ASCO 2018: Dendritic Cell Vaccine Has Been Proven to Be a Promising Maintenance Treatment Option to Delay Progression of Epithelial Ovarian Carcinoma

ASCO 2018Dendritic cell vaccine improved progression-free survival when administered sequentially after chemotherapy. The vaccine provides a promising maintenance treatment option to delay progression of epithelial ovarian carcinoma.

This outcome of an interim analysis of a phase II, open-label, randomized, multicenter trial was reported at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, from June 1 – 5.

Lukas Rob, MD, PhD, of Charles University, Prague, Czech Republic, explained that most patients with epithelial ovarian cancer will relapse after primary debulking surgery and chemotherapy. Autologous dendritic cell vaccine can present tumor antigens to elicit a durable immune response.

Dr. Rob and colleagues hypothesized that adding the dendritic vaccine to chemotherapy would improve outcomes, including progression-free survival.

“Despite available treatment options,” Dr. Rob told Elsevier’s PracticeUpdate, “relapsed disease remains inevitable. Effective maintenance treatment options in the frontline setting are limited and represent an unmet medical need.”

“An innovative option,” he continued, “to prevent relapse is active cellular immunotherapy administered as maintenance treatment after adjuvant platinum-based chemotherapy.”

Key eligibility criteria were International Federation of Gynecology and Obstetrics stage 3 epithelial ovarian carcinoma (serous, endometrioid, or mucinous), performance status 0 – 2, post primary debulking surgery with <1 cm maximal residuum and no prior systemic therapy. Patients were randomized up to 6 weeks after primary debulking surgery, 1:1:1, into:

  • Arm A, n=34, dendritic cell vaccine + chemotherapy
  • Arm B, n=34, dendritic cell vaccine sequentially after chemotherapy
  • Arm C, n=31, chemotherapy alone

Patients were stratified by tumor residuum (0 or <1 cm). Chemotherapy consisted of 6 cycles of carboplatin (area under the curve 5 – 7) and paclitaxel (175 mg/m2 of body surface area). Patients in arms A and B were randomized to 10 doses of dendritic cell vaccine (1 × 107 dendritic cells per dose).

The primary endpoint was investigator-assessed progression-free survival. Key secondary endpoint was overall survival.

Between 2013 and 2016, 99 patients were randomized in 3 countries. Median age was comparable in all arms (range 61.5 – 62.0 years). The percentage of patients with complete cytoreduction was 85% in arms A and B, and 84% in arm C.

At the planned interim analysis, the intent-to-treat population included 31 patients in arm A, 30 patients in arm B, and 31 patients in arm C. Patients who failed leukapheresis or manufacturing were excluded.

A mean of 9.6 and 9.5 doses of dendritic cell vaccine were administered in arms A and B, respectively. Median follow-up duration was 26.8 (range 3.24 – 43.0) months. One patient withdrew informed consent early in the trial. Median progression-free survival was 18.3 months in arm A, 24.3 months in arm B, and 18.6 months in arm C.

Compared with arm C, hazard ratios for progression-free survival (95% confidence interval) were 1.08 (0.53 – 2.21) in arm A and 0.43 (0.18 – 1.03) in arm B. The gain in progression-free survival in the sequential arm was statistically significant (P = .05).

This improvement was supported by the same trend in overall survival. Median overall survival was not reached in any arm (14% events). No grade ≥3 adverse events related solely to dendritic cell therapy were observed.

“When we looked at baseline characteristics,” Dr. Rob noted, “they were well balanced across arms. In the frontline setting, the ability to prolong progression was clinically meaningful. Not only has the vaccine prolonged the time to progression, but patients are surviving longer based on the current hazard ratio (0.13; 95% confidence interval 0.02 – 1.08; P = .03). The results look very promising and if confirmed, the dendritic cell vaccine could be practice-changing.

