Combo Tx Active in Recurrent, Platinum-Resistant Ovarian Cancer

Ixabepilone plus bevacizumab yielded responses in a third of patients.

By Ian Ingram

Combination treatment with a microtubule stabilizing agent plus bevacizumab (Avastin) proved active for patients with recurrent chemotherapy-resistant ovarian cancer, a randomized phase II trial found.

Median progression-free survival (PFS), the study’s primary endpoint, was superior with the combination of ixabepilone (Ixempra) plus bevacizumab, as compared with single-agent ixabepilone, an epothilone B analog that is thought to retain efficacy in paclitaxel-resistant disease (5.5 vs 2.2 months; HR 0.33, 95% CI 0.19-0.55), reported Dana Roque, MD, of University of Maryland Medical Center in Baltimore.

One-third of patients responded to ixabepilone plus bevacizumab versus 8% with ixabepilone (P=0.004), according to findings presented at the virtual Society of Gynecologic Oncology (SGO) annual meeting.

“Heavily pretreated platinum-resistant or -refractory ovarian cancer patients lack therapeutic options,” Roque said during her presentation. “Weekly ixabepilone and biweekly bevacizumab is well tolerated and effective, even in the platinum-refractory setting.”

While the trial was not powered to detect differences in overall survival, patients on ixabepilone-bevacizumab lived a median 10 months from the start of treatment versus 6 months with ixabepilone alone (HR 0.52, 95% CI 0.31-0.87). Prior receipt of bevacizumab did not appear to have an effect on PFS or overall survival, nor did age, number of prior therapies, performance status, or histology.

TUBB3 staining, thought to be a potential marker of response, was not correlated with response rates or disease control, said Roque.

Ixabepilone gained FDA approval in 2007 for pretreated breast cancer, and has shown activity in other tumor types, including ovarian cancer. Bevacizumab is an approved agent in ovarian cancer.

Roque said the study was modeled after the AURELIA trial, which showed that bevacizumab plus chemotherapy was superior to chemotherapy alone in platinum-resistant ovarian cancer. The current study, however, included a far more heavily treated patient population, and with ixabepilone-bevacizumab produced similar rates of response as seen with bevacizumab-chemotherapy in AURELIA (33% vs 27%, respectively).

SGO discussant Thomas Herzog, MD, of the University of Cincinnati Cancer Institute in Ohio, pointed out that paclitaxel arms of AURELIA achieved responses of 28.8% with chemotherapy alone and 51.7% with the addition of bevacizumab, and the combination was associated with a median PFS of 10.4 months.

But he agreed that the current trial involved a “much more heavily pretreated” group than AURELIA, which was restricted to no more than two prior lines of treatment and had no platinum-refractory patients, as compared with 18% in the current study.

“This was a very exciting trial, the efficacy looks very promising,” Herzog said, though he added that the lower bounds of the confidence intervals might still be similar to what is seen with conventional agents and that it typically takes a couple of trials to sway guideline committees.

The phase II study randomized 76 women with advanced platinum-resistant or -refractory epithelial non-mucinous ovarian cancer, fallopian tube cancer, or primary peritoneal cancer at two U.S. centers. Eligibility requirements included at least three cycles of paclitaxel, and patients were stratified by receipt of prior bevacizumab and study site. Over 28-day cycles, patients received either ixabepilone 20 mg/m² (on days 1, 8, and 15) or ixabepilone plus bevacizumab 10 mg/kg (on days 1 and 15), with both delivered intravenously.

Median patient age was 67 years, 76% of patients were white, and 16% were Black, with the vast majority having serous tumor type (83%). About half had received four or more lines of prior therapy and 55% had previously received bevacizumab. In the monotherapy arm, 11% were considered refractory to chemotherapy versus 26% in the combination arm.

Serious adverse events occurred in 36% of patients on the combination treatment and 32% of those on single-agent ixabepilone. Hypertension was significantly more common in the combination group (36% vs 8%), as was peripheral neuropathy (51% vs 19%), and one patient on ixabepilone-bevacizumab experienced bowel perforation.

Dose reductions were required in 59% and 64% of patients in the monotherapy and combinations arms, respectively, with dose-limiting toxicities including peripheral neuropathy, neutropenia, and fatigue. Roque suggested a starting ixabepilone dose of 16 mg/m² to limit toxicity and dose reductions.

At data cutoff, 78% of patients in the ixabepilone arm had died versus 72% of those in the ixabepilone-bevacizumab arm.

Limitations cited by Roque included incomplete immunohistochemistry for TUBB3 staining, a lack of a bevacizumab control arm, and that patients weren’t stratified by their extent of prior taxane treatment.

This article was published by MedPage Today.

HIPEC Combo Doubles PFS in Advanced Ovarian Cancer

Cisplatin/paclitaxel boosts outcomes without increasing complications in registry study.

By Charles Bankhead

Two drugs outperformed one for hyperthermic intraperitoneal chemotherapy (HIPEC) after interval surgical debulking of advanced ovarian cancer, data from a prospective registry showed.

