more than six months,” Oza said.

An adjusted analysis that excluded patients who crossed over from chemotherapy to Rubraca showed favorable median overall survival in the Rubraca group at 19.4 months, compared to 9.1 with the chemotherapy group. When data were censored at crossover, overall survival outcomes were similar between groups. Overall survival with time-varying covariate adjustment showed no difference between treatment groups.

Looking at results for time to second progression, Rubraca and chemotherapy resulted in similar outcomes in those with platinum resistance and full platinum sensitivity; outcomes showed slight favorability in those with partial platinum sensitivity who were treated with Rubraca.

“We also tried to look at the impact of post-randomization treatment,” Oza said. “In the patients randomized to (Rubraca) or chemotherapy with platinum-resistant disease, there was no difference (in progression-free survival); whereas with subsequent treatment, there was a significant advantage to patients treated with (Rubraca) compared with subsequent chemotherapy.”

Better Progression-Free Survival Outcomes

He continued by pointing out that those with both partially and fully platinum-sensitive disease had better progression-free survival outcomes with initial Rubraca, and those who initially received chemotherapy had better time to second progression when they crossed over to receive the PARP inhibitor.

There were no new safety signals noted. Side effects of special interest included the occurrence of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) — types of blood cancers — that was reported in seven patients (3%) initially randomized to Rubraca, compared with zero treated with chemotherapy.

The investigators concluded their research by raising unanswered questions about the optimal sequencing of PARP inhibitors in advanced stage disease.

“Further work is also ongoing to understand the biologic basis of resistance and the optimal sequence of treatment in patients,” concluded Oza.

For more news on cancer updates, research and education, don’t forget to 

Articles

Rubraca improved progression-free survival in patients with BRCA1/2-mutant, platinum-sensitive, relapsed ovarian cancer, according to findings from the ARIEL4 clinical trial.

Rubraca Staves Off Disease Progression Better Than Chemotherapy in BRCA-Mutant Relapsed Ovarian Cancer, Research Shows

The combination of twice-a-day Jakafi (ruxolitinib) plus the chemotherapies carboplatin and paclitaxel proved to be a feasible regimen for the upfront pre- and post-surgical treatment of patients with stage 3 or 4 ovarian cancer, according to findings from the phase 1/2 NRG-GY007 clinical trial presented at the 2022 American Society of Clinical Oncology Annual Meeting.

The results indicate that further study of the Jakafi/chemotherapy combination is warranted.

At a median follow-up of 24 months, the median progression-free survival (time from treatment until disease worsens) was 14.6 months with Jakafi plus chemotherapy, compared to 11.6 months for chemotherapy alone. Analysis of overall survival favored the Jakafi-containing group as well.

“This trial demonstrates the feasibility of early-phase randomized studies with novel agents and biospecimen collection in the front-line neoadjuvant treatment of the ovarian family of cancers,” Dr. Charles ‘Chip’ Landen, Jr, an associate professor of obstetrics and gynecology at the University of Virginia in Charlottesville, said during a presentation of the data.

Patients who were candidates for neoadjuvant (treatment given to shrink the tumor prior to a main treatment, which may include surgery) chemotherapy with a histologic diagnosis and image-guided core or laparoscopic biopsy confirming epithelial ovarian, fallopian tube or primary peritoneal cancer were eligible for treatment in the phase 1 portion of weekly intravenous paclitaxel, intravenous carboplatin and oral Jakafi. Patients were treated with three cycles of the regimen, followed by interval tumor reductive surgery, three additional systemic treatment cycles and maintenance Jakafi.

The main goal of the study was to determine the safety and tolerability of Jakafi plus chemotherapy.

In the phase 2 portion of the trial, patients were treated with either carboplatin and paclitaxel alone or in combination with Jakafi for three cycles, followed by surgery and another three cycles of therapy with a primary endpoint of progression-free survival. There were enough dose-limiting side effects in the phase 1 portion so that the dose of carboplatin in phase 2 was updated. Overall, 42 patients were treated with carboplatin and paclitaxel alone and 105 received additional Jakafi.

Patient characteristics were well balanced, except for a higher rate of BRCA mutations in the experimental (16.2%) compared with the control (7.1%) group. In both groups, the median patient age was 66 years (range, 33-86) with most patients being White (90.5%), non-Hispanic (87.8%) and with serous/endometrioid histological disease (98.0%). ECOG performance score was 0 (indicating that the disease and/or treatment had no impact on patients’ ability to perform daily tasks) in 51%, 1 in 43.5%, and 2 in 5.4%.

Higher rates of serious or severe anemia (a condition where the body lacks enough healthy red blood cells) were reported with the Jakafi combination at 64.2% compared with 26.8% with chemotherapy alone, which Laden said is to be expected with a drug targeting stem cells. Other serious or severe side effects of note included decreased neutrophils (52.6% with Jakafi and 29.2% with chemotherapy), infections (19.1% and 17.1%, respectively), decreased platelets (10.5% and 14.6%) and thrombotic events (12.7% and 2.4%).

