While second-generation androgen receptors such as apalutamide (Erleada) and enzalutamide (Xtandi) have improved outcomes for men with nonmetastatic castrate-resistant prostate cancer (nmCRPC), they can come with adverse events (AEs) that are often unresolved, according to recent research presented at the 2021 Genitourinary Cancers Symposium.

“The objective of the present study was to describe the patient characteristics, the frequency of a disease or adverse events amongst patients receiving apalutamide or enzalutamide [and] how these adverse events are managed in a real-world setting, and what is the health care resource utilization for these patients,” said study author Arif Hussain, MD, professor of medicine at the University of Maryland Medical System.

The researchers analyzed 368 patients with nmCRPC who were taking apalutamide and 333 on enzalutamide. In this group, 72% and 78.8% experienced 1 or more AE in the apalutamide and enzalutamide group, respectively. Hussain noted that they did not investigate outcomes for darolutamide (Nubeqa) because they did not have sufficient data on the drug at the time of the study.

The most common AEs in the apalutamide and enzalutamide groups were:

Fatigue/asthenia (30.2% vs 38.7%, respectively)

Notably, cognitive and mental changes were also observed in 5.4% of men on apalutamide and 7.8% of men on enzalutamide.

From the total group, the researchers further analyzed 125 patients on apalutamide and 125 patients on enzalutamide who experienced 1 or more AE for a more in-depth evaluation. Nearly three-fourths of this group was Caucasian; 84% and 88% had an ECOG score between 0-1; and the median prostate-specific antigen (PSA) score was 13 ng/ml and 11 ng/ml for apalutamide and enzalutamide, respectively.

Many patients on apalutamide and enzalutamide (43.6% vs. 39.4%, respectively) did not have their AEs resolved. For those who did have toxicities resolved, it took an average of 60 and 56 days for the apalutamide and enzalutamide groups, respectively.

The most common approaches for AE management in the apalutamide and enzalutamide arms were:

Treatment for the AE (36.8% vs. 39.2%, respectively)

The researchers ultimately concluded that there is a resource use burden to manage AEs for these agents, and patients and providers should discuss toxicities before deciding on a treatment regimen.

“The results demonstrate the importance of safety and tolerability, which should be key considerations and shared clinician-patient decision-making regarding androgen receptor inhibitor targeted therapy in nmCRPC patients,” Hussain said.

Jiang S, Varghese D, Appukkuttan S, et. al. Frequency, management, and resource use of adverse events (AEs) in nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients receiving apalutamide or enzalutamide: A real-world study. Presented at: 2021 Genitourinary Cancers Symposium. Feb. 11-13. Virtual. Abstract 217.

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While the majority of patients on androgen receptor therapy experienced adverse events, more than a third did not have them resolved. 

Better Treatment Needed for Androgen Receptor Adverse Events

Fear of cancer recurrence is a common plight for people after they have completed cancer treatment, and recent research analyzed which patient characteristics were associated with higher rates of fear of recurrence.

 recently spoke with study author Jacqueline Galica, PhD, RN, about her findings – and what oncology nurses can do to help mitigate fear of recurrence in their patients.

 What puts oncology nurses specifically in a good role to discuss fear of recurrence with their patients?

: Nurses are often that first point of contact to the healthcare system, and we are in this really unique position of trust, and this unique relationship develops. So I envisioned that if we could clarify what are the characteristics of survivors who are most likely have highest fears of cancer recurrence, this could be used by oncology nurses who are regularly seeing these people coming back to the clinics in their follow ups. [Nurses can help by] having that recurring conversation and that assessment that goes on in those conversations. And so that's what I really was striving for – for this work to be useful for oncology nurses in in those settings.

What were your findings? Which patients and patient characteristics were at most risk to experience fear of recurrence?

We used a theory, Leventhal’s Common Sense model, which is a theory that's commonly used to understand fear of cancer recurrence. We used this to identify what could be important characteristics to look at amongst cancer survivors. We looked at a number of characteristics.