Median progression-free survival (PFS) doubled from 11 months with cisplatin alone to 22.2 months with the addition of paclitaxel. A similar difference existed for the proportion of patients who remained recurrence free at 12 months.

The improvement occurred with no adverse impact on complications, length of hospitalization, or discharge status, Laura Chambers, DO, of the Cleveland Clinic, reported during the virtual Society of Gynecologic Oncology annual meeting.

“We demonstrate that the combination of paclitaxel/cisplatin is associated with a significantly improved progression-free survival and 1-year recurrence-free survival compared to cisplatin alone without significantly increased morbidity in women with optimally cytoreduced stage III and IV ovarian cancer undergoing interval debulking surgery plus HIPEC,” she said during the closing late-breaking abstract session.

“While further validation is needed in larger cohorts, the combination of paclitaxel with cisplatin may be considered at the time of interval debulking with HIPEC in selected women with advanced ovarian cancer,” she said.

The improvements associated with combination chemotherapy did not result from underperformance of single-agent cisplatin, Chambers reported. The median PFS with cisplatin alone approximated that of a recent randomized trial that demonstrated a PFS benefit with cisplatin-based HIPEC versus surgery alone.

The findings continued the revival of an issue that emerged with much fanfare almost 2 decades ago only to fade away in an accumulation of negative data and clinical opinion.

The controversial history of HIPEC began with the GOG 172 trial, which showed an unprecedented 16-month improvement in overall survival (OS) with intraperitoneal (IP) versus intravenous (IV) adjuvant chemotherapy. However, the IP regimen proved difficult to tolerate, as only 42% of patients assigned to the IP arm completed the planned six cycles of therapy.

Subsequent clinical trials yielded mixed results, and toxicity remained an issue with IP regimens. Five years ago the randomized, multiarm GOG 252 study — thought to be the definitive clinical evaluation of IP chemotherapy — showed little difference in PFS between IP and IV regimen, and toxicity continued to complicate IP treatment. Two years ago an update of GOG 252 still showed no PFS or OS benefit with IP chemotherapy.

Interest in HIPEC for ovarian cancer evolved from evidence that hyperthermia increases peritoneal penetration of chemotherapy at the peritoneal surface and cancer sensitivity to chemotherapy. Hyperthermia also induces apoptosis and activates proteins and signaling that are involved in a variety of anticancer activities.

The first large randomized trial of HIPEC in ovarian cancer showed a statistically significant 3.5-month improvement in median PFS and a 12-month improvement in OS in patients who received HIPEC with single-agent cisplatin following neoadjuvant chemotherapy and interval surgical debulking. Chambers and colleagues speculated that adding paclitaxel to cisplatin might further improve outcomes with HIPEC.

Data for the study came from a prospective registry of HIPEC-treated patients with stage III/IV ovarian cancer. The study included patients treated at the Cleveland Clinic from 2017 to 2020, all of whom responded to neoadjuvant chemotherapy prior to interval debulking surgery with optimal cytoreduction to less than 1 cm of residual disease. Following surgery, each patient received HIPEC with single-agent cisplatin or the combination of cisplatin and paclitaxel.

Data analysis included 42 patients who received HIPEC with cisplatin alone and 33 who received cisplatin and paclitaxel. The primary endpoint was PFS. The patient population did not differ significantly with respect to age (about 63), race, body mass index, American Society of Anesthesiologists score, disease histology, comorbidities, genetics, preoperative CA125 level, or number of cycles of neoadjuvant therapy.

Interval debulking for the two treatment groups differed only with respect to operative time, which was slightly longer for the cisplatin group (6.1 vs 5.3 hours, P=0.03). The groups were similar with regard to R0 status, blood loss, type of procedure, surgical complexity, need for intraoperative pressor support, or intraoperative blood transfusion. Rates and types of complications also did not differ between the groups.

More patients in the cisplatin/paclitaxel arm required admission to the intensive care unit (P=0.05). Otherwise, the postoperative complication rates were similar.

The median follow-up duration for all patients was 15.7 months. The 11.2-month absolute difference in median PFS represented a 59% reduction in the hazard for disease progression or death (P=0.011). Recurrence-free survival at 1 year was 82.9% for patients who received cisplatin and paclitaxel versus 36.7% for those who received HIPEC with single-agent cisplatin.

The study added more data to the discussion about HIPEC’s role in the management of advanced ovarian cancer but did not make a case for changing clinical practice, said invited discussant Thomas Herzog, MD, of the University of Cincinnati. In particular, the median PFS (11.0 months) for the single-agent cisplatin HIPEC arm was almost identical to that of patients who received only surgery in the recent randomized trial, he said.

“I think we need some further explanation as to what’s going on there. The strength of the study is that this is a very hot topic, and we could spend a lot more time talking about the value of HIPEC in ovarian cancer,” Herzog said.

“I think that to convert the nonbelievers, unfortunately, we are going to have to see a randomized trial as we move forward,” he added.

This article was published by MedPage Today.