There were five events that led to death, with all but one event of febrile neutropenia (a low white blood cell count accompanied by a fever) being deemed unrelated to treatment.

“There were many practical lessons learned in this first trial conducted by NRG in the neoadjuvant up-front setting,” Landen said. “The most common trial deviations relevant to this design include the initial pretreatment biopsy stating adenocarcinoma but not committing to a serous endometroid or clear cell phenotype; a difference in histologic subtype between the initial biopsy and the specimen taken at interval debulking; the treatment team being reluctant to perform an interval cytoreductive surgery after cycle 3 even in the setting of no progressive disease; a delay in initiating cycle 4 of chemotherapy within four weeks of surgery; and a desire of the treating team to continue chemotherapy, either as a cytotoxic drug or as maintenance after six cycles.”

Landen concluded the presentation and stated that further study of this combination should be considered and should include maintenance Jakafi added after six cycles of treatment to prevent tumor regrowth.

The use of Jakafi plus chemotherapy shows promise in the pre- and post-surgical treatment settings for patients with stage 3 and 4 ovarian cancer, warranting further study of the combination. 

Pre- and Post-Surgical Jakafi Plus Chemo Shows Potential in Advanced Ovarian Cancer

Treatment with Keytruda (pembrolizumab) plus Cyramza (ramucirumab) proved more beneficial to patients with non-small cell lung cancer previously treated with chemotherapy and immunotherapy than other standard-of-care treatments.

The findings of the Lung-MAP nonmatched phase 2 substudy S1800A, which were presented during the 2022 American Society of Clinical Oncology Annual Meeting, showed that Keytruda plus Cyramza induced an improvement in median overall survival (time a patient remains alive) at 14.5 months versus 11.6 months with standard-of-care therapies.

“Most patients with advanced non–small cell lung cancer will receive immunotherapy as part of their initial therapy. Despite improved survival and clinical benefit, resistance develops,” Dr. Karen L. Reckamp, medical oncology director of the Lung Institute at Cedars-Sinai Medical Center in Los Angeles, said during a presentation of the data. “Developing therapies to overcome resistance to immunotherapy is a major area of unmet need for our patients.”

In a previous early-phase study, the use of Keytruda with Cyramza induced an overall response rate (percentage of patients whose disease fully or partially responds to treatment) of 30% and a disease control rate of 85% in patients with previously treated non-small cell lung cancer.

Patients included in S1800A were those who were not eligible for a biomarker-matched substudy of the Lung-MAP protocol and had acquired resistance to immune checkpoint inhibitors, which was defined as prior immunotherapy for at least 84 days with progressive disease on or after therapy. Patients must also have received prior platinum-based doublet therapy, either sequentially or in combination with immunotherapy.

In total, 130 eligible patients were enrolled from May 17, 2019, to Nov. 16, 2020, and were randomized to receive either Keytruda combined with Cyramza (69 patients) or standard of care (67 patients), which could include either docetaxel plus Cyramza (45 patients), docetaxel (3 patients), gemcitabine (12 patients), pemetrexed (1 patient), or no treatment (6 patients).

“Importantly, over two-thirds of patients received docetaxel and (Cyramza) as a standard-of-care therapy, representing the most active treatment in this setting for the majority of patients in the (standard-of-care group),” Reckamp said.

Measuring the overall survival benefit between the two treatment groups was the main goal of the study. The investigators also wanted to analyze overall response rates, as well as duration of response (length of time a tumor responds to treatment without getting worse), investigators-assessed progression-free survival (time a patient is alive without disease progression) and safety.

The median progression-free survival between the two treatment groups was similar, at 4.5 months in the Keytruda plus Cyramza group versus 5.2 months with standard of care.

The overall response rates were also similar between the two groups: 22% in those who received the Keytruda and Cyramza combination versus 28% with standard of care.

Treatment with the combination, however, elicited a much better duration of response (12.9 months) than standard of care (5.6 months).

A subgroup analysis showed the most pronounced overall survival benefit with Keytruda plus Cyramza was in those with squamous cell or mixed histology disease. Additionally, although the total number of patients with 

 mutations was small (n = 7), there appeared to be a benefit with the combination vs SOC (HR, 0.23; 95% CI, 0.10-0.54; 

 = .01) that will require further follow-up.

The investigators used data from a previous trial to explain the discrepancies between overall survival benefit and similar outcomes in terms of response and progression-free survival. For instance, results of the phase 3 OAK trial of Tecentriq (atezolizumab) versus the chemotherapy docetaxel showed that the study drug improved overall survival, but that progression-free survival and responses to treatment were similar between the two groups.

Findings from that trial were subsequently used by the Food and Drug Administration in 2016 to 

 with metastatic non-small cell lung cancer whose disease progressed after treatment with a prior platinum-containing regimen.

Serious or greater treatment-related side effects in the combination group occurred in 42% of patients versus 60% in the standard of care group.