What we found was consistent with other findings: people who are younger, have higher fears of cancer recurrence. And this could be for a number of different reasons, families, etc. Those who identified as female had higher fears of cancer recurrence and those who identified as male. Interestingly, people who had been diagnosed longer – so they there was a longer duration since they were diagnosed – they had higher fears of cancer recurrence, versus people who are shorter in their in their duration. And that's really interesting, because longitudinal studies that follow people for years show there's no trend, there's no trends could be anything for fear of cancer recurrence over time, people who were continued to be followed up in this cancer survivorship clinic. So they’re coming back to the clinic years and years after they were diagnosed, had higher fears of cancer recurrence. And so we think it was those reminders of coming back to the clinic where there were their experiences, reminders of these cancer experience.

Interestingly, people's perceptions were a strong predictor of higher fear of cancer recurrence. For instance, it wasn't about people who had more symptoms, but it was people who had more symptoms that they believed or caused from their cancer or caused from their treatment, these people had higher fears of cancer recurrence. People with lower self-esteem had had higher fears of cancer recurrence. And interestingly, people who were more pessimistic, had actually a lower fear of cancer recurrence. This might be their type of coping strategy that they use; they're more likely to be more pessimistic or more likely to deny or disengage, give in to their circumstances.

What should nurses do if they identify patients who are experiencing or who are at high risk of experiencing fear of recurrence?

The first thing is to normalize that fear of cancer recurrence is a normal feeling after completing treatment for cancer. In our subsequent research, [we found that] people who've had their fear of cancer recurrence normalized [felt] liberated and that they weren't alone in this feeling. There wasn't something wrong with them with experiencing this feeling. So that is, first and foremost, to normalize. This is a normal reaction to completing cancer treatment.

But then, nurses have a very special role to provide education. This means educating: what are some symptoms to watch out for that could indicate a recurrence, when to report a symptom, who to report it to, what are some things that aren't symptoms of recurrence, but just maybe long-term symptoms or side effects from treatment. So just helping patients navigate those uncertainties can help reduce the likelihood of their fear of cancer recurrence.

Encourage patients to really engage in positive coping, stress reducing activities. So recreational hobbies, that they enjoyed pre-cancer, yoga meditation. Also, remind patients that there will be some triggers to further fear of cancer that will trigger fear of cancer recurrence, this may be the anniversary of their diagnosis, this may be a mammogram or some sort of follow up testing. It's normal to have these feelings coming back around those milestones. And so that that awareness about that, even asking things like, “it sounds like you've been worrying a lot about this. Can you tell me more about that?”.

Encourage that dialogue – it helps further to normalizing how patients are feeling or survivors are feeling. It's making it a part of their cancer care, and it's helping people externalize some of those feelings. Yeah, I think that's one of the things that nurses can do.

Fear of cancer recurrence is a common plight for people after they have completed cancer treatment, and recent research analyzed which patient characteristics were associated with higher rates of fear of recurrence. 

Patient Perceptions, Other Factors Linked to Fear of Recurrence

Patients with metastatic urothelial carcinoma (mUC) who had a higher tumor mutational burden (TMB) tended to have more immune-related adverse events (irAEs) than those with low TMB. Additionally, high TMB and irAEs rates were associated with better response rates with immunotherapy, according to recent research presented at the 2021 Genitourinary Cancers Symposium.

“It has been shown previously in the literature that TMB serves as a candidate biomarker of clinical outcomes from immune checkpoint inhibitors in urothelial carcinoma. In addition, the immune-related adverse events have been associated with a better [immune checkpoint inhibition] efficacy in multiple cancers,” said study author Elie W. Akl, MD, of the Dana-Farber Cancer Institute.

“So, we hypothesized that the immune response against new antigens is partly responsible for [irAEs] and investigated the association between [irAEs] and TMB and response to [immune checkpoint inhibition].”

The study involved 101 patients with mUC who were being treated with immune checkpoint inhibition (either single-agent or combination) at the Dana-Farber Cancer Institute.

About a third of patients (32%) reported irAEs. Six patients had grade 1 irAEs, 20 patients had grade 2, and 6 patients had grade 3. Those who experienced irAEs had a higher average TMB (15.4/mb) than those without irAEs (9.8/mb). Notably, the cutoff for TMB-high was 10/mb (non-synonymous exonic mutations per megabase).