PARP Inhibition Shows Efficacy in Ovarian Cancer Regardless of Number of Prior Lines of Chemotherapy, BRCA Mutation Status

By Chase Doyle

Treatment with olaparib is safe and effective for patients with platinum-sensitive relapsed ovarian cancer, regardless of the number of prior lines of chemotherapy received and BRCA mutation status, according to data presented from the phase II LIGHT study by Karen A. Cadoo, MD, at the Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer.

Secondary efficacy results from the trial demonstrated CA-125 responses and complete responses across all four patient cohorts: germline BRCA–mutated, somatic BRCA–mutated, homologous recombination deficiency (HRD)-positive, and HRD-negative disease.

Consistent with previous studies, the greatest efficacy was observed in the BRCA-mutated cohorts, with similar findings for germline and somatic BRCA mutations. For patients without a BRCA mutation, greater efficacy with olaparib was seen in patients with HRD-positive disease.

“Objective response rates and progression-free survival with olaparib treatment were generally consistent irrespective of the number of prior lines of chemotherapy received,” said Dr. Cadoo, a medical oncologist at Memorial Sloan Kettering Cancer Center. “Our findings are consistent with the previously reported primary analysis of this study.”

For patients with platinum-sensitive relapsed ovarian cancer, platinum sensitivity acts as a biomarker for poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity, and olaparib maintenance therapy has demonstrated efficacy regardless of BRCA mutation status. More recently, said Dr. Cadoo, results of the phase III SOLO3 trial showed that treatment with olaparib was effective for patients with BRCA-mutated platinum-sensitive ovarian cancer who have received at least two prior lines of platinum-based chemotherapy.

LIGHT Study

The LIGHT study assigned patients with platinum-sensitive ovarian cancer to cohorts based on their BRCA mutation status (germline or somatic) and HRD status (positive or negative based on genomic instability score). All patients received olaparib monotherapy: 300 mg tablets twice daily.

Of the 272 patients enrolled, 271 received olaparib; 270 had measurable disease at baseline and were included in the efficacy analyses. A total of 176 patients were evaluable for CA-125 response.

Although CA-125 responses were observed across all four cohorts, said Dr. Cadoo, the greatest efficacy was seen in patients with BRCA-mutated disease, with similar findings for germline and somatic BRCA mutations. In these cohorts, CA-125 response rates were 93% for germline BRCA and 70% for somatic BRCA, while CA-125 complete response rates were 68% and 60%, respectively.

Median time to any disease progression was also greatest in the BRCA mutation cohorts and was approximately 11 months, said Dr. Cadoo. Among patients with BRCA wild-type ovarian cancer, greater efficacy was seen in the HRD-positive cohort than the HRD-negative cohort.

Key Points

• Secondary efficacy results from the phase II LIGHT study demonstrated effective CA-125 response and time to any progression for patients with platinum-sensitive relapsed ovarian cancer treated with olaparib.
• Subgroup analyses showed that objective response rate and progression-free survival on olaparib were generally consistent, irrespective of the number of prior lines of chemotherapy.

Disclosure: This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co.

This article was published by The ASCO Post.

Niraparib Plus Bevacizumab Shows Clinical Benefit in Patients With Advanced Ovarian Cancer

By Chase Doyle

The addition of niraparib maintenance to first-line platinum-based chemotherapy with bevacizumab demonstrated clinical benefit in patients with advanced ovarian cancer, according to data from the OVARIO study presented by Melissa M. Hardesty, MD, MPH, during the Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer.

Landmark analysis of the phase II OVARIO study showed that 62% of patients in the overall population remained progression-free at 18 months, including 76% of patients in the homologous recombination–deficient (HRD) subgroup and 47% of patients in the homologous recombination–proficient (HRP) subgroup.

“OVARIO enrolled a high-risk population of patients with ovarian cancer,” said Dr. Hardesty, a gynecologic oncologist at Alaska Women’s Cancer Care in Anchorage. “Despite these high risks, results were favorable compared to other upfront maintenance treatment trials.”

As Dr. Hardesty reported, monotherapy with niraparib, a small-molecule inhibitor of poly ADP-ribose polymerase (PARP), has been shown to improve progression-free survival in patients with newly diagnosed, recurrent, and heavily pretreated ovarian cancer after platinum-based chemotherapy in all biomarker-defined subgroups. It is also hypothesized that bevacizumab may sensitize tumors to PARP inhibition. In the AVANOVA study, the addition of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, demonstrated a significant improvement in progression-free survival compared with niraparib alone in patients with recurrent, platinum-sensitive ovarian cancer.

Results From OVARIO

OVARIO, a single-arm, open-label study, evaluated niraparib plus bevacizumab maintenance treatment in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy plus bevacizumab. All patients with newly diagnosed high-grade serous or endometrioid stage IIIB to IV ovarian cancer who had a complete response, partial response, or no evidence of disease after first-line platinum-based chemotherapy plus bevacizumab were eligible, as were patients receiving neoadjuvant chemotherapy or primary debulking surgery. All patients also underwent tissue testing for HRD or HRP at enrollment.