Reckamp stated that the trial was the first in the immune checkpoint inhibitor–refractory setting to demonstrate a benefit of treatment without a chemotherapy backbone compared with standard-of-care treatment options. Further evaluation of the approach is warranted.

Despite similar responses to treatment, patients with previously treated non-small cell lung cancer derived a better overall survival benefit from treatment with Keytruda combined with Cyramza than the usage of standard-of-care therapies.

Keytruda-Cyramza Combo Bests Standard-of-Care Therapies in Previously Treated Non-Small Cell Lung Cancer 

Patients with previously treated pancreatic ductal adenocarcinoma, which is the most common type of cancer that forms in the pancreas, and other non-colorectal gastrointestinal tumors harboring KRAS G12C mutations derived encouraging responses after receiving treatment with adagrasib, according to recent study findings.

The study results also showed that at a median follow-up of 6.3 months, treatment with the study drug resulted in a disease control rate (percentage of patients who achieve complete response, partial response or stable disease while receiving treatment) of 100%. Moreover, the data demonstrated that 41% of the 27 evaluable patients enrolled in a cohort of the phase 2 KRYSTAL-1 trial achieved a partial response to treatment.

“Adagrasib is (a) KRAS G12C selective, covalent inhibitor with a long half-life that enables exposure above a target threshold throughout the dosing interval (with) monotherapy demonstrating promising clinical activity with 100% disease control rate for those patients with pancreas cancer and other (gastrointestinal) non–colorectal cancers harboring G12C mutations,” Dr. Tanios S. Bekaii-Saab, medical director of the Cancer Clinical Research Office and vice chair and section chief for Medical Oncology in the Department of Internal Medicine at Mayo Clinic in Phoenix, said during a presentation of the data at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

Previous reports have indicated that the frequency of KRAS mutations in pancreatic cancer is about 90%, with 2% of those being KRAS G12C. Adagrasib, a covalent inhibitor of KRAS G12C, irreversibly attaches to the protein in its inactive form and shuts down its activity. Continuous exposure to the agent above a target threshold leads to KRAS-dependent signaling inhibition and maximizes depth and duration of antitumor activity.

Forty-two patients (median age, 65.5 years; 60% male; 67% White) were enrolled into this cohort, of which, 30 had other gastrointestinal tumors that harbored a KRAS G12C mutation. Of those patients with that mutation, there were 12 cases of pancreatic ductal adenocarcinoma, eight biliary tract cancers, five appendiceal cancers, two gastro-esophageal junction cancers, two small bowel cancers and one esophageal cancer.

Previously reported data from the phase 1/2 trial established clinical activity with 

 including gastrointestinal malignancies as well as lung and gynecologic cancers. Patients analyzed herein were treated with the recommended phase 2 dose of 600 mg twice per day administered orally.

Measuring the objective response rate (percentage of patients with partial and complete responses to treatment) served as the main goal of the study. Additional goals included assessing overall survival, progression-free survival (the time during and after treatment when the patient lives without disease progression) and safety.

Ten out of 12 patients with pancreatic ductal adenocarcinoma were evaluable for clinical activity, in whom median follow-up was 8.1 months and median number of prior therapies was 2.5 (range, 1-4). Five partial responses were noted, which included one unconfirmed partial response. Median time to treatment response was 2.8 months and the median duration of response was 6.97 months.

The results demonstrated that the median progression-free survival in this group was 6.6 months and treatment was ongoing in 50% of patients.

In 17 patients with other gastrointestinal tumors who were evaluable for response, there were six partial responses, which included two that were unconfirmed. Responses were noted in five patients with biliary tract cancer and one patient each with gastro-esophageal junction and small bowel cancer. Median time to treatment response was 1.3 months and median duration of response was 7.85 months in this patient group. Median progression-free survival was 7.85 months, and 11 patients were still receiving treatment at the time of data cutoff in September.

“When you look at biliary tract cancer, 50% of the patients had the response. These are small numbers, but these are solid responses,” Bekaii-Saab said.

There were no serious or fatal treatment-related toxicities and there were minimal non-gastrointestinal side effects among this patient population. The most common side effects of any severity included but were not limited to nausea (48%), vomiting (43%), diarrhea (43%) and fatigue (29%).

Single-agent adagrasib was associated with encouraging treatment responses in patients with previously treated non-colorectal gastrointestinal tumors and pancreatic ductal adenocarcinoma.

Audrey Sternberg

Rubraca Staves Off Disease Progression Better Than Chemotherapy in BRCA-Mutant Relapsed Ovarian Cancer, Research Shows

Pre- and Post-Surgical Jakafi Plus Chemo Shows Potential in Advanced Ovarian Cancer

Keytruda-Cyramza Combo Bests Standard-of-Care Therapies in Previously Treated Non-Small Cell Lung Cancer

Adagrasib Confers High Response Rates in Several Gastrointestinal, Pancreatic Tumors

Latest News