Ninety-four patients had radiological data available at the time of the study. Among them, 50% of patients with irAEs responded, to therapy, compared to only 16% of patients without irAEs (

“However, when both adverse events and response were included in the multivariable regression, the association between adverse events and TMB was not significant,” Akl explained.

Patients who experienced an irAE and had a high TMB had an overall response rate of 56%, about double the rate of patients who had an irAE but low TMB, at 28.6%. That finding was statistically significant. A total of 21.2% of patients with high TMB but no irAE responded, and 10.3% of patients with low TMB and no irAE responded.

The researchers did not find any correlation between TMB and grading of irAE.

Looking ahead, Akl said the further research is warranted to better understand the associations between TMB, irAEs, and immunotherapy response.

“Further evaluation in metastatic urothelial carcinoma is needed to confirm this relationship between TMB adverse events and response, a larger cohort and explore specific mutations signature that may be associated with immune-related adverse events,” he said.

Patients with metastatic urothelial carcinoma with higher tumor mutational burden and who experienced immune-related adverse events tended to have higher response rates to immune checkpoint inhibitor. 

High TMB, Adverse Events May Predict Immunotherapy Response in mUC 

Sapanisertib failed to show significant activity and a favorable toxicity profile in patients with refractory metastatic renal cell carcinoma (mRCC) regardless of mTOR or PTEN status, according to findings from a phase 2 study (NCT03097328) that were presented during the 2021 Genitourinary Cancers Symposium.

At a median follow-up of 10.4 months (range, 1.0-27.4), the objective response rate (ORR) was 5.3% (n = 2; 90% CI, 1.0%-15.6%). The median progression-free survival (PFS) was 2.5 months (95% CI, 1.8-3.7), and the median overall survival (OS) was 11.2 months (95% CI, 9.3-not reached).

“Sapanisertib had poor tolerability and minimal activity in patients with treatment refractory metastatic RCC, and there was no clear benefit among patients with mTOR or PTEN alterations,” Bradley McGregor, MD, lead study author, and clinical director of the Lank Center for Genitourinary Oncology, senior physician at Dana-Farber Cancer Institute, and instructor of medicine at Harvard Medical School, said in a virtual presentation of the data.

Treatment options following progression on a checkpoint inhibitor and VEGF TKI are limited for patients with mRCC. Approved rapalogs, which have modest activity in mRCC, inhibit only mTORC1, whereas sapanisertib inhibits the entire mTOR pathway by targeting mTORC1 and mTORC2.

The multicenter, single-arm study enrolled 38 patients with clear cell mRCC who had received at least 2 prior lines of therapy and non-clear cell mRCC who had received at least 1 prior line of therapy with an ECOG performance status of 0 to 2.

Patients underwent a mandatory baseline biopsy that evaluated PTEN status and over 477 genes, including TSC1, TSC2, mTOR, PIK3CA, and PTEN, prior to receiving 30 mg of oral sapanisertib weekly.

The primary end point was ORR. Secondary end points included PFS, OS, safety, and toxicity. ORR and PFS by PTEN immunohistochemistry status and oncopanel-identified mutations in the mTOR pathway served as correlative end points.

Regarding patient characteristics, the median age at the time of enrollment was 62 (range, 28-75). The majority of patients had clear cell histology (73.7%; n = 28), followed by non-clear cell RCC (26.3%; n = 10), which encompassed chromophobe RCC (n = 2), papillary RCC (n = 6), translocation RCC (n = 1), and unclassified RCC (n = 1). The majority of patients had intermediate-risk disease (76.3%; n = 29) per International Metastatic RCC Database Consortium risk assessment, followed by favorable- (13.2%; n = 5) and poor-risk disease (10.5%; n = 4).

The majority of patients were heavily pretreated, having received 4 or more prior lines of therapy (39.5%; n = 15). Though, patients who received 1 (13.2%; n = 5), 2 (21.1%; n = 8), and 3 (13.2%; n = 5) prior lines of therapy were also represented. A total of 5 patients (13.2%) had an unknown number of prior treatments.

The majority of patients had received a prior checkpoint inhibitor (75.8%; n = 25) but not an mTOR inhibitor (60.6%; n = 20).

Additional results showed that 2 patients experienced an unconfirmed partial response (PR; 5.3%), 15 patients experienced stable disease (SD; 39.4%), 17 patients experienced progressive disease (44.7%), and 2 patients were not evaluable (5.3%).

