Breakthrough Therapy Designation Granted to VS-6766 Plus Defactinib for Pretreated Low-Grade Serous Ovarian Cancer

A RAF/MEK plus FAK inhibitor combination will be given an expedited review by the FDA as therapy for patients with recurrent low-grade serous ovarian cancer.

By Audrey Sternberg

The combination of the RAF/MEK inhibitor, VS-6766, plus the FAK inhibitor, defactinib, was granted breakthrough therapy designation for the treatment of patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after at least 1 prior therapy line, according to the company responsible for both agents, Verastem, Inc.

The ongoing phase 1/2 FRAME trial (NCT03875820) is looking at the combination as therapy for patients with advanced solid tumors across different cohorts, including patients with KRAS-mutant non–small cell lung cancer, RAS-mutant solid tumors, and colorectal cancer. Recent data from a cohort of patients with LGSOC (n = 24) revealed an overall response rate (ORR) of 52% after 11 of 22 response-evaluable patients demonstrated at least a partial response to therapy.

By KRAS status, patients whose tumors were positive for KRAS mutations (n = 10) had an ORR of 70% versus those with wild-type KRAS (n = 9) at 44%. Two patients without a known KRAS status had an ORR of 0%.

The most common adverse effects of therapy were rash, creatine kinase elevation, nausea, hyperbilirubinemia, and diarrhea. These adverse effects were mostly grade 1/2 in severity and reversible.

Based on some patients remaining on therapy for 1 year or more, the company believes the combination has a strong potential for long duration of clinical benefit.

Given the frequency of RAS mutations and the resulting aggressive nature of disease, VS-6766 offers a unique potential to inhibit oncogenic activity by its vertical, dual inhibition of the RAS/MEK pathway.

“Breakthrough Therapy designation will facilitate our efforts to verify the robust and durable response and compelling safety profile of VS-6766 with defactinib that we have seen in patients with LGSOC and potentially bring a new therapy to these patients as quickly as possible,” Brian Stuglik, CEO of Verastem Oncology, said in a press release. “The majority of LGSOC is RAS pathway–driven, and we are committed to exploring the potential for VS-6766 as a backbone therapy across RAS pathway–driven solid tumors.”

The phase 2 RAMP 201 (ENGOTov60/GOG3052) registrational trial (NCT04625270) is currently evaluating VS-6766 with or without defactinib in patients with recurrent LGSOC in an adaptive 2-part multicenter, parallel cohort, randomized, open-label fashion. The trial aims to recruit 100 patients to determine the optimal regimen (monotherapy or combination) and efficacy, which both serves as primary end points of Part A and Part B, respectively. Secondary end points include ORR, duration of response, disease control rates, progression-free survival, and overall survival.

To be included, patients must have histologically proven LGSOC, known KRAS status, progression or recurrence following at least 1 systemic therapy for metastatic disease, measurable disease by RECIST 1.1, and ECOG performance status of 1 or less, adequate organ function, and recovery from toxicities of prior therapies.

This designation by the FDA will allow for expedited development and review of the drugs for this indication and is based on prior clinical evidence that indicates the therapy could lead to substantial disease improvement over other available regimens.

“Patients with low-grade serous ovarian cancer urgently need better solutions due to low response rates and tolerability issues associated with current therapies,” Melissa Aucoin, CEO of the National Ovarian Cancer Coalition, said in a press release. “A Breakthrough Therapy designation in this disease is a significant step forward for the women who often, at a relatively young age, start a lengthy battle with this highly recurrent and impactful disease.”

This article was published by Cancer Network.

Atezolizumab Regimen Fails to Extend PFS in Newly Diagnosed Ovarian Cancer

By Jennifer Southall

The addition of atezolizumab to chemotherapy and bevacizumab failed to significantly prolong PFS for women with newly diagnosed stage III or stage IV epithelial ovarian cancer, according to a phase 3 study in Journal of Clinical Oncology.

“IMagyn050 is the first randomized trial to provide efficacy and safety results for the addition of an immune checkpoint inhibitor to standard-of-care bevacizumab [Avastin, Genentech] in epithelial ovarian, fallopian tube or primary peritoneal cancer,” Kathleen N. Moore, MD, director of the Oklahoma TSET phase 1 program and associate professor in the section of gynecologic oncology at The University of Oklahoma College of Medicine, and colleagues wrote. “In the PCD4989g study, responses to single-agent atezolizumab [Tecentriq, Genentech] were limited to patients whose tumors showed high PD-L1 expression, whereas responses to atezolizumab plus bevacizumab were seen irrespective of PD-L1 expression in the small ovarian cancer cohort of the GP28328 study. This provided the rationale to evaluate outcomes in both PD-L1-positive and all-comer populations in IMagyn050.”

The double-blind, randomized, two-arm IMagyn050 study enrolled 1,301 women across North and South America, Europe, Asia and Australia with newly diagnosed epithelial ovarian cancer between March 8, 2017, and March 26, 2019. All women had macroscopic residual disease after undergoing cytoreductive surgery or planned to receive treatment with neoadjuvant chemotherapy and interval surgery.

The researchers assigned women 1:1 to either the anti-PD-L1 antibody atezolizumab, dosed at 1,200 mg, or placebo on day 1 of cycles one to 22, plus 175 mg/m² paclitaxel and carboplatin area under the curve 6 on day 1 of cycles one to six and 15 mg/kg bevacizumab on day 1 of cycles two to 22. They omitted perioperative bevacizumab for women in the neoadjuvant cohort.

More than half (60%; n = 784) of the study population had PD-L1-positive tumors.

Investigator-assessed PFS and OS in the intention-to-treat population and among women with PD-L1-positive tumors served as co-primary endpoints. Objective response rate, duration of response, patient-reported outcomes, and occurrence and severity of adverse events serve as secondary endpoints.

Median duration of follow-up in the intention-to-treat population was 19.9 months in the atezolizumab group and 19.8 months in placebo group. Among women with PD-L1-positive tumors, median duration of follow-up was 19.6 months in the atezolizumab group and 19.4 months in the placebo group.

The primary PFS analysis occurred after 664 PFS events in the intention-to-treat population and 366 PFS events in the PD-L1-positive population.

Results showed longer median PFS with atezolizumab vs. placebo in the intention-to-treat population (19.5 months vs. 18.4 months; HR = 0.92; 95% CI, 0.79-1.07), and the PD-L1-positive population (20.8 months vs. 18.5 months; HR = 0.8; 95% CI, 0.65-0.99). However, neither of these differences met the study’s criteria for statistical significance.

OS results were immature at the time of data cutoff but showed no significant benefit with atezolizumab. Researchers observed 219 deaths in the intention-to-treat population and 116 deaths in the PD-L1-positive population.

Common grade 3 or grade 4 adverse events included neutropenia (21% for both groups), hypertension (18% with atezolizumab vs. 20% with placebo) and anemia (12% for both).

“IMagyn050 showed no significant PFS improvement in patients with PD-L1-positive tumors defined as [PD-L1 expression of 1% or greater]. However, in an exploratory analysis using threshold of [PD-L1 expression of 5% or greater] … the PFS HR was 0.64 (95% CI, 0.43-0.96),” the researchers wrote. “Relevant current evidence does not support adding PD-L1-targeted immune checkpoint inhibitors to the standard-of-care regimen for patients with newly diagnosed ovarian cancer.”