Progression-free survival rates in the overall population were 90% and 75% at 6 months and 12 months, respectively. At 18 months, the progression-free survival rate was 62% in the overall population and 76% in the HRD population.

The safety of niraparib plus bevacizumab maintenance was also consistent with the known side effects of each drug as monotherapy. Findings showed that 99% of patients experienced a treatment-emergent adverse event of any grade, with 77% of patients experiencing a grade ≥ 3 treatment-emergent adverse event. The most common grade ≥ 3 or grader treatment-related adverse events were thrombocytopenia (39%), anemia (34%), and hypertension (27%).

Twenty-seven percent of patients discontinued treatment due to a treatment-related adverse event; although the rate of treatment discontinuation was higher for the combination therapy than for monotherapy alone, authors of the study noted that it was consistent with other studies that examined the combination of a PARP inhibitor plus bevacizumab.

Key Points

• At the 18-month landmark analysis of the phase II OVARIO study, 62% of patients receiving niraparib plus bevacizumab maintenance remained progression-free following response to first-line platinum-based chemotherapy with bevacizumab.
• No new safety signals were observed.

Disclosure: This study was funded by GlaxoSmithKline.

This article was published by The ASCO Post.

Recent Chemotherapy or Immunotherapy for Gynecologic Cancer Does Not Raise Risk of Death Due to COVID-19

Although some studies show that patients with cancer have a greater risk of health complications from COVID-19, a new study has found that recent chemotherapy or immunotherapy for gynecologic cancer does not raise the risk of hospitalization or death due to COVID-19. The study results were presented by Lara et al at the Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer (Abstract ID: 10663).

“We can reassure women with gynecologic cancer that they can continue anticancer therapy,” said the study’s presenting author, Olivia Lara, MD, MS, a gynecologic oncology fellow at New York University (NYU) Langone Health.

Dr. Lara said she and her colleagues conducted the study because gynecologic cancer was underrepresented in past studies of COVID-19 outcomes in patients with cancer. Also, she said some of her patients were concerned that chemotherapy, which can weaken the immune system, would increase their risk of more severe illness if they became infected with the novel coronavirus.

Analysis and Results

The researchers analyzed data from 193 patients infected with COVID-19 at eight New York City–area hospitals treated between March and May 2020. All patients had gynecologic cancer, primarily endometrial/uterine, ovarian, and cervical cancers. Overall, 106 patients (54.9%) required hospitalization.

When the investigators analyzed the odds of death or hospitalization due to COVID-19, they found that the use of cytotoxic chemotherapy did not predict increased risk for either, said Dr. Lara. The same held true for immunotherapy. Although her research team last year reported that immunotherapy was a risk factor for increased COVID-19–related deaths in women with gynecologic cancer, that was not the case in this larger study, she noted.

However, the researchers did find greater odds of death due to COVID-19 among current or former smokers vs nonsmokers; smoking is a known risk factor for severe COVID-19 infection.

The need for hospitalization due to COVID-19 was reportedly associated with age 65 years or older, Black race, and having three or more additional coexisting long-term health conditions. Additionally, women who had a low performance status score, indicating their ability to independently perform activities of daily living, had increased odds of hospitalization compared with those with better performance status.

Of the 193 patients in this study, 34 (or 17.3%) died of COVID-19. Dr. Lara said this fatality rate is similar to that of age-matched women with COVID-19 who did not have cancer. She added that fatality rates may be lower now than early in the pandemic, when their study took place.

This article was published by The ASCO Post.

Small Molecule Inhibitor Shows Promise in Resistant Ovarian Cancer

Responses in 37% of patients with AVB-500, higher without prior bevacizumab.

By Charles Bankhead

More than a third of patients with platinum-resistant ovarian cancer had objective responses to chemotherapy plus a small-molecule inhibitor that targets resistance-associated signaling, a preliminary study showed.

Seven of 19 patients responded to the combination of paclitaxel and the GAS6/AXL inhibitor AVB-500, as did four of 26 patients who received AVB-500 plus pegylated liposomal doxorubicin (PLD). Subgroup analyses showed greater activity with paclitaxel/AVB-500 in patients with a platinum-free interval (PFI) of less than 3 months and in those who had not received bevacizumab (Avastin).

A majority of patients had grade 3/4 adverse events (AEs), primarily associated with chemotherapy, reported Katherine Fuh, MD, PhD, of Washington University in St. Louis, at the Society of Gynecologic Oncology virtual meeting.

“There is substantial evidence for benefit of AVB-500 and paclitaxel,” said Fuh. “The objective response rate was 37% for the entire cohort, 50% for the high MEC, or minimal efficacious concentration-high group, and 67% for the no-prior bevacizumab exposure group versus 10% in the prior bevacizumab group.”

“Proprietary serum soluble AXL/GAS6 may be able to identify who will best respond. This will continue to be evaluated in GOG 3059/ENGOT OV66, an upcoming phase III clinical trial comparing weekly paclitaxel to weekly paclitaxel/AVB-500,” she stated.