The median time on treatment was 1.6 months (range, 0.3-13.8). At the time of data cutoff, 2 patients remained on treatment (5.3%), 36 had discontinued treatment (94.7%), 29 had progressive disease (PD; 76.3%), 4 had unacceptable toxicity (10.5%), 1 withdrew (2.6%), 1 discontinued by patient decision (2.6%), and 1 discontinued by physician discretion (2.6%).

No clear benefit between mTOR and PTEN alterations and clinical benefit with sapanisertib was reported.

Among patients with intact PTEN (n = 12), 1 experienced a PR, 6 experienced SD, and 5 experienced PD. Among patients with diminished PTEN expression or PTEN loss (n = 7), 1 experienced an unconfirmed PR, 2 experienced SD, and 4 experienced PD.

Among patients with an mTOR pathway mutation (n = 6), 1 experienced an unconfirmed PR, 1 experienced SD, and 4 experienced PD. Among patients without an mTOR pathway mutation (n = 21), 2 experienced a PR, 1 experienced an unconfirmed PR, 8 experienced SD, and 9 experienced PD.

Treatment-related adverse effects consisted of nausea (50%; n = 19) fatigue (39%; n = 15, vomiting (34%; n = 13), mucositis (32%; n = 12), anorexia (21%; n = 8), diarrhea (18%; n = 7), rash (18%; n = 7), dyspnea (13%; n = 5), hyperglycemia (13%; n = 5), constipation (11%; n = 4), hyperkalemia (11%; n = 4), cough (8%; n = 3), dehydration (8%; n = 3), dry mouth (8%; n = 3), muscle weakness (8%; n = 3), pruritus (8%; n = 3), hyponatremia (5%; n = 2), elevated creatinine (3%; n = 1), myocardial infarction (3%; n = 1), syncope (3%; n = 1), and pneumonitis (3%; n = 1). No grade 4 or 5 toxicities occurred.

“Additional work is needed to find new targets for patients with advanced RCC,” concluded McGregor.


McGregor BA, Adib E, Xie W, et al. Biomarker-based phase II study of sapanisertib (TAK-228), an mTORC1/2 inhibitor in patients with refractory metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2021(suppl 6):306. doi:10.1200/JCO.2021.39.6_suppl.306

This article was originally published on OncLive as, "Sapanisertib Imparts Poor Activity and Toxicity Profile in Refractory mRCC."

Sapanisertib failed to show significant activity and a favorable toxicity profile in patients with refractory metastatic renal cell carcinoma (mRCC) regardless of mTOR or PTEN status. 

Sapanisertib: Poor Activity, More AEs in mRCC

The coronavirus disease 2019 (COVID-19) pandemic has increased symptom burden – including anxiety and depression rates – in patients with cancer, according to ongoing research presented at the National Institute of Nursing Research’s Symptom Science Advances in Oncology Nursing virtual event.

“Oncology patients, during COVID-19, are experiencing a very high symptom burden,” study author Christine Miaskowski, PhD, RN, FAAN, Sharon A. Lamb Endowed Chair in Physiological Nursing and professor in the department of physiological nursing at the UCSF Helen Diller Family Comprehensive Cancer Center, said during her presentation.

More than 600 cancer survivors completed an online survey about symptom burden, which were compared to statistics from patients before the COVID-19 pandemic and the general population. The majority were female; 40% were on active treatment; about 25% lived alone; and a third had metastatic disease.

“The general population is experiencing a high amount of stress during the COVID-19 pandemic,” Miaskowski said. “So in some ways, we’re adding insult to injury. There’s a large [body] of literature on the fact that a cancer diagnosis itself and treatment is stressful for patients. And now we add these stressors in the context of COVID-19.”

Before COVID-19, about 15% to 30% of cancer survivors reported high depression scores (indicated by a score of 16% or higher per the Center for Epidemiological Studies scale). This number increased to 40.7% during the pandemic, which was also higher than the general population, which had a 33.7% rate of depression.

Trait- and state-related anxiety rates also increased in cancer survivors during the COVID-19 pandemic, increasing from 30% and 50%, respectively, prior to the pandemic, increasing to 58.3% and 48.4% after. In the general population, there was a 31.9% rate of anxiety during the COVID-19 pandemic.