The results of IMagyn050, coupled with those of the JAVELIN-100 and JAVELIN-200 trials, indicate that immunotherapy findings in other tumor types, such as non-small cell lung cancer, bladder cancer or melanoma, cannot be extrapolated to ovarian cancer, according to an accompanying editorial by Panagiotis A. Konstantinopoulos, MD, PhD, researcher at Dana-Farber Cancer Institute, and Stephen A. Cannistra, MD, researcher at Beth Israel Deaconess Medical Center.

“Although several recent studies of immune checkpoint blockade in ovarian cancer have not met their primary endpoints, we should remain optimistic about the potential of immunotherapy in this disease,” Konstantinopoulos and Cannistra wrote. “Emerging technologies such as single-cell RNA sequencing and multiplexed single-cell imaging using cyclic immunofluorescence now enable the study of tumors and their microenvironment at the single-cell level, thus providing unique mechanistic insights into response and resistance to immunotherapy.”

This article was published by Healio.

‘Devastated and Sad’ After 36 Years of Research — Early Detection of Ovarian Cancer Doesn’t Save Lives

By Professor Ian Jacobs

I was motivated to improve the outcome for women with ovarian cancer by my experience as a junior doctor in London in 1985. But 36 years on, the results aren’t what we’d hoped.

My colleages’ and my efforts to develop a screening test for the early detection of ovarian cancer capable of saving lives arrived at a sad moment last week. The final trial results of the research I’ve focused on for 36 years, published in The Lancet, found early ovarian cancer detection doesn’t save lives.

The advances we have seen in science and technology over the past three decades have been nothing short of phenomenal. Each smartphone has more computational power than NASA had at its disposal during the moon landings. In medicine, researchers have sequenced the human genome, created life-saving treatment for HIV and rapidly developed vaccines for COVID-19.

There have been significant improvements in ovarian cancer treatment involving surgery and chemotherapy, but the sad and frustrating truth is of the four women diagnosed with ovarian cancer in Australia each day, three will eventually die from the disease.

The diagnosis of ovarian cancer is dependent on women reporting symptoms to their doctor. However, few develop symptoms until they have advanced stage cancer, by which time the outlook is poor. Of all women’s cancers, ovarian cancer has the lowest survival rate, with just 46% of patients in Australia surviving five years. For breast cancer, it’s now 91%.

Back in the 80s

I was motivated to improve the outcome for women with ovarian cancer by my experience as a junior doctor in London in 1985. I was training with a brilliant surgeon who undertook operations for many women with ovarian cancer. In spite of the exhaustive surgery and the chemotherapy that followed, we saw far too many women suffer and die from ovarian cancer.

That experience inspired me to initiate a program of research designed to find a screening test to detect this cancer early. Women with the earliest stage of ovarian cancer had survival rates of 70%, but less than 20% of women with ovarian cancer were diagnosed that early.

My hypothesis was that if we could detect more cancers at an early stage it would save lives.

Based on evidence from other cancers, there was reason to be hopeful and two potential tests were available – a blood test called CA 125 and the use of ultrasound scanning which was then widely used in obstetrics.

Over the next 15 years, working with colleagues in the United Kingdom and United States, I developed and refined the screening tests and had great hope for what we called “multimodal screening”. This involved a “risk of ovarian cancer algorithm” for interpreting the change in blood levels of CA 125 over time to identify women who had a rising pattern, indicating an elevated risk of ovarian cancer. Women with an elevated risk could then have a secondary test involving ultrasound scanning.

During those 15 years, we published convincing evidence in studies involving over 50,000 women that this approach to screening was safe, acceptable to women, could detect over 85% of the cancers early and would probably be cost effective if sufficient lives were saved.

Promising early results

Before advocating screening of the general population, a massive trial would be needed to determine whether the screening would actually save lives.

The trial needed to involve screening and follow up of approximately 200,000 women for around 20 years. This would eventually include 2,000 women with ovarian cancer – enough to determine whether or not screening saved lives.

Work got underway in the United Kingdom in 2000 and optimism grew as initial results confirmed the ability of multimodal screening to detect cancer early in over 85% of cases.

By 2015, the preliminary mortality data were available and were tantalising. The curves hinted at a 20% or more reduction in deaths from ovarian cancer, but the findings did not quite reach statistical significance. So another five years of painstaking follow up was needed.

Disappointing final results

The final results of the UK Collaborative Trial of Ovarian Cancer Screening showed the multimodal screening approach could detect cancers early and increase the number of early-stage ovarian cancers by almost 50%.

But to our surprise and despair, that did not reduce the number of deaths from ovarian cancer. All it seemed to do was to bring forward the time of diagnosis of the cancers in these women, without improving their survival.

This is deeply disappointing. Disappointing of course for those who like myself have dedicated much of their professional lives to this effort, but much more importantly for the women across the world who we had hoped would have access to an effective screening test able to save lives.

The hope had been to deploy ovarian cancer screening for women in the general population alongside breast and cervical cancer screening, but that will not happen – for a while at least.

Why didn’t early detection save lives?

To answer that, we need to further analyse samples and data from the trial. Our suspicion is that the women whose cancers were detected early by screening had more aggressive cancers than those (the 10%) whose cancers were detected early without screening, on the basis of symptoms.

So even with early detection, their cancers progressed relentlessly despite them receiving the best available surgery and chemotherapy.

If that is the case, we are likely to require screening tests which can detect ovarian cancer even earlier than our algorithm, which we estimate picks up ovarian cancer 18 to 24 months early. Saving lives may require a test capable of picking up the cancers five or more years early.

Fortunately, there are exciting avenues of research involving advances in protein and DNA technologies which researchers in Australia and around the world are exploring. So there is hope.

But realistically, given the five-plus years needed to develop better screening tests and the ten to 15-plus years needed to have enough cases to conduct another large randomised trial, the solution is likely to be more than 20 years away.

Still, we’ve learnt a lot

This massive commitment of expertise, time, energy and funding has most definitely not been wasted. Much has been achieved along the way in this 36-year journey in developing ways to assess risk, diagnose cancer and prevent ovarian cancer which are now used in clinical practice.

New generations of researchers have been trained. The data and the blood bank collected is available to all researchers seeking new and better screening tests and is a unique resource. And the ability to detect ovarian cancer early may be invaluable in assessing new treatments.

I feel privileged to have led this effort and will always be grateful to the collaborators, researchers, health professionals, funding agencies and above all the 200,000 women who took part in the trial.

I feel a deep sadness that lives will not yet be saved by ovarian cancer screening, but I’m confident the next generation of researchers will build on our work and find approaches to screening and treatment of ovarian cancer which dramatically reduce the loss and suffering caused by this insidious disease.

This article was published by UNSW.

Disappointment: Screening for Ovarian Cancer Does Not Cut Deaths

By Pam Harrison

Results from a huge British trial that involved more than 200,000 women who were followed for a median of 16 years have turned out negative. Investigators found that annual screening for ovarian cancer with either multimodal screening (MMS) or transvaginal ultrasound screening (USS) did not reduce the death toll from this aggressive cancer, even though MMS picked early-stage disease.

“We are disappointed, as this is not the outcome we and everyone involved in the trial had hoped and worked for over so many years,” commented Usha Menon, MD, MRC Clinical Trials (MCT) Unit, Institute of Clinical Trials and Methodology, London, the United Kingdom, and lead investigator of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

“UKCTOCS is the first trial to show that screening can definitely detect ovarian cancer earlier. However, this very large, rigorous trial shows clearly that screening using either of the approaches we tested did not save lives,” she said in a statement.

“We therefore cannot recommend ovarian cancer screening for the general population using these methods,” she added.