The dendritic cell vaccine did not worsen the side effects of chemotherapy. The most common leukapheresis-related adverse events were mild pyrexia and moderate hypocalcemia.

Dr. Rob concluded that the dendritic cell vaccine improved progression-free survival when administered sequentially after chemotherapy. The vaccine provides a promising maintenance treatment option to delay progression of epithelial ovarian carcinoma.

To read this full article on Practice Update, please click here.


Bevacizumab Rechallenge Benefit in Recurrent Ovarian Cancer?

ASCO 2018A new study suggests that a rechallenge with bevacizumab in combination with platinum-based chemotherapy may prolong progression-free survival (PFS) in patients with recurrent ovarian cancer (ROC) who already received this agent during first-line treatment. The study was presented by Italian researchers at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.

Sandro Pignata, PhD, of the Istituto Nazionale Tumori IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico – Oncologico) “Fondazione G. Pascale,” Naples, Italy, and colleagues evaluated whether adding bevacizumab to a platinum-based chemotherapy prolongs PFS for ROC patients for whom the agent failed as first-line therapy. They found that a rechallenge with bevacizumab in combination with platinum-based chemotherapy was associated with a significantly prolonged PFS and no unexpected toxicities.

Bevacizumab is a recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF), a pro-angiogenic cytokine. It binds to VEGF and inhibits VEGF receptor binding, preventing the growth and maintenance of tumor blood vessels. Currently, bevacizumab is FDA approved for ROC patients not previously treated with it, and for the treatment of adults with recurrent glioblastoma.

This randomized phase III trial enrolled FIGO stage IIIB–IV ROC patients relapsing at least 6 months after the last dose of platinum. All patients had received bevacizumab during first-line treatment and were randomized to 6 cycles of platinum-based doublets (carboplatin/paclitaxel or

carboplatin/gemcitabine or carboplatin/pegylated liposomal doxorubicin), with or without bevacizumab. Bevacizumab was administered concomitantly with chemotherapy and as maintenance therapy until disease progression.

A total of 405 patients (mean age, 61 years) were enrolled, and the primary endpoint was PFS.  Among these patients, 64% had progressed ≥ 12 months after their last dose of platinum-based therapy, and 72% had progressed after completion of first-line bevacizumab maintenance. After a median follow-up of 20.3 months, there were 304 PFS events and 147 deaths. Median PFS was 8.8 months without bevacizumab and 11.8 months with bevacizumab (HR, 0.51; 95%CI, 0.41–0.64; P < .001). Median OS was similar in the two groups: 27.1 months without bevacizumab and 26.7 months with bevacizumab (P = NS).

The most common severe side effects (grade 3 or higher) were hypertension (27.5% in the bevacizumab arm vs 9.7% in the non-bevacizumab arm) and proteinuria (4% in the bevacizumab arm vs 0% in the non-bevacizumab arm.

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My Stomach Pain Proved To Be Advanced Ovarian Cancer, and I Didn’t Like The Odds.

By: Susan Lisovicz

My Stomach Pain Proved To Be Advanced Ovarian Cancer, and I Didn’t Like The Odds.I’m glad I was lying down when the doctor told me the true cause of my stomach pains.

“Well, you’ve got a tumor” were his first words to me. I had just awakened in a hospital bed on the morning after emergency surgery. It was Tuesday, Oct. 31, 2017. Halloween.

The doctor’s scary outlook came after two agonizing trips to the emergency room that had begun the preceding Friday night. After looking at abdominal X-rays, an ER doctor said constipation was making me feel as though a drawer full of forks was trying to pierce through my belly. He recommended an over-the-counter laxative.

By Saturday evening I was throwing up, and the pain was still relentless. I went back to the ER Sunday, where I was treated with additional laxatives and the first of five enemas. Finally a gastrointestinal specialist, whom my partner had texted in desperation, came on board Monday and performed a partial colonoscopy, then called in the surgeon after discovering that a tumor was causing a nearly complete blockage of my large intestine.