When it came to sleep disturbances, more than twice the amount of patients with cancer experienced the symptom (61.4%) compared to those without a cancer history (18%-30%) during the COVID-19 pandemic.

Additionally, many patients reported feelings of loneliness as a result of social isolation. Considering that the bulk of the participants in the study were White, educated, and finished with active treatment, Miaskowski noted her concerns for those in more vulnerable populations and what they may be going through.

“I have a long list of questions about what’s happening to other groups of individuals who are less fortunate,” she said.

Moving forward, Miaskowski encouraged oncology nurses to talk to their patients about symptom burden and loneliness – during the pandemic and beyond.

“I’m going to pressure the clinicians in the room that we need to assess for stress and types of stressors. I think in some cases, it might just be enough to acknowledge that the patient is experiencing stress,” she said. “I know these conversations take time, but I think in the era of COVID-19, the vaccine administration, and post-COVID-19, we need to think about who can have these conversations and when.”

The COVID-19 pandemic increased rates of stress in the general public, adding to that of survivors who may already be feeling anxious. 

COVID-19 Amplifies Stress, Loneliness in Cancer Survivors 

Oncology nurses should discuss mental health issues with testicular cancer survivors, as recent data published in the 

 showed that this patient group is more likely to seek mental health services than their cancer-free counterparts.

The researchers analyzed 2,619 Canadian testicular cancer survivors and matched them with 13,095 individuals without a cancer history. At baseline, the 2 groups had the same rate of mental health services used.

However, in the peritreatment time period (1 month before to 1 month after orchiectomy) and the post-treatment period (1 month after treatment to end of follow-up), those with a history of testicular cancer were significantly more likely to seek an outpatient mental health service.

Participants in the study were followed for 12 years, and as time passed, the cancer survivors became even more likely to seek mental health services.

“Such persistence of mental health needs beyond the time of the diagnosis or immediate treatment (i.e. orchiectomy) suggest that the mental health concerns experienced by testicular cancer survivors are not restricted to time-limited mental health disturbances,” the authors wrote. “This also highlights that the long-term and late-effect complications of testicular cancer diagnosis and treatment extend well beyond the 5-year period during which early-stage patients are typically followed by their cancer care providers.”

Testicular cancer survivors are at an increased risk of secondary illnesses, such as cardiovascular disease, pulmonary toxicities, liver issues, neurotoxicity, and decreased fertility. While these outcomes are usually related to cancer and its treatment, the researchers found that the survivors usually sought out advice from their primary care providers, rather than their oncology team.

“The long-term mental health sequelae associated with testicular cancer, together with the fact that most visits for these problems were with family physicians and not oncologists, highlights the importance of open lines of communication between the cancer care team and primary care providers,” the researchers wrote.

Survivors who had baseline mental health treatment and/or sought out additional treatments for their testicular cancer had an increased rate in mental health service use. Since the researchers did not stratify participants by cancer stage, they cannot say if those who had adjuvant treatment for stage 1 disease had less anxiety than those who followed with surveillance.

The number of cancer survivors continues to grow, and as testicular cancer is the most common solid cancer in young adult males and had a high cure rate, understanding the long-term effects of the disease is now more important than ever.

“Accordingly, there has been an increased emphasis on understanding the long-term and late-effect treatment complications affecting testicular cancer survivors,” the researchers wrote.

Oncology nurses should be sure to talk about potential mental health issues that testicular cancer survivors may see down the road, while also maintaining open lines of communication with other members of the individual’s care team.

“Efforts to increase awareness of mental health consequences and ensure that appropriate resources and support are in place beyond the acute phase of diagnosis and treatment to support the long-term mental health of testicular cancer survivors are warranted,” the researchers wrote.

Testicular cancer survivors had a higher rate of mental health service utilization than their healthy counterparts.
 

Discuss Mental Health in Testicular Cancer Survivorship Plans

A recent study found that 19% of patients with cancer engaged in nonmedical opioid use. In this episode of “The Vitals,” we spoke with study author Sriram Yennu, MD, MS, FAAHPM, study author and professor in the department of palliative care and rehabilitation medicine at MD Anderson. Yennu outlined the risk factors that he and his team found for opioid misuse, as well as what nurses can do to promote safer opioid use.