Binding of the ligand GAS6 to AXL can lead to therapy resistance and induce the epithelial-to-mesenchymal transition, which is involved in tumor progression, metastatic expansion, and generation of tumors cells that have stem cell-like properties. Fuh and colleagues have shown that increased AXL expression correlates with chemoresistance and poor prognosis, and inactivation of AXL increases tumor cell susceptibility to paclitaxel and increased intratumoral concentrations of the chemotherapeutic drug.

AVB-500 is an AXL decoy protein that selectively inhibits GAS6/AXL signaling. By means of protein engineering, the decoy receptor has a high affinity for GAS6, an activator of AXL in preclinical cancer models. The safety of AVB-500 was demonstrated in a study of healthy volunteers, leading to the phase Ib trial reported by Fuh.

Eligible patients had platinum-resistant, high-grade serous ovarian cancer, endometrioid or undifferentiated adenocarcinoma histology, and one to three prior lines of therapy. The trial comprised two patient cohorts: paclitaxel plus escalating doses of AVB-500 or PLD plus AVB-500. The primary outcomes were safety and antitumor activity.

Data analysis included 53 patients (23 in the paclitaxel arm, 30 in the PLD group) who had a mean age of 64. Almost 90% of the patients had high-grade serous disease. Almost half of the patients had received bevacizumab, and a fourth had received a PARP inhibitor prior to enrollment. About 80% of the patients had received one or two prior lines of therapy. A third of the study population had a PFI of ❤ months and the rest had PFIs of 3-6 months.

The safety analysis included all 53 patients enrolled in the trial. Treatment-related adverse events (TRAEs) occurred in 18 (78.3%) patients in the paclitaxel group and 19 (63.3%) of the PLD group. Grade ≥3 TRAEs in the paclitaxel and PLD groups included fatigue (26.1% vs 16.7%), infusion-related reaction (21.7% vs 20.0%), anemia (21.7% vs 6.7%), and nausea (13% vs 13.3%).

The efficacy analysis included 44 patients from the two arms combined. In the paclitaxel arm, seven of 19 (36.8%) patients had objective responses, including two complete responses. An additional six patients had stable disease, resulting in a clinical benefit rate (CBR) of 68.4%.

In the PLD arm, four of 25 (16%) patients responded, all partial responses. Eleven patients had stable disease, resulting in a CBR of 60%.

Median progression-free survival was 3.6 months in both treatment groups. Media overall survival (OS) was 14.1 months in the paclitaxel group and 12.6 months in the PLD group.

An analysis of survival by MEC in the paclitaxel arm (trough level of 13.8 mg/L) showed that 10 patients with trough levels exceeding the MEC had a median PFS of 7.5 months, objective response rate of 50%, and median OS of 19.0 months. Among nine patients with MEC below 13.8 mg/L had median PFS of 2.8 months, response rate of 22.2%, and median OS of 8.7 months.

Analysis of the paclitaxel group by prior bevacizumab exposure showed that six of nine patients with no prior exposure responded to the treatment, and one had stable disease. Among 10 patients previously treated with bevacizumab, one patient had an objective response and five had stable disease.

A preliminary biomarker analysis showed that patients with a higher baseline AXL/GAS6 ratio were significantly (P=0.047) more likely to respond to AVB-500, said Fuh. Specifically, all responding patients had a baseline ratio exceeding 0.773.

The finding that prior bevacizumab exposure might influence response to AVB-500 is intriguing, according to invited discussant Ursula A. Matulonis, MD, of Dana-Farber Cancer Institute in Boston. That observation should be evaluated further in the phase III trial, including an investigation into potential mechanisms underlying the interaction.

This article was published by MedPage Today.

PARP Inhibitor Tops Chemo for Recurrent BRCA Ovarian Cancer

Modest improvement in PFS with rucaparib but worse outcome for reversion mutation.

By Charles Bankhead

A PARP inhibitor slowed progression of recurrent, advanced BRCA-positive ovarian cancer as compared with standard chemotherapy, a randomized trial showed.

Treatment with rucaparib (Rubraca) led to a median progression-free survival (PFS) of 7.4 months versus 5.7 months with chemotherapy. The advantage persisted in per-protocol and intention-to-treat (ITT) analyses and investigator- and independently assessed PFS.

In an exploratory analysis of tumors with BRCA-reversion mutations, which restore homologous recombination repair of DNA and confer treatment resistance, chemotherapy resulted in a longer PFS in a small number of patients, Rebecca Kristeleit, MD, of Guy’s and St. Thomas’ Hospital in London, reported at the Society of Gynecologic Oncology virtual meeting.

“Patients with BRCA-mutated advanced, relapsed ovarian cancer who received rucaparib had a significant improvement in progression-free survival versus standard of care chemotherapy,” Kristeleit concluded. “The rucaparib safety profile was consistent with that reported in prior studies. This is the first prospective cohort from a randomized study showing that the presence of a BRCA-reversion mutation may predict for primary resistance to rucaparib.”

Follow-up for analysis of overall survival will continue until data are sufficiently mature, she added.