Echoing these sentiments, coinvestigator Ian Jacobs, MD, the University of New South Wales, Sydney, Australia, who led the UKCTOCS from 2001 to 2014, acknowledged that although MMS did succeed in detecting ovarian cancer at an earlier stage of disease, “sadly, that did not save lives.

“This is deeply disappointing and frustrating given the hope of all involved that we would save the lives of thousands of women who are affected by ovarian cancer each year,” he added in a statement.

The study was published online May 12 in The Lancet.

At a UK press briefing, Menon emphasized that ovarian cancer is an aggressive disease, with a 10-year survival of 35%. It is difficult to diagnose, and more than half the cases are diagnosed when the disease is in late stages.

Because screening cannot be recommended at this time, she urged that women and doctors be alert to, and not ignore, symptoms that may suggest ovarian cancer.

NHS Trust Recruitment

The trial involved a total of 202,562 evaluable postmenopausal women aged 50 to 74 years who were recruited through the National Health Service (NHS) Trust in England, Wales, and Northern Ireland.

Women were randomly assigned to receive no screening, annual screening with an ultrasound scan, or annual MMS that involved a CA125 blood test followed by an ultrasound scan. The primary outcome was death due to ovarian or tubal cancer.

At a median follow-up of 16.3 years, the incidence of and mortality from ovarian and tubal cancer were identical in the three groups, at 1.0% for the incidence of ovarian and tubal cancer and a 0.6% risk for death.

The final outcomes were perhaps even more disappointing because there was evidence from the trial that MMS did pick up earlier-stage disease, for which survival rates are better.

At 9.5 years after the end of screening, there was a 47.2% higher incidence of stage I disease in the MMS group compared to the no-screening group as well as a 24.5% lower incidence of stage IV disease.

Overall, there was a 39.2% higher incidence of stage I or II cancer and a 10.2% lower incidence of stage III or IV cancer in the MMS group compared with the no-screening group. There was little change in the incidence of stage III disease.

There was also no difference in the stage of cancers detected in the USS group compared to the no-screening group.

Speculating as to why the finding of earlier-stage disease did not translate into a reduction in deaths overall in this trial, Menon emphasized that this is an aggressive disease and that perhaps the treatments that were available at the time (10 years ago) were not able to stop its progression.

Since the end of this trial 10 years ago, there have been significant improvements in the treatment of advanced ovarian cancer, noted Mahesh Parmar, PhD, MRC Clinical Trials Unit at the Institute of Clinical Trials and Methodology, United Kingdom, and senior author of the article.

“Our trial showed that screening was not effective in women who do not have any symptoms of ovarian cancer,” Parmar said.

However, he added that in “women who do have symptoms, early diagnosis, combined with this better treatment, can still make a difference to quality of life and, potentially, improve outcomes,” Parmar said in a statement.

The investigators emphasized that this screening trial involved healthy women with no symptoms and no family history of ovarian cancer. They noted that among women who are at high-risk for ovarian cancer, MMS performed every 3 to 4 months, together with risk-reducing surgery, has resulted in a significant reduction in the number of women diagnosed with advanced disease.

Not the First Trial to Disappoint

UKCTOCS is not the first large screening trial to show that annual screening for ovarian cancer does not reduce mortality over a long-term follow-up period, noted Lauren Hurwitz, PhD, National Cancer Institute, Rockville, Maryland, and colleagues in an accompanying editorial.

The first randomized controlled trial of ovarian cancer screening that was powered to assess cancer-specific mortality was the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. In that trial, more than 68,000 women were randomly assigned either to undergo annual CA125 testing combined with transvaginal ultrasound or to receive usual care.

“After a median follow-up of 12.4 years, screening was not found to reduce ovarian cancer mortality,” Hurwitz and colleagues observe. Furthermore, almost 10% of women in the intervention group received a false positive diagnosis. A sizeable proportion of those patients subsequently underwent surgery.

The editorialists note that in the current UK trial, the incidence of stage IV ovarian cancer may may have been lower among women in the MMS group compared to women in the no-screening group.

Somewhat paradoxically, however, “this difference was accompanied by a higher case fatality rate for stage I cancers (14.8% in the MMS group vs 9.4% in the no screening group),” the editorialists observe.

One limitation of the study is that it the investigators did not analyze mortality on the basis of ovarian cancer histotypes, such as high-grade serous ovarian cancer, the most common and lethal histotype, the editorialists observe.

The editorialists agree with the study authors that alternative approaches to screening that target higher-risk women and not women in the general population might prove more effective at reducing ovarian cancer deaths and may lessen the possibility of harm from false positive screens.

“Screening for ovarian cancer remains elusive but is not a lost cause; there is simply more work to be done,” Hurwitz and colleagues conclude.

Investigator Jacobs remains hopeful that a more effective screening test will eventually be found, although by the time any new screening test is evaluated in a large clinical trial, “we have to reluctantly accept that population screening for ovarian cancer is more than a decade way.”

This article was published by Medscape Oncology.

ARIEL2 Analysis Sheds Light on Biomarkers of Response to Rucaparib in Ovarian Cancer

RAD51C and RAD51D mutations and high-level BRCA1 promotor methylation are predictive of response to rucaparib in patients with recurrent ovarian cancer, while genomic scars linked with homologous recombination deficiency is predictive of response only in those with platinum-sensitive disease.

By Kristi Rosa

RAD51C and RAD51D mutations and high-level BRCA1 promotor methylation are predictive of response to rucaparib (Rubraca) in patients with recurrent ovarian cancer, while genomic scars linked with homologous recombination deficiency (HRD) is predictive of response only in those with platinum-sensitive disease, according to data from a post-hoc exploratory biomarker analysis of the phase 2 ARIEL2 trial (NCT01891344).

“Given its general tolerability and efficacy…we propose that the administration of rucaparib, as active treatment, should be considered in earlier lines of therapy, before the emergence of platinum resistance,” the study authors wrote.

Platinum sensitivity was a strong predictor of response to rucaparib in a population of patients who were naïve to PARP inhibitors, particularly subgroups who had disease that was BRCA-mutated or BRCA wild-type with high loss of heterozygosity (LOH). HRD mechanisms like BRCA mutation, RAD51C/D alterations  and high BRCA1 promoter methylation were shown to result in sensitivity to both platinum treatment and rucaparib.

“Alterations in RAD51C and RAD51D correlated with meaningful clinical activity of rucaparib similar to that of BRCA-mutated high-grade ovarian cancer [HGOC],” the study authors added. “Therefore, we propose utilizing panels incorporating RAD51C/D when considering targeted therapies. Importantly, we previously showed that reversion mutations also occur in RAD51C/D as a resistance mechanism, supporting their essential role in generating synthetic lethality with PARP inhibitors.”

Additionally, investigators demonstrated that high-level methylation of the BRCA1 promoter proved to be a strong biomarker of sensitivity to the PARP inhibitor. Those who had this modification or tumors that harbored RAD51C/D had a progression-free survival (PFS) that proved to be comparable to those with BRCA-mutated HGOC who received rucaparib.

It has been known that genetic, epigenetic, and genomic biomarkers can potentially be indicative of HRD; these markers can help to select which patients are at a higher likelihood to respond to PARP inhibitors.

Germline and somatic BRCA1 and BRCA2 mutations have served as well-defined biomarkers of response for these agents spanning several cancer types, such as breast, ovarian, pancreatic, and prostate. Although genes in the homologous recombination repair (HRR) pathway like PALB2, RAD51C, and RAD51D have previously been linked with better response to rucaparib and other PARP inhibitors, the extent to which these genes contribute to drug sensitivity has been largely unclear.