The following factors were independently associated with nonmedical behavior: Marital status

Edmonton Symptom Assessment Scale pain level

Read more: https://www.oncnursingnews.com/web-exclusives/1-in-5-patients-engage-in-nonmedical-opioid-use

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A recent study found that 19% of patients with cancer engaged in nonmedical opioid use.

Nonmedical Opioid Use: Identify the Risks

Data from a recent analysis demonstrated that more than one in five people experienced depression or anxiety, either before or not long after receiving a blood cancer diagnosis, highlighting the need for further mental health screening in these individuals.

“(This study) highlights the critical need for systematic mental health screening and management for individuals with hematologic malignancies,” said Dr. Thomas M. Kuczmarski during a virtual presentation of the data at the ASH Annual Meeting and Exposition.

Historically, according to Kuczmarski, most of the available data detailing the impact of depression and anxiety on individuals with cancer involve patients with solid tumors. In fact, there are very little data assessing mental health disorders in those with blood cancers.

“These mental health disorders can decrease the quality of life, delay onset of cancer therapy and even decrease overall survival,” Kuczmarski, a resident physician at Brigham and Women’s Hospital, said.

As a result, Kuczmarski and colleagues wanted to evaluate the prevalence of mental health disorders in a cohort of patients with blood cancers who were aged 67 years and older.   

Using data from the Surveillance Epidemiology and End Results (SEER) Medicare database, the researchers identified a large cohort of patients who were diagnosed with a blood cancer between 2000 and 2015. Patients were included in the analysis if they had died between 2000 and 2016, but were excluded if they did not survive greater than 30 days from when they were first diagnosed.

Researchers measured a patient’s depression or anxiety prior to diagnosis, which was defined as one or more inpatient, or two or more outpatient claims for either mental health disorder 24 months to one month prior to blood cancer diagnosis. Moreover, researchers analyzed cancer-associated depression or anxiety, which consisted of either one or more inpatient, or two or more outpatient claims for either disorder one month prior to, or three months after, cancer diagnosis.

More than half of the 64,018 patients included in the analysis were diagnosed with lymphoma (53.4%). The remaining patients were either diagnosed with myeloma (18.6%), leukemia (18%) or myelodysplastic syndromes (10%).

Among the entire patient cohort, 20.7% had at least one of the assessed mental health disorders. Some of the patients (10.6%) had depression prior to their blood cancer diagnosis, and an additional 4.4% developed depression that was associated with their cancer. Additionally, 7.4% of the cohort had pre-diagnostic anxiety, and an additional 2.8% developed the mental health disorder after their cancer diagnosis.

Following a univariable analysis, patients with cancer-associated depression were more likely to have had pre-diagnostic anxiety (10.7%) compared with patients who did not have cancer-associated depression (7.3%). Patients with cancer-associated anxiety were also more likely to have presented with pre-diagnostic depression (18.9%) compared with patients who did not have cancer-associated anxiety (10.4%).

“Given our finding that the biggest risk factor for developing cancer-associated depression or anxiety was actually a preexisting mental health disorder, we believe that additional psychosocial support for individuals with baseline mental health illness is crucial,” said Kuczmarski.

However, he acknowledged that there were some limitations with the data.

“We use billing claims as merely a proxy for depression and anxiety diagnoses, and therefore, they may underestimate the true rate of these mental health disorders,” he concluded. “Secondly, we were unable to obtain the strategies that oncologists used to diagnose and manage cancer-associated depression and anxiety. And lastly, our cohort was all age 67 years or older. So therefore, the generalizability of our findings to younger patients may be limited.”

Data from a recent analysis demonstrated that more than one in five people experienced depression or anxiety, either before or not long after receiving a blood cancer diagnosis, highlighting the need for further mental health screening in these individuals.
 

Mental Health Screening Is Needed in Blood Cancer Space

Gastrointestinal (GI) adverse events (AEs) that occurred in patients with metastatic breast cancer who were treated with oral paclitaxel and encequidar can be managed by the use of 5- HT3 inhibitors and early intervention with loperamide, according to research presented at the 2020 San Antonio Breast Cancer Symposium.