The tumor turned out to be Stage 3 ovarian cancer. It also created another life-threatening situation: the imminent possibility that my colon would rupture. The surgeon relieved the obstruction by performing a temporary colostomy, in which a piece of the colon is diverted to an artificial opening in the abdomen.

The doctor told me he had left the tumor for another day, for which I am forever grateful because this gave me the opportunity to consult with specialists on how to proceed.

Ovarian cancer will kill an estimated 14,000 American women this year. Mine was advanced. Stage 3 means that cancer cells have spread to tissues outside the pelvis or to lymph nodes in the back of the abdomen. Most women diagnosed with Stage 3 ovarian cancer have a five-year survival rate of 39 percent. With statistics like that, I instinctively knew I would opt for an aggressive response and, ultimately, experimental treatment.

You never know how you are going to react when you hear something so devastating. I had been healthy all my life and was literally standing on my head in a 6 a.m. yoga class the day before everything turned upside down in the ER.

All that slow, deep yoga breathing helped keep me calm — and so did my experience as a journalist. I’d covered my share of complicated stories during my 25 years at CNN and CNBC. The ability to line up experts and to make sense of what they’re saying in a short amount of time is deeply ingrained. And I felt as though I was on deadline now.

Cancer can move quickly. I wanted my cancer OUT. I wanted it eviscerated. That ultimately meant a drive out of the New York metro area to Baltimore’s Mercy Medical Center. A family friend had told me about the surgical oncologist Armando Sardi, who has performed nearly 600 cytoreductive surgeries.

CRS is the aggressive removal or destruction of all or most of the visible tumors in the abdomen. It may also include removal of multiple organs. Some people who have been through it call it MOAS — for “mother of all surgeries.” They are complex, meticulous and long surgeries. Sardi says his longest was 19 hours; his average is seven to 10.

I also wanted something else that can come immediately after this surgery: heated chemotherapy on the operating table.

Because it is likely that microscopic disease still remains after surgery, hyperthermic intraperitoneal chemotherapy, or HIPEC, is used to deliver treatment directly to cancer cells in the abdomen. It is believed that heating the solution — in my case, to 107.5 degrees — may improve the absorption of the drugs.

HIPEC has been used for years in some abdominal cancers, but researchers are just beginning to test it on advanced ovarian cancer. Mercy says it is the only U.S. institution investigating CRS with HIPEC in women newly diagnosed with ovarian cancer to see if it could be a new standard of care.

One surgical oncologist, whose hospital did not offer HIPEC in newly diagnosed cases like mine, told me during consultation that heated chemotherapy was the “cherry on the cake,” that impeccable surgery was what really counted. Well, I wanted the cake AND the cherry on the top.

The anesthesia began at 7:39 a.m. on Nov. 30. The surgery ended at 7:37 p.m. During that time, Sardi and gynecologic oncologist Teresa Diaz-Montes performed a complete hysterectomy, removed my gallbladder, spleen and the fatty tissue that covers the intestines and organs in the abdomen known as the omentum, cut out about a third of my stomach and about three feet of small bowel and reversed the colostomy. All visible traces of cancer were removed.

“We pretty much peeled off the inside of the belly,” Sardi said. MOAS, indeed. And then I had the 90-minute chemo bath. No, I was not expecting THAT big of a surgery beforehand, but neither was Sardi. “Until I am in surgery, it is unpredictable and the CAT scan usually shows less than what is found,” he said.

It took me more than two months before I had the nerve to read the chilling pathological report and operative note. “You had massive disease,” Sardi told me in a recent phone call. “The good thing is, we were able to take it out.”

I have had no complications. I was released from the hospital nine days after surgery and then stayed in an apartment nearby for another 11 days. Then the staples from my 12-inch scar were removed and I went home to celebrate Christmas with my family. Sardi said there were only about 10 facilities in the world that did CRS/HIPEC when he began doing it in 1994. While many more places offer it now, it is still not mainstream.