Moreover, patients with BRCA-wildtype HGOC and high LOH have been shown to benefit more from rucaparib than those with low LOH. Although high LOH has been linked with better responses to platinum treatment and other PARP agents, genomic scars in HRD cancer cells make this an imperfect marker for sensitivity to this class of agents.

In the international, open-label, phase 2 ARIEL2 trial was done in 2 parts. In the first part, investigators examined rucaparib in patients with platinum-sensitive HGOC who had received 1 or more chemotherapy regimens.² A total of 204 patients were enrolled to part 1 of the trial and they received a twice-daily dose of 600 mg for a continuous 28-day treatment cycle.

Of these patients, 192 were stratified into 3 groups based on their HRD status: 20.8% had BRCA-mutant disease, 42.8% had LOH-high disease, and 36.4% had LOH-low disease. The median PFS in these subgroups with rucaparib was 12.8 months, 5.7 months, and 5.2 months. The PFS was determined to be significantly longer in those who fell in the BRCA-mutant subset (HR, 0.27; 95% CI, 0.16-0.44; P <.0001) and in the LOH-high subset (HR, 0.62; 95% CI, 0.42-0.90; P = .011) vs the LOH-low subset.

Part 2 of the trial enrolled patients with disease that was sensitive, resistant, or refractory to platinum therapy, who had received 3 to 4 prior chemotherapies. A total of 287 patients were enrolled to part 2 of the trial and they were again divided into 1 of 3 HRD subgroups: those with BRCA-mutated disease (n = 138), those with BRCA wild-type LOH-high disease (n = 156), and those with BRCA wild-type LOH-low disease (n = 168).

Results indicated that the objective response rate (ORR) with rucaparib, which was the primary end point of the trial, was 31.0% (95% CI, 21.3%-42.0%), 6.8% (95% CI, 2.3%-15.3%), and 5.6% (95% CI, 2.1%-11.8%) in the 3 subgroups, respectively. Notably, durable responses were observed across the HRD subgroups analyzed.

In the post-hoc biomarker analysis, investigators utilized the dataset of archival tissue samples and screening biopsies collected from patients on both parts of the trial to examine the link between molecular characteristics and outcomes in participants, as well as to determine mechanisms of sensitivity and resistance to rucaparib.

Additional results demonstrated that both ORR and PFS different significantly among the subgroups, with those in the BRCA-mutated group experiencing better outcomes than the other 2 groups. Here, the median PFS was 7.8 months, and the ORR with rucaparib was 45.7% (95% CI, 37.2%-54.3%).

In the BRCA wild-type/LOH-high disease group and the BRCA wild-type/LOH-low disease group the median PFS was 4.3 months and 4.0 months, respectively; in these 2 groups, rucaparib elicited an ORR of 16.7% (95% CI, 11.2%-23.5%) and 7.7% (95% CI, 4.2%-12.9%), respectively.

Moreover, among patients in the BRCA-mutated group who were noted to be sensitive to their most recent line of platinum therapy received, the median PFS was 9.4 months, and the ORR was 64.9%, while patients who were refractory to their last platinum treatment had a significantly worse PFS and OS, at a median of 7.2 months (HR, 0.44; 95% CI, 0.30-0.63; P = <.0001) and an ORR of 23.4% (95% CI, 13.8%-35.7%; P <.0001).

Additionally, among those in the BRCA wild-type LOH-high disease subgroup who were platinum sensitive yielded better outcomes than those in the subgroup who were either platinum resistant or refractory in terms of PFS (HR, 0.46; 95% CI, 0.33-0.65) and ORR (95% CI, 0.9%-11.5%) and those in the BRCA wild-type LOH-low subgroups, irrespective of platinum status.

As such, investigators noted that genomic scarring is a good predictor of sensitivity to the PARP inhibitor prior to cross resistance, but LOH-low disease may lack HRD mechanisms necessary to sensitize these tumors to PARP inhibitors. As such, even those in this subgroup without previous exposure to platinum treatment still do not derive significant efficacy from rucaparib.

“Rucaparib efficacy in BRCA-mutated and BRCA wild-type/LOH-high but not BRCA wild-type/LOH-low HGOC was better for patients with platinum-sensitive disease who had received 1 or 2 prior therapies than those who had 3 or 4 prior chemotherapy regimens with predominantly platinum-resistant/refractory disease,” the authors noted. “These observations suggest that platinum sensitivity and fewer lines of prior platinum treatments are both linked to better outcomes on rucaparib in HRD-associated HGOC.”

Investigators also examined the link between BRCA mutational status and response to PARP inhibitors by taking a closer look at HRR gene mutational status and response to rucaparib. Twenty-eight percent of patients (n = 138/491) had deleterious or germline somatic BRCA mutations and ORRs in these agents proved to be similar to what had previous analyses in these subgroups of patients, at 48.2% and 45.5%, respectively. When examining HRR genes beyond BRCA, investigators did not find differences in median PFS and ORR in those who had BRCA wild-type disease associated with a HRR gene mutation vs those without a HRR gene mutation.

In light of prior evidence indicating that PALB2, RAD51C, and RAD51D mutations have been associated with sensitivity to PARP inhibitors, investigators decided to take a closer look. Seven patients had a deleterious RAD51C/D mutation, while no patients harbored a PALB2 mutation.

High responses with rucaparib were observed in the RAD51C/D-mutated subset, at 71.4% (95% CI, 29.0%-96.3%). Data from a multivariate analysis also determined that this mutation was a significant predictor of ORR with rucaparib. The median PFS in this subgroup was comparable to the benefit seen in the BRCA-mutant subgroup, at 11.0 months and 7.8 months, respectively (HR, 1.52; 95% CI, 0.67-3.44; P = .32). Notably, because 4 of the 7 patients whose tumors harbored this mutation had previously received 3 or more lines of chemotherapy, investigators concluded that rucaparib has the potential to be highly effective in this subgroup, even in those who are receiving it in later lines.

Investigators did not identify any difference in PFS in patients with BRCA wild-type disease who were examined for HRD-associated epigenetic events leading to rucaparib sensitivity based on either archival or screening methylation status, which indicates that the presence of methylation alone at the 2 promoters is not a biomarker for outcomes with the PARP inhibitor.

Although archival BRCA1 methylation levels were not linked with differential PFS with rucaparib, PFS outcomes were more favorable for patients with BRCA wild-type HGOC that had high BRCA1 methylation right before rucaparib initiation vs those with disease that was unmethylated or had low levels of methylation.

“Overall, our analysis highlights significant overlap between molecular mechanisms resulting in platinum and PARP inhibitor sensitivity and the extent of cross resistance that exists between these 2 drug classes,” the study authors concluded. “In addition to BRCA mutations, RAD51C/D mutations and high-level BRCA1 promoter methylation are strong predictors of sensitivity to a PARP inhibitor.”

This article was published by OncLive.

Smart Cell Therapies for Solid Cancers Ready to Move Toward Clinical Trials

By Lindzi Wessel

Immunotherapies that fight cancer have been a life-saving advancement for many patients, but the approach only works on a few types of malignancies, leaving few treatment options for most cancer patients with solid tumors. Now, in two related papers published April 28, 2021, in Science Translational Medicine, researchers at UCSF have demonstrated how to engineer smart immune cells that are effective against solid tumors, opening the door to treating a variety of cancers that have long been untouchable with immunotherapies.