This combination regimen allows for fewer AEs, but investigators looked to find a way to prevent GI AEs that were found to be higher following treatment with oral paclitaxel and encequidar.

“Paclitaxel is substrate of the intestinal e-flux pump p-glycoprotein that leads to low oral bioavailbailty. Encequidar is a specific p-glycoprotein absorbed by patients to help bioavailbailty,” explained lead investigator Hope Rugo, MD, from the University California San Francisco Helen Diller Family Comprehensive Cancer Center, in a poster presentation at SABCS. “This avoids the need for Cremophor risk and allows for at home dosing with patients and eliminates the need for IV infusions.” However, she added, the incidence of gastrointestinal adverse events from this combination was high.

The researchers investigated preventive measures for GI AEs associated with oral paclitaxel and encequidar or IV paclitaxel — which were evaluated in a multinational trial looking at the safety of this combination in 442 patients.

Patients were randomized 2:1 on either oral paclitaxel and encequidar (205mg/m2/day x3 weekly) or IV paclitaxel (175 mg/m2 every three weeks) until disease progression or toxicity. The primary end point of the study was efficacy as defined by tumor response with secondary endvpoints of progression-free survival (PFS) and overall survival (OS).

All patients on IV paclitaxel (n = 111) were given dexamethasone and antihistamine premedication and after 30% (n = 70) of patients were enrolled to include those on oral paclitaxel and encequidar the protocol was amended to address the imbalance of GI AEs. Treatments included loperamide taken at home at the onset of diarrhea along with prophylactic anti-emetic therapy.

The most frequently prescribed anti-emetic therapies included ondanesteron, granisetron, palenosetron, aprepitant, metoclopramide, domperidone, and aprepitant. The majority of patients in the combination (59%) and monotherapy (54%) arms received ondanesteron.

After the amended use of prophylactic anti-emetic therapy, there was a marked decrease of grade 2 or higher vomiting and diarrhea in patients on oral paclitaxel and encequidar, from 24% to 7% and 27% to 16% respectively. A greater incidence of both AEs were seen in patients treated with IV paclitaxel.

Of note, prior to the amendment, overall GI AEs occurred less frequently in patients on IV paclitaxel compared to the combination regimen, with a rate of only 1% of grade 3 vomiting and diarrhea occurring. Grade 3 incidences prior to the amended treatment in patients on the oral regimen were 7% in vomiting and 9% in diarrhea, showing a slight decrease to 4% and 3%, respectively.

Rugo H, Umanzor G, Barrios F J et al. Oral paclitaxel and encequidar (oPac+E) in the treatment of metastatic breast cancer (mBC): management of gastrointestinal adverse events (GI AE). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual.

This article was originally published on OncLive as, "

GI AEs Associated With Oral Paclitaxel Plus Encequidar Subside with Antiemetics, Loperamide in Metastatic Breast Cancer.

Managing GI AEs in Metastatic Breast Cancer

Following the approvals of tisagenlecleucel (tisa-cel; Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta), several research efforts have been dedicated to the development and exploration of CAR T-cell therapies in the realm of leukemias and lymphomas, according to Olalekan O. Oluwole, MBBS, MD, who added that although this modality has moved the needle forward, this approach is not without toxicity.

“CAR T-cell therapy has transformed the treatment paradigm for patients with relapsed/refractory leukemia and lymphoma. However, it’s critical to remember that despite the great results we have seen thus far [with this approach], some toxicities are associated with these products,” said Oluwole. “Looking forward, we hope to lessen these toxicities and use cellular therapy in combination with other agents. Ultimately, we hope that, with time, the success that has been achieved in hematologic malignancies will roll over to solid tumors.”

, during the 2020 Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Oluwole, who is an assistant professor of medicine, hematology, and oncology at Vanderbilt-Ingram Cancer Center, highlighted the evolution of CAR T-cell therapy in leukemia and lymphoma, targets under investigation, and next steps for exploration.

: Could you expand on research that led to the rise of CAR T-cell therapy in leukemia and lymphoma?

: The ZUMA-1 trial led to the approval of the first CAR T-cell product in diffuse large B-cell lymphoma (DLBCL): [axi-cel]. This product has been the poster child for what [the regulatory] process looks like [for this modality] in lymphomas.