A Dutch study published in January in the New England Journal of Medicine showed that patients with advanced ovarian cancer who were treated with HIPEC had longer recurrence-free survival than those who received surgery alone, and they did not experience higher rates of side effects. The stats are still bleak —the median overall survival was 45.7 months in the surgery-plus-HIPEC group vs. 33.9 months in the surgery alone group — but that is almost a year’s difference of life. I’ll take that.

The single most motivating thing I read before surgery was a 2013 study that said nearly two-thirds of women with ovarian cancer received substandard care, which is linked to reduced survival rates and underscored the urgency of being your own best advocate. This is just unacceptable for the fifth-leading cause of cancer for women.

Also unacceptable is the fact that there is still no test to catch ovarian cancer early. The vast majority of cases are diagnosed at Stage 3 or 4, so getting it right from the outset is critical. You simply have less time for mistakes.

Patients need to “ask the provider and hospital how many ovarian cancer patients they treat, how many ovarian cancer surgeries they perform and their ovarian cancer patients’ rate of survival,” said Robert E. Bristow, director of gynecologic oncology at the University of California at Irvine Medical Center and the lead author of the 2013 study.

A common approach to treating ovarian cancer is chemo to shrink the tumor, followed by surgery. One gynecologic oncologist advised me to take that route. He outright dismissed HIPEC.

“It’s not the standard of care,” he said. “If it was, we’d all be doing it.” He frowned upon having such a big operation just one month after my emergency surgery. He had a point. Because CRS often involves the removal of multiple organs, there are additional risks, including bleeding, infection and even death. The chemo immediately afterward adds to the danger.

“If you don’t know what you’re doing, the mortality can be very high,” Sardi said.

A 2012 study in the Annals of Surgery said that CRS and HIPEC have a “steep learning curve requiring 140 procedures to acquire expertise.”

Diaz-Montes said she and Sardi have worked together so frequently that they often did not need to speak during the long operation. “It’s as if we’re dancing,” she said.

There are also financial factors to consider. While HIPEC is standard of care for appendix cancer, peritoneal carcinomatosis and mesothelioma tumors, it is considered “investigational” for ovarian cancer, said Yolanda Brockington, HIPEC coordinator at the Institute for Cancer Care at Mercy. Many insurance companies don’t pay for that portion of the procedure, which costs $5,000, Brockington said.

Mercy performs two or three CRS/HIPEC surgeries a week, according to Michelle Sittig, an oncology research coordinator at the hospital. That modest number is due in part to the length of the surgeries.

“You have to have the stamina to do it and not give up,” Sardi says.

After seven weeks of recovery from surgery, I began an aggressive round of chemotherapy at New York’s Memorial Sloan Kettering Cancer Center. 18 weeks. Every. Damn. Week. My oncologist there, Carol Aghajanian, said she would manage the worst side effect — nausea — with a pre-chemo IV. Not once was I nauseous. But there is still no cocktail for the humbling fatigue synonymous with chemo. My signature achievement on a few days was simply changing out of my pajamas before dark.

But then I would look at the lab results, and I wanted to shout from the rooftops. My CA-125, a cancer biomarker, has been 10 or below since January. Normal is 35 and under. It was just over 300 when I was diagnosed in early November.

“It’s as good as it gets,” Aghajanian says.

I am grateful for the outstanding medical care that helped save my life. But that is not enough. You need to be an active participant — body and mind — in fighting cancer. You’re supposed to stay positive. So I got married in the 31-day window between surgeries. My partner proposed at a time when I was forced to carry a bag of my own waste on my stomach and faced a colossal surgery. Now that’s my idea of (Prince) Valiant.