By “programming” basic computational abilities into immune cells that are designed to attack cancer, the researchers have overcome a number of major hurdles that have kept these strategies out of the clinic up to now. The two new papers show that the resulting “smart” therapies are more precise, flexible and thorough than previous approaches, and the researchers say that their approach may be ready for clinical trials in the near future.

In one paper, research teams led by Wendell Lim, PhD, chair and Byers Distinguished Professor of cellular and molecular pharmacology, and Hideho Okada, MD, PhD, the Kathleen M. Plant Distinguished Professor of neurological surgery, tested the system in glioblastoma, the most aggressive form of brain cancer that affects adults and children, and which physicians have yet to successfully treat with immunotherapies due to the complexity of the tumors. The team showed the new system, which uses a two-step process to hunt down cancer cells, could completely clear human patient-derived tumors from the brains of mice without the dangerous side effects or high risk of recurrence currently associated with immunotherapy treatment in solid tumors.

In the second paper, Kole Roybal, PhD, assistant professor of microbiology and immunology, and Bin Liu, PhD, professor of anesthesia at UCSF, led a study showing how components of this system can be switched out like the heads of an interchangeable screwdriver to target other difficult-to-treat cancers in other parts of the body. The team also identified a particularly important set of “screwdriver heads” that could make powerful tools against cancers of the ovaries, lungs and other organs, which together kill tens of thousands every year.

In addition, both papers address the issue of so-called “T-cell exhaustion,” a long-standing challenge in which traditional CAR-T cells — the re-programmed intruder-hunting immune cells behind some of the most promising cancer immunotherapies — tire out when engaged in prolonged battles against the cancer. The new smart cells stay consistently strong through the entire fight, conserving their energy by switching to a standby mode when not directly engaged with the cancer.

“These findings address all critical challenges that have been in the way of developing immunotherapies for patients who suffer from these cancers,” said Okada, who also serves as director of the Brain Tumor Immunotherapy Center at UCSF. “This science is ready to move towards clinical trials.”https://www.youtube.com/embed/f4pwNIhylDo?autoplay=0&start=0&rel=0

Expanding Immunotherapies to Deadly Brain Cancers

Glioblastomas are a particularly tragic case in which patients so far haven’t been able to benefit from CAR-T cells. Every year, over 20,000 adults in the United States are diagnosed with glioblastoma or other types of malignant brain cancer, and with current treatments, the prognosis is grim.

“It’s like a death sentence,” says Okada, noting that brain tumors are also the leading cause of cancer-related mortality and morbidity in children. “The outcome for malignant brain tumors in kids remains dismal.”

Okada, who is an expert in brain cancers, partnered with Lim, who was developing novel cell engineering technologies, in the hopes of changing this.

Previous work had identified a molecule that is frequently found on glioblastoma cells, giving researchers hope that CAR-T cells could target this molecule and do away with the deadly cancer. Though this strategy was effective in killing some glioblastoma cells, not all glioblastoma cells display this molecule. This allowed some cancer cells to evade the CAR-T therapy and eventually resulted in the cancer’s return.

Targeting other molecules came with the opposite, but equally perilous problem. Though some molecules are found on glioblastoma cells, they’re also found on healthy, non-brain tissues such as the liver, kidney, esophagus and genital organs. Targeting cells that display these molecules with CAR-T could damage healthy tissue and put patients in danger. This catch-22 leaves clinicians without an ideal molecular target, a pervasive problem that has thwarted CAR-T’s use in most solid tumors.

The scientists devised a solution to this problem by employing a system called synNotch, a customizable molecular detector that Lim’s lab has been perfecting for several years. The synNotch system lets scientists program CAR-T cells to detect specific molecules found on the surface of cancer cells, ensuring that CAR-Ts attack only when they encounter the molecules they’re programmed to target.

To kill glioblastomas, the team took a novel, two-step approach. The first step uses synNotch to give CAR-Ts the ability to carefully judge if they are in a tumor versus other parts of the body, while a second set of synNotch sensors ensures a strong and comprehensive tumor killing response. Once the CAR-T cells confirm that they are in the tumor, the second set of sensors are activated, allowing the CAR-Ts to detect and kill glioblastoma cells based on multiple brain-tumor molecules. This two-step process leads to more complete tumor killing and prevents tumor cells from accumulating simple mutations that would allow them to evade CAR-Ts.

Experiments described in the paper show that this strategy is effective. In mice with human patient-derived glioblastomas, synNotch CAR-Ts wiped out tumors that weren’t cleared by normal T-cells or traditional CAR-Ts, with no signs of dangerous side effects.

“We’ve been saying for a while that we should think of these cells like computers — smart enough to integrate multiple data points and make complex choices,” said Lim, who also directs the Cell Design Institute at UCSF. “Now we’re seeing this working in a real-world model of a very deadly cancer for both adults and children.”

SynNotch Is a Flexible, Powerful System for Building Smarter Immunotherapies

The second paper further demonstrated the efficacy of this approach by identifying additional molecular targets for the synNotch system. The researchers searched public cancer databases for molecules found in tumor cells that could be useful in CAR-T therapies against now-intractable diseases. They found a molecule called ALPPL2 that’s common to many forms of cancer, including the asbestos-driven mesothelioma as well as ovarian, pancreatic and testicular malignancies. Importantly, the molecule is rarely found in healthy tissue.

In tests of synNotch circuits that were engineered to detect ALPPL2, CAR-T cells were able to recognize and kill mesothelioma and ovarian cancer cells with precision. “We can build cells that recognize ALPPL2 and then upregulate other sensors against more general tumor antigens,” said Roybal, also a founding member of the Cell Design Institute. “This is a completely viable, clinical grade antigen we can use to build cell therapies for use in people.”

A striking finding from both studies is that synNotch CAR-Ts maintained stable levels of activity throughout the cancer killing process, eliminating the challenge of T-cell exhaustion, which hinders traditional CAR-T therapies. Researchers believe exhaustion occurs because traditional CAR-Ts are designed to continuously express a kill switch, meaning they are always on and eventually deplete their resources, leading to a “cell that isn’t doing much of anything,” Roybal said.

“Amazingly this wasn’t the case in our synNotch systems,” he said. The researchers found that synNotch CAR-T cells remain in standby mode until they identify the cancer, conserving their energy. “These papers show that there are a variety of reasons these synNotch T-cells could be better than the current state-of-the-art CAR-T cell technology.”

This article was published by UCSF.

Carboplatin Alone Not Adequate for Ovarian Cancer in Frail Seniors

Worse survival than with combination carboplatin-paclitaxel regimens for vulnerable older patients with ovarian cancer.

For vulnerable older patients with ovarian cancer, single-agent carboplatin is less active, with worse survival, than combination carboplatin-paclitaxel regimens, according to a study published online April 22 in JAMA Oncology.

Claire Falandry, M.D., from the Université Lyon in France, and colleagues randomly assigned 120 women aged 70 years and older with newly diagnosed stage III/IV ovarian cancer with a Geriatric Vulnerability Score of 3 or higher to receive one of the following regimens: six cycles of carboplatin plus paclitaxel every three weeks; single-agent carboplatin every three weeks; or weekly carboplatin plus paclitaxel on days 1, 8, and 15 every four weeks.

Because single-agent carboplatin was associated with significantly worse survival, an independent data monitoring committee’s recommendation led to the termination of the trial during its third meeting. The researchers found that in the every-three-weeks combination, single-agent carboplatin, and weekly combination groups, 65, 48, and 60 percent of patients, respectively, completed six cycles. Treatment-related adverse events occurred less often with the standard every-three-weeks combination versus the single-agent carboplatin or weekly combination therapy groups (43 versus 58 and 58 percent, respectively). There were four treatment-related deaths; two in each combination group.

