Updated American Society of Clinical Oncology (ASCO) guidelines advise offering patients with high-risk, early-stage human epidermal growth factor receptor 2 (HER2)-negative breast cancer and germline 

 mutations 1 year of adjuvant therapy with olaparib (Lynparza) following completion of neoadjuvant chemotherapy and local treatment, including radiation.

The recommendation follows a new ASCO initiative intent on providing clinicians with updated and timely guidelines that represent the latest practice-changing research. ASCO, the American Society for Radiation Oncology (ASTRO), and the Society of Surgical Oncology (SSO) will be updating their guidelines in accordance with the new recommendation.

The newly updated recommendation reflects data provided by the randomized OlympiA trial, which was published in the 

 and presented at the 2021 ASCO Annual Meeting.

The OlympiA trial found that patients with high-risk, HER2-negative early breast cancer and germline 

 pathogenic or likely pathogenic variants who had completed local treatment and neoadjuvant or adjuvant chemotherapy demonstrated significantly longer invasive and distant disease-free survival when receiving adjuvant olaparib compared with placebo.

The study did not indicate that olaparib had a meaningful effect on global patient-reported quality of life.

The pre-specified event interim analysis had a median follow-up of 2.5 years. In total, 1836 patients were randomized 1:1 to receive either oral olaparib or placebo. The primary end point was invasive disease-free survival.

At 3 years, invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group, while distant disease-free survival rates were 87.5% and 80.4%, respectively.

In addition, the olaparib group reported fewer deaths than the placebo group (59 vs. 86, respectively).

“The OlympiA trial was designed to test the efficacy of adjuvant PARP inhibitor therapy with olaparib in patients with early breast cancer and impaired 

 homologous-recombination function, identified by the presence of a 

 germline pathogenic or likely pathogenic variant as a patient-selection biomarker,” said Andrew N.J Tutt, MB, ChB, PhD, and colleagues. “The trial shows that olaparib given for 52 weeks as adjuvant therapy after neoadjuvant or adjuvant chemotherapy and local therapy resulted in significantly longer survival free of invasive or distant disease than placebo in such patients.”

Following randomization, routine medical history reports and physical examinations occurred at predetermined intervals: 4 weeks for the first 24 weeks, every 3 months from 24 weeks through year 2, every 6 months between 3 and 5 years, and annually thereafter.

Mammography and breast magnetic resonance imaging measured the development of metastatic diseases. Following a first event, patients were monitored for first distant relapse (if not the first event), central nervous system metastases, locoregional relapses, contralateral breast cancer, second primary cancers, and survival status.

As defined at the time of randomization, primary end points consisted of the date of the first occurrence of the following events: ipsilateral invasive breast tumor, locoregional invasive disease, distant recurrence, contralateral invasive breast cancer, second primary invasive cancer, or death from any cause, in accordance with the standardized definitions for efficacy end points (STEEP) system.

Disease-free survival, overall survival, and safety all served as secondary end points.

Adverse events (AEs) were consistent with those previously reported. The olaparib group did not report more serious AEs than the placebo group and the majority of AEs associated with olaparib were grade 1 or 2. In regard to toxic effects over grade 3, 8.7% of patients reported anemia but no other serious AE was reported by more than 5% of patients. Although the anemia infrequently led to infusion, dose interruption and reductions proved to be effective management strategies.

The 2021 updated recommendation is as follows: For patients with early-stage, human epidermal growth factor receptor 2 (HER

)–negative breast cancer with high risk of recurrence and germline 

 pathogenic or likely pathogenic variants, 1 year of adjuvant olaparib should be offered after completion of neoadjuvant chemotherapy and local treatment, including radiation. For those who had surgery first, adjuvant olaparib is recommended for patients with [triple-negative breast cancer (TNBC)] and tumor size > 2 cm or any involved axillary nodes for patients with hormone receptor-positive disease, adjuvant olaparib is recommended for those with at least 4 involved axillary lymph nodes. For patients who had neoadjuvant chemotherapy, adjuvant olaparib is recommended for patients with TNBC and any residual cancer. Adjuvant olaparib is recommended for patients with residual disease and an estrogen receptor status and tumor grade (CSP+EG) score ≥3.