I wore an oatmeal woolen Eileen Fisher dress that I had ordered online a few days before. It was loose enough to cover the temporary colostomy, and it was perfect — except for the plastic magnetic tag that the store had forgotten to remove before shipping. I didn’t see it when I first tried it on. Hey, when you’ve got cancer, you don’t sweat the small stuff. I wore the dress during my vows in municipal court with the tag still attached.

For a couple of hours in the morning there was champagne and laughter. And then by early afternoon I was back in a hoodie and leggings on the subway for a call-back on my mammograms, the first time I had ever been called back. I went alone by choice, and as I was riding on the Q train, I thought there is NO WAY I could be told bad news on my wedding day.

I took my place with about a dozen other women, all of us in our blue and white seersucker robes. When the technician called me back for the screening, I told her that I had literally just gotten married. She said, “You mean there’s still hope for me?”

Hope. It’s so important, whatever our priorities might be. She took exactly one picture. That was the closer look that was needed. I was clean.

Ovarian cancer is a disease with a high recurrence rate. “You had the right operation that will give you the best chance,” Sardi told me.

On my last day of treatment on May 15, my chemo nurse, a breast cancer survivor, said, “I never ever want to see you here again.”

My CT scan on June 11 was “beautiful, crystal clear,” according to Aghajanian.

Now I hope to return fully to an active and purposeful life, which often begins with sunrise headstands — and may include a honeymoon.

To read this entire article by The Washington Post, please click here.

FDA Approves Bevacizumab Plus Chemotherapy in Advanced Ovarian Cancer Following Initial Surgery

FDA Approves Bevacizumab Plus Chemotherapy in Advanced Ovarian Cancer Following Initial SurgeryToday, the U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin) in combination with chemotherapy (carboplatin and paclitaxel) followed by bevacizumab as a single agent for the treatment of women with advanced (stage III or IV) ovarian cancer following initial surgical resection.

“Today’s approval is an important advance for women newly diagnosed with this type of ovarian cancer,” said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development at Genentech. “We’re committed to advancing medicines in areas of unmet need and this FDA approval of bevacizumab plus chemotherapy gives women with advanced ovarian cancer a new treatment option that has been shown to significantly delay disease progression or death.”

“This approval represents an important milestone as the first medicine, other than chemotherapy, for women with advanced ovarian cancer after their initial surgery,” said Melissa Aucoin, Chief Executive Officer, National Ovarian Cancer Coalition.


The approval for bevacizumab in combination with carboplatin and paclitaxel followed by bevacizumab as a single agent for the treatment of women with stage III or stage IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection is based on data from the phase III Gynecologic Oncology Group (GOG)-0218 trial.

Participants were randomly assigned to one of three treatment arms: chemotherapy alone (carboplatin and paclitaxel), bevacizumab (15 mg/kg) plus chemotherapy followed by placebo alone, or bevacizumab plus chemotherapy followed by bevacizumab alone for a total of up to 22 cycles. The primary endpoint of the study was investigator-assessed progression-free survival, and secondary endpoints included overall survival. The study was conducted by the GOG, and initial results were previously published in The New England Journal of Medicine.

Women who received bevacizumab in combination with chemotherapy, and continued use of bevacizumab alone, had a median progression-free survival of 18.2 months compared to 12.0 months in women who received chemotherapy alone (hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.52–0.75; P < .0001). This progression-free survival benefit was achieved with a fixed-duration treatment (up to 22 cycles of bevacizumab total).

Bevacizumab has boxed warnings for gastrointestinal perforation, surgery and wound healing complications, and hemorrhage.

To read this full article by The ASCO Post, please click here.

FDA Clears Paxman Scalp-Cooling System For All Patients With Solid Tumors

FDA Clears Paxman Scalp-Cooling System For All Patients With Solid TumorsThe FDA granted expanded clearance to the Paxman Scalp Cooling System, allowing the device to be used by patients with any type of solid tumor.