“These results suggest that even vulnerable older women with newly diagnosed ovarian cancer should be offered carboplatin-paclitaxel combination therapy,” the authors write.

This article was published by HealthDay.

Tislelizumab Plus Sitravatinib Demonstrates Antitumor Activity, Maintains Safety in Platinum-Resistant Epithelial Ovarian Cancer

For patients with recurrent platinum-resistant epithelial ovarian cancer who were naïve to PD-1/PD-L1 inhibition, the combination treatment of tislelizumab plus sitravatinib showed early antitumor activity while maintaining a manageable safety profile.

By Kristi Rosa

For patients with recurrent platinum-resistant epithelial ovarian cancer who were naïve to PD-1/PD-L1 inhibition, the combination treatment of tislelizumab (BGB-A317) plus sitravatinib showed early antitumor activity while maintaining a manageable safety profile, according to data from a phase 1b trial (NCT03666143) presented during week 1 of the virtual AACR Annual Meeting 2021.

The doublet resulted in an objective response rate (ORR) of 26% (95% CI, 15.3%-40.3%), which comprised all partial responses (n = 14). Fifty-one percent of patients had stable disease (n = 27), and 17% of patients had progressive disease (n = 9). The median duration of response was 4.7 months (95% CI, 2.83–not evaluable), and the disease control rate was 77% (95% CI, 63.8%-87.7%).

Per investigator assessment, the median progression-free survival (PFS) was 4.1 months (95% CI, 4.0-22.8) at a median follow-up of 6.9 months, and the median overall survival (OS) was 12.9 months (95% CI, 6.2-17.0) at a median follow-up of 7.5 months.

“Tislelizumab in combination with sitravatinib was generally well tolerated and had a manageable safety/tolerability profile in patients with anti–PD-1/PD-L1 antibody–naïve recurrent platinum-resistant ovarian cancer,” lead study author Jeffrey C. Goh, MBBS, FRACP, of Icon Cancer Centre in Brisbane, Australia, said in a presentation on the data. “The results from this phase 1b study support tislelizumab in combination with sitravatinib as a potential treatment option for patients with platinum-resistant ovarian cancer and further investigation is warranted.”

The frontline standard of care of patients with ovarian cancer is platinum-based chemotherapy with or without bevacizumab (Avastin). However, disease recurrence is frequent and almost all patients will become refractory or develop resistance to platinum-based treatment, according to Goh.

Findings from several early phase 1/2 trials have demonstrated the limited effectiveness of PD-1/PD-L1 immune checkpoint inhibitors when used as single agents in heavily pretreated patients with ovarian cancer. The estimated ORRs in these patients ranged from 10% to 15%, Goh said.

Tislelizumab, a humanized, anti–PD-1 monoclonal antibody, is designed to minimize binding to Fcγ receptor on macrophages to abrogate antibody-dependent phagocytosis, which can overcome the attack of normal lymphocytes by immune cells.

Sitravatinib is an oral spectrum-selective TKI designed to target TAM and split family receptor kinases in VEGFR/KIT. Inhibition of these receptors serves to reduce the number of myeloid-derived suppressor cells and regulatory T cells and increase the ratio of M1/M2 polarized macrophages; this could overcome an immunosuppressive tumor microenvironment and enhance antitumor responses.

For the phase 1b trial, investigators hypothesized that the combination of a PD-1 inhibitor and a TKI with immunomodulatory and antitumor components could result in enhanced antitumor activity.

The multicohort trial has been undertaken in several solid tumor indications. Cohorts A and B of the trial are examining the doublet in patients with nonsquamous non–small cell lung cancer (NSCLC) that was relapsed/refractory or naïve to PD-1/PD-L1 inhibition, respectively. Cohort C will include patients with renal cell carcinoma (RCC) that is relapsed/refractory to PD-1/PD-L1 inhibition, while cohort D will comprise Chinese patients with metastatic/advanced RCC without previous systemic treatment.

Additionally, cohort F is examining the combination in patients with metastatic squamous NSCLC treatment with a PD-1/PD-L1 inhibitor. Cohort G will comprise patients with unresectable or metastatic melanoma who are relapsed/refractory to PD-1/PD-L1 agents; cohort H will include patients with nonsquamous NSCLC who have treatment-naïve, metastatic, PD-L1–positive disease; and cohort I will include those with squamous NSCLC who have treatment-naïve, metastatic, PD-L1–positive disease.

At the meeting, Goh shared data from the study regarding the use of the combination in cohort E, which was comprised of patients with recurrent platinum-resistant ovarian cancer who were naïve to PD-1/PD-L1 inhibitors.

To be eligible for enrollment, patients had to be at least 18 years of age, have histologically or cytologically confirmed advanced or metastatic unresectable solid tumors, an ECOG performance status of 0 or 1, and acceptable organ function. For cohort E, specifically, patients could not have platinum-refractory disease, nor could they have previously been exposed to a PD-1/PD-L1 agent.

Participants received intravenous tislelizumab at a dose of 200 mg every 3 weeks plus oral sitravatinib at a once-daily dose of 120 mg. Treatment was given until either disease progression, intolerable toxicity, death, withdrawn consent, or study termination.

The primary end point was safety and tolerability, while antitumor activity served as the secondary end point. Other exploratory objectives included pharmacokinetics and immunogenicity, potential pharmacodynamic biomarkers, and a retrospective analysis of PD-L1 expression.

As of the data cutoff of October 13, 2020, a total of 60 patients were enrolled to cohort E of the trial; of these patients, 13 remained on the doublet. The median duration of follow-up in this population was 6.0 months (range, 0.2-23.4).

The median age was 64 years (range, 26-80), the majority (80%) were White, and 57% had an ECOG performance status of 1. Seventy-three percent of patients had their primary tumor located in the ovary, while 12% had it in the fallopian tube, 8% in the peritoneum, and 7% in another area. The majority (95%) of patients had serous histology, while the rest had either mucinous (2%), endometrioid (2%), or clear cell (2%) disease.

Moreover, the median number of previous regimens was 4 (range, 1-11). The type of previous systemic therapy was metastatic in 83% of patients, adjuvant in 67%, neoadjuvant in 35%, locally advanced in 18%, and metastatic and locally advanced in 10%. Thirty-five percent of patients previously received bevacizumab.

Regarding PD-L1 expression at baseline, 33% of patients had tumor cell expression of 1% or greater, 48% had expression of less than 1%, and 19% did not have that information available. PD-L1 immune cell expression was 10% or greater in 43% of patients and less than 10% in 38%; 19% of patients did not have that information available.

Additional data indicated that responses were comparable across all subgroups analyzed. “However, patients who received more than 4 lines of therapy observed lower response rates compared with those who had received less than 3 prior lines of treatment,” Goh noted. “The same sample size in each group could be a confounding factor.”

In patients with tumor cell PD-L1 expression of 1% or greater (PD-L1 high), the median PFS was 4.1 months vs 4.2 months in those with tumor cell expression of less than 1% (PD-L1 low). The median OS in the PD-L1 high and low groups was 14.6 months and 11.8 months, respectively. “No significant difference was observed between the 2 groups, but the numbers are fairly small, and the follow-up is not mature,” Goh said.

Similar findings were observed in patients with immune cell PD-L1 expression of 1% or greater (PD-L1 high) and those with immune cell expression of less than 1% (PD-L1 low), with a median PFS of 4.1 months and 4.2 months, respectively. The median OS in the PD-L1–high group was 14.6 months vs 6.9 months in the PD-L1–low group.