In late 2016, the FDA granted accelerated approval of rucaparib for previously treated BRCA-mutant advanced ovarian cancer. Final approval remained contingent on accumulation of additional data to support existing evidence of rucaparib’s safety and efficacy for the indication. Kristeleit reported findings from the confirmatory ARIEL4 trial designed to satisfy data requirements for final approval.

Eligible patients had relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer associated with a deleterious BRCA mutation (germline or somatic), treated with two or more prior chemotherapy regimens, including at least one platinum-containing regimen. Prior treatment with a PARP inhibitor or single-agent paclitaxel was not allowed.

Investigators stratified patients by response to prior platinum-containing therapy: 1 to 6 months, resistant; 6 to 12 months, partially sensitive; and ≥12 months, fully sensitive. Patients were randomized 2:1 to single-agent rucaparib or standard-of-care chemotherapy. Patients received single-agent rucaparib, irrespective of platinum response status. Those allocated to chemotherapy received weekly paclitaxel (resistant and partially sensitive patients) or platinum-based chemotherapy (fully sensitive).

Treatment continued until disease progression, unacceptable toxicity, or death. Patients allocated to chemotherapy could cross over to rucaparib at disease progression. The primary endpoint was investigator-assessed PFS in the efficacy population (BRCA-reversion mutations excluded), followed by an ITT analysis if rucaparib proved superior in the efficacy population.

Data analysis included 349 randomized patients, 233 assigned to rucaparib and 116 to chemotherapy. The study population had a median age of 58 and median time from diagnosis of about 3.5 years. About 15% of BRCA mutations were somatic, and the rest were germline. A majority of patients had received two prior regimens, but 38% had received three or more prior regimens.

The median platinum-free interval for the most recent platinum regimen was 5.7 months. About half the patients had platinum-resistant disease, about a fourth had partially sensitive disease, and the rest had platinum-sensitive cancers.

The primary analysis showed that rucaparib was associated with a 36% reduction in the hazard for disease progression or death (95% CI 0.49-0.84, P=0.001). The ITT analysis yielded a median PFS of 7.4 months with rucaparib and 5.7 months with chemotherapy (HR 0.67, 95% CI 0.52-0.86, P=0.002).

Kristeleit said 23 patients had BRCA-reversion mutations, 13 in the rucaparib arm. Chemotherapy led to numerically better PFS in that analysis, 5.5 versus 2.9 months (HR 2.77, 95% CI 0.99-7.76).

Rucaparib offered a numerically higher response rate (40.3% vs 32.3%, P=0.13) and a significantly longer duration of response (9.4 vs 7.2 months, HR 0.59, 95% CI 0.36-0.98). Quality-of-life outcomes were similar between treatment groups.

Analysis of treatment-emergent adverse events (TEAEs) showed that rucaparib was associated with more anemia, nausea, elevated liver enzymes, vomiting, abdominal pain, and thrombocytopenia. The most common grade ≥3 TEAEs were anemia (22.4% with rucaparib and 5.3% with chemotherapy) and neutropenia (15.0% with chemotherapy and 10.3% with rucaparib).

Data from trials of olaparib (Lynparza) showed that response to single-agent PARP inhibition decreases with increasing platinum resistance and number of prior lines of therapy, said invited discussant Ursula A. Matulonis, MD, of Dana-Farber Cancer Institute in Boston. Prior investigation of rucaparib revealed that patients with BRCA-reversion mutations do not benefit from the PARP inhibitor.

“Data from ARIEL4 fit the paradigm that single-agent activity of PARP inhibitors in BRCA-mutated recurrent ovarian cancer may be comparable to chemotherapy and may at times be superior, depending on the study population, trial design, and treatment for control patients,” she said. “The BRCA-reversion mutation data from ARIEL4 is intriguing. Strategies to overcome and better understand this type of resistance mechanism are needed.”

This article was published by Medpage Today.

Two Pathways, One Destination: Promising Drug Combination to Treat Ovarian Cancer

By R. Colon-Thillet

Treatment for ovarian cancer across subtypes typically consists of platinum-based chemotherapies. However, this standard therapy is less effective against ovarian clear cell carcinoma (OCCC), a rare subtype of ovarian cancer with distinct pathology and genetic drivers. Advanced OCCC has a poor prognosis, and effective targeted therapies are thus urgently needed. New research from the Kemp lab, now published in the journal Molecular Cancer Therapeutics, identifies BET proteins BRD2 and BRD3 as therapeutic targets for OCCC and describes a synergistic drug combination targeting the BET and PI3K-AKT pathways as a potentially effective therapeutic strategy.

In the study, Shigeta and colleagues first identified potential therapeutic targets for OCCC using a high-throughput siRNA strategy to screen >2,000 genes of interest. They performed the screen in two cell lines, one derived from OCCC and the other derived from a common ovarian cancer subtype known as high-grade serous or endometrioid ovarian carcinoma (HGSC). Comparison of gene candidates from both cell lines allowed the researchers to identify potential subtype-specific targets. More than a hundred genes were identified in each cell line, yet only 20 were shared between both, highlighting distinct functional differences between OCCC and HGSC subtypes.