The Paxman Scalp Cooling System (Paxman) — designed to reduce hair loss among patients who undergo chemotherapy — received clearance last year for use among patients with breast cancer.

“Scalp cooling has been a real game changer for so many of our patients with breast cancer, minimizing the risk of one of the most dreaded side effects of chemotherapy,” Steven Jay Isakoff, MD, PhD, medical oncologist at Massachusetts General Hospital Cancer Center, said in a press release. “Thanks to the recent expanded FDA indication for the Paxman Scalp Cooling system, so many more patients with solid tumors in the US can now consider this option as a safe and effective way to keep their hair during chemotherapy. We are already working on plans to make this available to all of our patients with solid tumors.”

The Paxman system reduces the temperature of the scalp by a few degrees immediately before, during and after the administration of chemotherapy.

The device is intended to reduce the amount of chemotherapy that reaches the hair follicles, reduce drug diffusion through the cell membrane, decrease cell division, reduce active transport mechanisms and generally reduce metabolic activity.

Paxman has installed approximately 225 scalp cooling systems in the United States since its initial FDA clearance last spring. Another 65 systems are awaiting delivery and installation.

“This is another step forward in making cancer therapy more personalized and putting the patients in the driver’s seat as we create more options and pathways our patients,” Debu Tripathy, MD, professor in and chairman of the department of breast medical oncology at The University of Texas MD Anderson Cancer Center, said in the release.

To read this full article on Healio, please click here.

ASCO Poster Rounds: Combo Tx Effective in Ovarian Cancer

ASCO 2018Combination of the investigational agent cediranib and olaparib (Lynparza) was active against ovarian cancers that were both platinum-sensitive and platinum therapy resistant, researchers said here.

In her poster presentation, Joyce Liu, MD, of Dana-Farber Cancer Institute/Harvard Medical School in Boston, said that 74% of the 35 women in the study who had platinum-sensitive tumors had an objective response to the combination of the agents, including several patients whose response has continued for more than a year.

She also told MedPage Today at the annual meeting of the American Society of Clinical that about 20% of the 35 women in the study who had platinum-resistant tumors also responded to the combination therapy.

Liu said that one of the objectives of the current study was to determine if there were biomarkers that could be used to guide therapy. “We don’t have a great sense of the mechanism of synergy,” she said. “We confirmed the activity of the combination in platinum-sensitive patients. We see that BRCA status is a biomarker of response for this combination but we think there will be other biomarkers as well.”

The average age of the women in the study was 60.9 years; 49% of the women had BRCAwild-type genetics; 27% of the women had BRCA mutations; the BRCA status was unknown in 17% of the women. About 40% of the women had tried one previous line of therapy; another 40% had gone through two lines of therapy and 20% had three or more previous therapies.

Women entered the trial if they had recurrent high-grade serous or high-grade endometroid primary peritoneal, Fallopian tube or ovarian cancer. Patients were ineligible if they had previously been treated with a PARP inhibitor or an anti-angiogenic agent.

“Further molecular studies are needed,” Liu said, suggesting that further findings would be available at later meetings.

No Survival Benefit With Bevacizumab

The final analysis of a government-supported clinical trial showed no overall survival difference between patients who were treated with chemotherapy plus bevacizumab (Avastin) compared with ovarian cancer patients treated with chemotherapy alone.

However, Krishnansu Tewari, MD, of the University of California Irvine, said at his poster presentation, “This result is not surprising because it is very difficult to show in these studies a survival benefit because this disease responds to so much chemotherapy. So once the patients comes off the trial, as investigators we can’t control the type of chemotherapy given. That ultimately dilutes the overall survival.”

In the trial the median overall survival for the patients who were not initiated on bevacizumab was 32.6 months while those who started on bevacizumab had median overall survival of 34.5 months (P=0.53), Tewari told MedPage Today.