“The association between PD-L1 expression and clinical efficacy are less clear due to small sample size in each subgroup,” Goh noted. “However, there was a trend toward a longer OS in patients with PD-L1 immune cell expression of more than 10%. Further investigation in future trials would be warranted to tease out this group.”

Additionally, the pharmacodynamic biomarker VEGF chemokine serum IP-10 increased following treatment. After treatment, increase of VEGF at cycle 2 day 1 and cycle 3 day 1 was observed, confirming the antiangiogenic properties of sitravatinib, Goh explained. The IP-10 level, which is involved in trafficking immune cells to inflammatory sites and mediating tumor regression, was also found to increase following treatment with the doublet.

“However, both biomarkers did not show any association with clinical response,” Goh said.

Ninety-seven percent of patients experienced at least 1 treatment-emergent adverse effect (TEAE) with tislelizumab/sitravatinib, and 68% reported an effect that was grade 3 or higher in severity. Seventy percent of patients had a serious TEAE with the doublet.

Additionally, 4 patients experienced a TEAE that resulted in death; these included 2 cases of dyspnea, respiratory failure, and malignant gastrointestinal obstruction, according to Goh. However, none of these effects were determined to be related to study treatment.

Fifteen percent of patients experienced a TEAE that resulted in discontinuation of tislelizumab, 12% of which were related to the drug, while 23% reported a toxicity that led to sitravatinib discontinuation, 20% of which were treatment related.

The median duration of treatment with tislelizumab was 18 weeks (range, 3-103), while it was 15 weeks (range, 3-103) with sitravatinib. The mean dose intensity with tislelizumab and sitravatinib was 94% and 69%, respectively. Forty-three percent of patients had their tislelizumab dose delayed, while 2% required dose interruption. Eighty-three percent of patients required a dose interruption of sitravatinib and 50% needed a dose reduction.

The most frequently reported any-grade AE with the doublet was diarrhea (67%), followed by nausea (57%), fatigue (48%), and hypertension (40%). The most commonly reported grade 3 or higher effects were hypertension and abdominal pain and these toxicities occurred in 18% and 12% of patients, respectively.

This article was published by Cancer Network.

Cancer Discovery Could Revive Failed Treatments for Solid Tumors

New research from the UVA Cancer Center could rescue once-promising immunotherapies for treating solid cancer tumors, such as ovarian, colon and triple-negative breast cancer, that ultimately failed in human clinical trials.

The research from UVA’s Jogender Tushir-Singh, PhD, explains why the antibody approaches effectively killed cancer tumors in lab tests but proved ineffective in people. He found that the approaches had an unintended effect on the human immune system that potentially disabled the immune response they sought to enhance.

The new findings allowed Tushir-Singh to increase the approaches’ effectiveness significantly in lab models, reducing tumor size and improving overall survival. The promising results suggest the renewed potential for the strategies in human patients, he and his team report.

“So far, researchers and protein engineers around the globe, including our research group, were focused on super-charging and super-activating tumor cell-death receptor targeting antibodies in the fight against cancer. Here at UVA, we took a comprehensive approach to harness the power of the immune system to create dual-specificity and potentially clinically effective oncologic therapeutics for solid tumors,” said Tushir-Singh, of the UVA School Medicine’s Department of Biochemistry and Molecular Genetics. “Our findings also have significant potential to improve further the clinical efficacy of currently FDA-approved PD-L1 targeting antibodies in solid tumors, particularly the ones approved for deadly triple-negative breast cancer.”

Optimized Immunotherapy for Solid Tumors

Immunotherapy aims to harness the body’s immune system to recognize and destroy cancer cells. Lab-engineered antibodies remain the core facilitator of immunotherapies and CAR T-cell therapies, which have generated tremendous excitement in the last decade. But these therapies have proved less effective against solid tumors than against melanoma (skin cancer) and leukemia (blood cancers). One major obstacle: It is difficult for immune cells to make their way efficiently into the core of solid tumors.

To overcome that problem, scientists have developed an approach that selectively uses antibodies to target a receptor on the cancer cells’ surface called death receptor-5 (DR5). This approach essentially tells the cancer cells to die and enhances the permeation of the body’s immune cells into a solid tumor. And it does so without the toxicity associated with chemotherapy.

Previously tested DR5-targeting antibodies have worked very well in lab tests and reduced tumor size in immune-deficient mouse models. But when tested in phase-II human clinical trials, these antibodies consistently failed to improve survival in patients – despite many big-name pharmaceutical companies spending billions of dollars on them.

Tushir-Singh, an antibody engineer, and his collaborators wanted to understand what was happening – why didn’t this promising approach work in patients who need it desperately? They found that the anti-DR5 antibody approaches unintentionally triggered biological processes that suppress the body’s immune response. This allowed the cancer tumors to evade the immune system and continue to grow.

Tushir-Singh and his team could restore the potency of the DR5-based antibody approach in human cancer cells and immune-sufficient mouse models by co-targeting the negative biological processes with improved, immune-activating therapy. The new combination therapy “markedly” increased the effectiveness of cancer killer immune cells known as T cells, shrinking tumors and improving survival in lab mice, they report in a new scientific paper.

That is an encouraging sign for the combination therapy’s potential in patients with solid tumors, such as ovarian cancer and triple-negative breast cancer – the deadliest cancers in women.

“We would like to see these strategies in clinical trials, which we strongly believe have huge potential in solid tumors,” Tushir-Singh said. “Our findings are extraordinary: Along with the translational impact, our work also explains, after more than 60 years of research in the field, why most approaches targeting apoptosis [cell death] have not done well in clinical trials and ultimately develop resistance to therapies.”

Findings Published

The researchers have published their findings in the scientific journal EMBO Molecular Medicine. The research team consisted of Tanmoy Mondal, Gururaj N. Shivange, Rachisan G.T. Tihagam, Evan Lyerly, Michael Battista, Divpriya Talwar, Roxanna Mosavian, Karol Urbanek, Narmeen S. Rashid, J. Chuck Harrell, Paula D. Bos, Edward B. Stelow, M. Sharon Stack, Sanchita Bhatnagar and Tushir-Singh. UVA is seeking a patent based on the new combination approach.

This article was published by Newswise.

What to Know About Telehealth for Ovarian Cancer

By Carrie Madormo, RN, MPH

Ovarian cancer is a serious gynecologic cancer and the fifth leading cause of cancer-related deaths among women in the United States.1 To minimize the risk of the coronavirus disease (COVID-19) transmission while still providing much-needed cancer care, oncology clinics and hospitals have increased access to telehealth services for their patients. This is especially important to people with cancer because they are at higher risk for COVID-19 as a result of immunosuppression caused by their treatment and the disease itself. While healthcare providers can address a number of health concerns that a person with ovarian cancer may have, such as mild side effects from cancer treatment, some aspects of their care like physical exams still need to be conducted in person.

When to Use Telehealth for Ovarian Cancer

While much of cancer treatment like chemotherapy and surgery needs to happen at the hospital, several appointment types and health needs can be addressed from home.

Before Your Next Appointment

Even if you’re scheduled for an in-person appointment with your doctor, you may still be asked to use telehealth services before your appointment. Your clinic may call you to screen you for COVID-19 symptoms. You may also have the chance to check in for your appointment and answer any insurance-related questions via a patient portal. This can help reduce wait times and potentially exposure to COVID-19 at the clinic.