Schematic of mechanisms of PI3K and BET inhibitor synergy. Knockdown or inhibition of BET proteins directly or indirectly alters PI3K signaling which synergizes with PIK3CA or AKT inhibition leading to p53-independent apoptosis. Image provided by Dr. Chris Kemp 

Gene set enrichment analysis (GSEA) in the siRNA screen hits from the OCCC cell line detected pathways in chromatin or transcription regulation, which led the investigators to hypothesize that OCCC might be more vulnerable than HGSC to epigenetic interventions. In recent years, epigenetic readers such as bromodomain and extraterminal domain (BET) proteins have gained recognition as targets for novel anticancer therapies. BET proteins are epigenetic readers that regulate gene expression and are involved in cancer pathogenesis. In the OCCC screen, BET proteins BRD2 and BRD3 were among the top targets identified. The investigators then knocked down BRD2, BRD3, and BRD4 using pooled or individual siRNAs. They observed a significant reduction in viability in addition OCCC cell cultures, validating the screen results and highlighting the vulnerability of OCCC to BET inhibition.

Recently, BET inhibitors have been clinically evaluated in the context of numerous cancer types but, although some show promise, their effect as a single agent is associated with a low-rate response in clinical trials. This observation led the group to evaluate potential synergistic combination therapies that could enhance BET inhibitors’ effect.  By performing BET inhibitor sensitizer drug screens, they identified PIK3-AKT pathway inhibitors as sensitizer drugs. To shed light on the mechanism underlying this synergism, the investigators monitored AKT phosphorylation following treatment with increasing doses of the PIK3-AKT inhibitor in the presence of a BET inhibitor. Their results demonstrated that less PIK3-AKT inhibitor was needed to reduce AKT phosphorylation in the BET inhibitor’s presence, suggesting that BET proteins may directly or indirectly regulate PI3K-AKT signaling.

Using RNA-seq analysis following individual BET protein knockdowns, the group determined that each BET protein has a unique role in gene expression. Furthermore, applying GSEA to the data set revealed that all BET proteins could modify PI3K-AKT signaling and apoptotic sensitivity, congruent with the observed reduction of AKT phosphorylation at lower PIK3-AKT inhibitor concentrations when BET is inhibited.

Accurate models for OCCC are scarce; however, the use of organoids derived from OCCC patient tumors provides a 3D culture model to test novel therapeutics. To evaluate if a synergistic drug approach would be effective in OCCC organoids, the researchers screened organoids derived from multiple patients. BET and PI3K inhibitors were among the top-scoring drugs in the organoids tested, confirming the findings in 2D models and suggesting that BET and PI3K pathway inhibition, alone or in combination, could be an effective therapy for OCCC.

Dr. Chris Kemp, the principal investigator in the study, highlighted the impact of their approach: “The combination of high throughput siRNA and drug screening applied to patient-derived cells and organoids really accelerates our ability to identify and validate new clinically relevant therapeutic options for patients.”

This article was published by Fred Hutch.

High Tumor Mutational Burden Predicts Immunotherapy Response in Some—but Not All—Cancers

High tumor mutational burden (TMB) was useful for predicting clinical responses to immune checkpoint inhibitors only in a subset of cancer types, according to a study published by McGrail et al in Annals of Oncology.

The findingssuggest that TMB status may not be reliably used as a universal biomarker for predicting immunotherapy response. While TMB status was capable of successfully predicting response to checkpoint blockade in certain cancers, such as melanoma, lung cancer, and bladder cancer, there was no association with improved outcomes in other malignancies, including breast, prostate, and brain cancers.

“This study represents the most comprehensive analysis to date of TMB as a biomarker for response to immune checkpoint blockade,” said lead study author Daniel J. McGrail, PhD, a postdoctoral fellow in Systems Biology at The University of Texas MD Anderson Cancer Center. “Our results do not support applying high TMB status as a universal biomarker for immunotherapy response, suggesting that additional tumor type–specific studies are needed to clarify how best to apply TMB status in cancer types where it does not appear to be associated with outcomes.”

TMB as a Biomarker

Genetic mutations within a tumor lead to the production of mutant proteins, or neoantigens, which can be recognized as abnormal by the immune system. It follows that a high TMB would render tumors more immunogenic, which is why TMB status has become a leading candidate biomarker for predicting immunotherapy response, explained Dr. McGrail.

In June 2020, the U.S. Food and Drug Administration approved the anti–PD-1 therapy pembrolizumab for patients with advanced and refractory cancers with a high TMB, as indicated by a defined threshold level of mutations. The approval was based on results from the phase II KEYNOTE-158 study, which found improved overall responses in patients with a high TMB. However, the trial did not include several cancer types, such as breast, prostate, and brain cancers, which have not typically responded to immune checkpoint blockade therapy.

“The FDA approval of pembrolizumab for patients with high TMB certainly provides an important option for many patients,” said senior study author Shiaw-Yih Lin, PhD, Professor of Systems Biology at MD Anderson. “However, we felt that it was important to look more closely at TMB status in a broader group of cancer types and establish approaches to harmonize TMB across various assays to enable clinicians to best utilize the recent FDA approval.”