In the leukemia space, tisagenlecleucel was the first to be approved for acute lymphoblastic leukemia. Additional products [have since emerged] for other types of leukemia, lymphoma, and multiple myeloma.

Could you further expand on the ZUMA-1 trial and the significance of this research?

ZUMA-1 was a phase 1/2 clinical trial that evaluated the cellular product axi-cel in patients with DLBCL. 

In the [manufacturing] process [for the product], T cells are collected from the patient, they are sent to a central laboratory where they are manipulated in a way that would express a specific antigen receptor that is able to recognize CD19. The T cells are then re-infused back into the patient, where they go after anything that harbors CD19. During this process, they wipe out the lymphoma. A brief course of lymphodepleting chemotherapy is given to patients prior to CAR T infusion and the purpose of is to facilitate rapid proliferation of the infused CAR T cells.

We have seen encouraging long-term reports. Four to 5 years [after] treatment, these patients have not needed any other therapy. About 82% of patients responded [to this modality] and 54% achieved a complete response (CR). This is interesting, because prior to this research, we had salvage therapy and autologous stem cell transplant, which many were not able to get to because they often get sick while receiving chemotherapy.

Historically, if you looked at patients with refractory lymphoma, within 1 year, many of them were in hospice or had died. Now, with CAR T-cell therapy, 54% of patients are achieving a CR and many have maintained durable responses for 4 or 5 years. As such, cellular therapy has changed the treatment paradigm. 

What are some of the targets that are currently under exploration?

When it comes to cellular therapy, we try to target something that is on the leukemia or lymphoma cell. The ones that we are targeting right now also exist on normal cells, but not believed to be on stem cells. As such, even if the CAR T-cell therapy wipes out the normal cells, over time, these cells can repopulate.

CD19 is one target but several other targets [are being examined]. Some FDA-approved or soon-to-be-approved products are targeting BCMA, which is a protein found on multiple myeloma cells and some B cell precursors. Others [products that are] under investigation are targeting CD20 in some lymphomas and leukemias, and CD22 in leukemias.

[Other products are being designed to] target more than one antigen simultaneously. If you only target 1 antigen, it is possible that the leukemia or lymphoma can escape by no longer expressing that target. However, if you target 2 antigens, you can increase the likelihood that the leukemia will not relapse. This method is still early in development.

What are some of the challenges with this modality?

CAR T cells are made from mature human T cells that have been engineered and redirected to target a tumor antigen. The method of engaging the antigen for destruction includes making a lot of cytokines that cause specific side effects including cytokine release syndrome (CRS). This can start as early as 1-4 days after infusion, can last up to 9 days, and consists of fever, low blood pressure and other symptoms. The field has learned how to adequately manage this adverse effect (AE) with agents such as tocilizumab (Actemra) and steroids. e are currently evaluating other ways to lessen the inflammation during treatment with CAR T-cell therapy. Being able to do this will improve make it easier for our patients to tolerate this therapy.

Other toxicities, such as neurological toxicity, have also been experienced; this occurs more often in patients who receive lymphoid-targeted products, although it has been described with almost all products. We are still learning more about what causes this toxicity, but it arises in the inflammatory process.

Some patients also experience delayed cytopenias which is sometimes related to the degree of intensity of the lymphodepleting regimen that they were given . Some protocols allow for the use of specific growth factors like G-CSF to minimize the impact of neutropenia.

Normal B cells are also reduced [with this approach], which could lead to B-cell aplasia. However, this is only temporary. Over time, normal B cells will repopulate.

What does the future of CAR T-cell therapy look like?

If anyone is going to hazard a guess as to what the future will look like, off-the-shelf products seem to be the way to go because we can avoid apheresis and the waiting period for the manufacturing of autologous CAR T cells. Even though this period can be as short as17 days, this is a long time for patients with relapsed/refractory disease. To transition to off the shelf products does have some nuances that need to be addressed. None of these products have obtained FDA approval yet, but several ongoing clinical trials are investigating [these approaches].

CAR T-Cell Therapy Transforms Leukemia and Lymphoma Treatment, But Toxicities Concerns Remain

Adverse Event Management