“What the study did show was a significant improvement in progression-free survival which was the primary endpoint of the study,” he said. “The progression-free survival was a difference of about 4 months – 14.1 months for patients on bevacizumab and 10.2 months for patients not taking bevacizumab (P<0.001).” Those results released in 2010 had 17.2 months of follow-up. The current analysis has 102 months of follow-up.

“There is a chance that the results of this study will allow bevacizumab to receive approval for use in the first-line setting,” Tewari said.

In the NRG Oncology/Gynecologic Oncology Group study, 1,873 women with newly diagnosed, incompletely resected Stage III or Stage IV ovarian cancer were recruited. Currently 204 women remain alive but have experienced a progression event; 178 women are alive without any progression.

The patients were assigned to three study arms: placebo plus carboplatin and paclitaxel with 625 women; bevacizumab, carboplatin and paclitaxel, with bevacizumab replaced by placebo after six cycles of treatment with 625 women enrolled; bevacizumab plus carboplatin and paclitaxel with bevacizumab maintenance therapy being continued throughout the trial after six cycles of chemotherapy with 623 women assigned to this arm.

To read this entire article by MedPageToday, please click here.

Olaparib Plus Vistusertib Promising in Early Trial of Endometrial, Other Cancers

ASCO 2018The combination of the PARP inhibitor olaparib with an mTORC1/2 inhibitor known as vistusertib was tolerable and had promising activity across endometrial, ovarian, and triple-negative breast cancers, according to a phase I trial. Results of the trial (abstract 5504) were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago.

“There are a number of different mechanisms of action for PARP inhibitors in gynecologic malignancies,” said Shannon N. Westin, MD, of the University of Texas MD Anderson Cancer Center in Houston. “Specifically, synthetic lethality seems to occur in those cancer cells that are deficient in homologous deficient pathways. What we’ve been wondering is, how can we get efficacy from PARP inhibition in more cancer types and more patients?”

A number of combination approaches are under investigation. Westin said that there is evidence of synergy between PARP inhibition and targeting of the PI3K pathway, which led to this phase I trial combining an mTORC1/2 inhibitor with olaparib.

A total of 74 patients were enrolled. All patients included had recurrent endometrial adenocarcinoma (32%), recurrent triple-negative breast cancer (27%), or recurrent high-grade serous or deleterious BRCA-mutant ovarian/primary peritoneal/fallopian tube carcinoma (41%). About three-quarters of the patients were white, and the median age was 60 years. Most patients (84%) were BRCA mutation–negative, and the median number of prior therapies was four.

There were two separate dose-escalation schedules, one using continuous dosing and another using an intermittent approach for vistusertib. Dose-limiting toxicities with the continuous dosing included grade 3 rash, mucositis, grade 4 thrombocytopenia, and allergic reaction; the third dose level—olaparib 200 mg twice daily and vistusertib 50 mg twice daily—was considered the recommended phase II dose.

In the intermittent group, dose-limiting toxicities included grade 3 neutropenia, hyperglycemia, and fatigue. A recommended phase II dose of olaparib 300 mg twice daily and vistusertib 100 mg twice daily in a 2-days-on/5-days-off schedule was selected.

Of 64 evaluable patients, the overall response rate was 19%, with a clinical benefit rate of 47%. The median duration of benefit was 14 months. The response rate was highest in the 22 endometrial cancer patients, at 27%, compared with 20% in the ovarian cancer patients, and 6% in the triple-negative breast cancer patients.

“We were able to successfully combine olaparib with the mTORC1/2 inhibitor vistusertib,” Westin concluded. “We did see durable anticancer activity across all cancer types, with really particularly promising response seen in both histologies of endometrial cancer.”

Gini F. Fleming, MD, of the University of Chicago, was the discussant for the session. She agreed that the response rate, especially in endometrial cancer, is very promising. “The combination still appears moderately toxic, and one question is whether a more traditional mTOR inhibitor would work as well,” she said. “However, further development of this and similar combinations are clearly warranted.”

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