Methodology

The researchers analyzed over 10,000 tumors across 31 cancer types from The Cancer Genome Atlas to study the relationship between TMB status and tumor immunogenicity, measured by the infiltration of immune cells (CD8-positive T cells) into the tumor. They identified two classes of tumors: those with and without a strong correlation between TMB status and T-cell infiltration.

The authors hypothesized that TMB status would not be able to predict immunotherapy response equally in these two groups. They evaluated this using previously published studies and MD Anderson patient cohorts.

Results

For cancers with a strong correlation between TMB status and T-cell infiltration, patients with a high TMB had improved clinical outcomes. Across all cancer types in this category, patients with a high TMB had a 39.8% overall response rate to checkpoint inhibitors, which was significantly higher than those with a low TMB.

In contrast, TMB status was not predictive of outcome in the second class of tumors. Within this category, patients with a high TMB had a 15.3% overall response rate, which was actually lower than the response rate for patients with low TMB.

“While TMB status does show value in predicting response to immune checkpoint blockade in several cancer types, this was not generalizable across all cancers,” said Dr. McGrail. “For those cancer types where a high TMB does not appear to increase immunogenicity, additional prospective studies are needed to determine if TMB status can be an effective clinical biomarker and at what threshold.”

Additionally, the researchers found that evaluating TMB status by sequencing a targeted panel of cancer-related genes may overestimate TMB when compared to whole-exome sequencing, which offers an unbiased approach. While whole-exome sequencing is not feasible in a clinical setting, the threshold for defining high TMB status may need to be evaluated in a cancer type–specific manner, Dr. McGrail explained.

The authors noted that this study is limited by retrospective analyses across various DNA sequencing approaches, as well as variations in the immune checkpoint inhibitors and clinical outcomes reported across the different cohorts included.

Disclosure: This study was supported by the National Cancer Institute, the George and Barbara Bush Endowment for Innovative Cancer Research, the Kidney Cancer Association Young Investigator Award, the Prostate Cancer Foundation Young Investigator Award, the Cancer Prevention & Research Institute of Texas, and the Breast Cancer Moon Shot^®, part of MD Anderson’s Moon Shots Program^®. For full disclosures of the study authors, visit annalsofoncology.org.

This article was published by The ASCO Post.

FDA Grants Priority Review to Pafolacianine Sodium Injection in Ovarian Cancer

The FDA has granted priority review to the new drug application for the novel compound pafolacianine sodium injection for use in the identification of ovarian cancer during surgery.

By Courtney Marabella

The FDA has granted priority review to the new drug application (NDA) for the novel compound pafolacianine sodium injection (formerly OTL38) for use in the identification of ovarian cancer during surgery, according to an announcement from On Target Laboratories, Inc.

Pafolacianine sodium injection has demonstrated the ability to bind to folate receptors and illuminate intraoperatively under near-infrared light; it can be administered intravenously prior to treatment-related surgeries. Utilizing the injection in ovarian cancer surgery could help to provide greater certainty of complete disease resection, as approximately 97% of patients with ovarian cancer express clear alpha-folate receptor proteins.

The use of pafolacianine sodium injection in ovarian cancer was investigated in phase 2 (NCT02317705) and phase 3 (NCT03180307) trials and was under Special Protocol Agreement from the FDA. Additionally, the agent has received both fast track and orphan designations from the regulatory agency.

“Our NDA is supported by our positive phase 2 and phase 3 clinical trials,” Christopher Barys, president and CEO of On Target Laboratories, stated in a press release. “As we move closer to FDA approval for ovarian cancer, we are realizing our mission to intraoperatively visualize more cancer and extend the benefits of a complete resection to patients.”

The phase 2 study enrolled 29 patients who were 18 years of age or older with a primary diagnosis, or high clinical suspicion, of ovarian cancer. Participants received pafolacianine sodium injection prior to planned debulking surgery.

Results showed that when controlling for correlation of detection among multiple lesions within a single patient, pafolacianine sodium injection had a sensitivity of 97.97% (95% lower boundary CI = 87.75) and a positive predictive value of 94.93% (95% lower boundary CI = 86.13). Additionally, 48.3% (n = 14/29; 95% CI, 0.29–0.67) of patients had at least 1 additional lesion detected by pafolacianine sodium injection.

In terms of safety, 8 patients experienced mild drug-related adverse effects (AEs). The most common AEs reported included infusion reaction, nausea, vomiting, and abdominal pain.

Data from the phase 2 trial led to the ongoing phase 3 trial, which is further evaluating the agent in that patient population.

Additionally, pafolacianine sodium injection is currently being investigated in the phase 3 ELUCIDATE trial (NCT04241315) for use in the intraoperative detection of lung cancer lesions. This multicenter trial will evaluate the safety, efficacy, and tolerability of pafolacianine sodium in patients with lung cancer and is expected to enroll up to 130 patients. The first patient was enrolled in the study in July 2020, and preliminary data is expected in 2021.

This article was published by OncLive.