After a Confirmed Diagnosis

Ovarian cancer is usually confirmed by a biopsy or surgery, which needs to be done at the hospital.1 Once a pathologist has examined your sample and determined the diagnosis, your doctor may be able to meet with you virtually to discuss next steps. They will discuss your results and recommend a comprehensive treatment plan.

Follow-up Appointments

Once you begin treatment for ovarian cancer, your oncology team will monitor your health through imaging studies, lab tests, and follow-up visits.1 Ask your oncologist if some of your follow-up visits could be conducted virtually. Your doctor may be able to speak with you on the phone or by video chat to update you on your latest lab test results and treatment plan, as well as answer any questions you may have.

New Symptoms or Side Effects

If you develop any new cancer symptoms or treatment side effects, don’t hesitate to reach out to your medical team. You may be able to send a message to your provider via the patient portal and set up a time to speak with them.

Any new symptoms or side effects severe enough to require emergency care always warrant an in-person visit, including uncontrolled vomiting or diarrhea, mental confusion, a high fever, or bleeding.

Post-surgical Follow-up Appointment

A common treatment modality for ovarian cancer is debulking surgery to remove as much of the tumor as possible. This surgery could affect your ovaries, uterus, cervix, fallopian tubes, lymph nodes, and even the small intestine.1 Depending on how involved your surgery is, your surgeon may be able to follow up with you after your procedure through a virtual visit. If your surgical incisions are red, painful, and oozing, you will need to see your doctor since these could be signs of an infection.

To Participate in Genetic Counseling

Doctors recommend that women who have been diagnosed with ovarian cancer undergo genetic counseling and discuss the results with their family members. Talk with your medical team about meeting with a genetic counselor virtually. There are also apps available to make the process more convenient.

To Enroll in a Clinical Trial

As part of your treatment, your oncologist may recommend joining a clinical trial to have access to a new medication or therapy that is not yet approved for cancer treatment. Due to the COVID-19 pandemic, many clinical trial research teams now work from home and are able to meet with study participants virtually. Also, medications used in these trials can now be mailed to your home, rather than having to be picked up in person.

Mental Health Help

Undergoing cancer treatment can be grueling, and it’s natural to feel down in the process. A recent study found that 89% of women undergoing treatment for ovarian cancer experienced high levels of worry about their health during the COVID-19 pandemic.1 If you have any concerns about your mental health, reach out to your medical team for support and resources. A therapist or psychologist can also meet with you virtually to discuss any problems you may be having with coping with your condition.

Some health concerns cannot be addressed through telehealth and require an in-person evaluation. You may need to visit your doctor’s office if:

• You have a high fever
• Your doctor recommends additional imaging studies
• You have a lab appointment to have blood drawn
• Your surgeon recommends a presurgical physical exam
• Your treatment plan include intravenous chemotherapy

Benefits and Challenges

There are several benefits to taking advantage of telehealth services for ovarian cancer, as well as a few challenges. Attending a virtual doctor’s appointment is usually more convenient than visiting the clinic in person. Research has shown that telehealth services save time and increase access to care. A 2020 study found that 82% of women with breast or gynecological cancer felt that using telehealth services like patient portals and virtual appointments improved their overall health.

Using telehealth options may be safer as well. It’s estimated that patients with cancer are about twice as likely to contract COVID-19 than the general public.5 Attending an in-person appointment raises the chance of being exposed to the virus both at the hospital and during the commute to the care location.

Because doctors offices now need to be more reliant on telehealth visits in response to the COVID-19 pandemic, care may be delayed. One survey found that 33% of American women with ovarian cancer reported delays in their care related to the pandemic, usually related to postponing surgeries.

The use of telehealth in ovarian cancer care has also been associated with heightened concern about their conditions among cancer patients.6 This may be due to the fact that meeting virtually does not always feel the same as seeing your doctor face-to-face. If your hospital’s patient portal is complicated or confusing, the process itself may even bring on anxiety.

How to Prepare for a Telehealth Visit for Ovarian Cancer

When preparing for your telehealth visit, think through any questions you may have for your provider. When making the appointment, ask the clinic representative how long the appointment will last and if you will be on the phone or video chat. Find out who will be attending your appointment and if you can include friends or family on the call.

Ensure that you have a reliable device with access to the internet or plan to borrow one from a friend. Also, call your hospital’s or doctor’s office billing department to find out if telehealth visits are covered by your insurance plan.

On the day of your appointment:

• Find a quiet place in your home where you’ll be able to talk with your provider without interruptions. If you are using a public computer, bring headphones.
• Install any needed software and test out the camera and microphone on your device. Ask a relative or friend for help if you’re having trouble getting it set up.
• Make sure your device is charged and that you have the phone number for the clinic in case you are disconnected.
• Think through the questions you’d like to ask and any updates for your team. Keeping written notes with you may help.
• Write notes about any changes to your treatment plan, including medications, chemotherapy schedule, or radiation therapy.

Will Insurance Cover Telehealth for Ovarian Cancer?

In 2020, the United States Congress passed three federal stimulus packages, which included guidelines for telehealth coverage. If you have Medicare, your virtual appointments should be billed the same as in-person visits, and there should not be any geographic or eligibility restrictions.7 If you have Medicaid, call your local Medicaid office to find out what is covered. If you have private insurance, call your insurance company directly to determine what services are considered telehealth. When researching telehealth coverage, a good starting place is the National Consortium of Telehealth Resource Center, which offers a database of telehealth billing policies by state.

What Happens During the Visit

The length and style of your telehealth visit will vary by the reason of your visit and will feel similar to an in-person appointment for the same purpose. Once both you and your provider have logged on to the call, you will discuss your treatment and any new problems. You will then work together to make a plan going forward.

Before starting the visit, you may be asked to acknowledge the fact that you understand the limitations of a telemedicine visit, including the inability to do a full medical exam, possibly missing subtle findings that might have been obvious on a face-to-face visit.

You have the right to refuse to participate in services delivered via telemedicine and ask for an in-person visit.

Visit with a New Provider

For initial consultations, your oncologist will review the results of your biopsy with you and explain your cancer stage and grade. Your doctor may recommend further testing to determine if cancer has spread.1 It’s common for your doctor to share their screen with you to show you lab results or pictures. Your doctor will also take time to review your entire health history and any family history that involves cancer or gynecological conditions. From there, your doctor will recommend a treatment plan and explain each type of therapy. Be sure to take notes during the appointment.

Follow-up Visits

For follow-up visits, your oncologist or another provider will ask for an update about how you’ve been feeling. They may share results from recent lab tests or imaging studies, as well as any alterations that need to be made to your treatment plan. These appointments are a good opportunity to discuss new symptoms or side effects, as well as any questions you may have. Ask your provider if future appointments will be conducted virtually or in person.

During telehealth visits, you are entitled to privacy just as you are during in-person appointments. Providers offering telehealth visits must comply with the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and protect your health information during and after the appointment. Protected health information includes any data that could identify you such as your name, date of birth, social security number, diagnosis, and more. Health providers must use “non-public facing remote communication product that is available to communicate with patients.”

A Word From Verywell

Undergoing treatment for ovarian cancer is an overwhelming experience, and hopefully, telehealth services can make the process just a bit easier. To get started, ask your oncology team about what telehealth services they offer and how to access them. Talk with your insurance company or hospital billing department about which types of calls and appointments are covered. If you feel intimidated by the patient portal or telehealth software, ask for help from a provider or friend. Virtual visits cannot replace in-person exams but they can certainly help you receive more of your care from the safety and convenience of your home.

This article was published by Verywell Health.