ASCO News Release. ASCO releases rapid guideline recommendation update for certain patients with hereditary breast cancer. Published June 15, 2021. 

https://www.asco.org/about-asco/press-center/news-releases/asco-releases-rapid-guideline-recommendation-update-certain

Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer 

 2021; 384:2394-2405. doi:10.1056/NEJMoa2105215.

Articles

ASCO updated its guidelines following a presentation of the OlympiA trial presented at its 2021 Annual Meeting. 

New ASCO Guideline Recommends Adjuvant Olaparib for Patients with Hereditary Breast Cancer

The implementation of electronic patient-reported outcomes (ePRO) in community oncology clinics in Texas proved to be feasible and necessary for symptom monitoring among patients receiving chemotherapy, according to a poster presentation at the 2021 ASCO Annual Meeting.

The study noted that utilization of ePROS began high and began to diminish, calling for health care providers to address barriers and optimize compliance.

A collaborative 2-part study between Texas Oncology and Navigating Cancer demonstrated that symptom-management times can be improved through the utilization of digital health care tools and real-time clinical informatics. While the COVID-19 pandemic placed limitations on complete implementations, it also exacerbated the need for modernized communication between patients and health care providers. The results of this study support the use of ePROS to improve symptom management in routine clinical oncology care.

“ePRO symptom management has been shown to be effective in improving outcomes. Pivotal data that showed a reduction in health care resource utilization and improved survival in the academic setting is compelling to promote use,” described Debra Patt, MD, PHD, MBA, FASCO, executive vice-president of Texas Oncology, during a virtual presentation of the poster. “Community oncology practices are well-positioned to replicate these outcomes but have yet to be studied at scale.”

Prior to implementation, Navigating Cancer’s implementation specialist and organizational operation leaders collaborated to prepare a training and rollout plan. The specialist then educated clinical teams via recorded virtual sessions which will continue to be made available to staff for future use.

Upon initiating new systematic therapy for cancer diagnoses, Patients were invited to enroll in the Navigating Cancer ePRO platform.A clinical team introduced patients to the digital monitoring program and provided educational materials. Once patients authorized enrollment, they had access to additional guidance though the electronic interface.

Implementation reached across 7 Texas regions and 210 sites of service. There were weekly PRO assessments for a 6-month period, during which time, patients were observed via the ePRO health tracker. The tracker, a modified PRO CTCAE symptom instrument, included 14 of the most common cancer-related symptoms. Patients were queried about medication compliance and daily side effects. If a side effect presented itself, patients were asked to describe, in lengthier detail, the frequency of their pain and whether it interfered with their daily activities.

The majority of patients were older than 65 years, and White (73%) or non-Hispanic/Latino (75%).

Notable findings included the preference for self-reported SMS text messaging data collection as opposed to email or clinic collection: 89% of participants demonstrated a preference for SMS in comparison to email (6%) and manual collection (5%). Although compliance for participating patients remained fairly consistent, in week 10, response rates fell from 73% to 53%. Findings noted a higher compliance rate among patients undergoing oral therapy as opposed to intravenous therapy (73% vs. 61%, respectively).

Since this symptom-reporting instrument was completely implemented during the pandemic, possible compliance barriers could be the result of COVID-19: lack of caregiver presence, practice workflow alterations, clinician burnout, and new mental health stressors all have the capability to affect participation performance with the new technology. Furthermore, a lack of reminders or prompts for patients to respond to might also be responsible for non-reporting patients.

“We sought to understand implementation facilitators and barriers. I would say facilitators include patient and staff engagement, clinician reinforcement on the benefits of the digital monitoring program, and the ease of the use of the tool,” Patt summarized. “Although the COVID-19 pandemic introduced barriers to implementation, it also accelerated the need for modernization of communication between patients and clinicians. Utilization of real-time clinical informatics and digital health care tools can help provide just-in-time symptom management.”

“Most importantly,” Patt added, “implementation of ePROs for symptom monitoring across a large, multisite statewide cancer practice is feasible. And our findings support the inclusion of ePROs in routine clinical care.”

Future studies will address different populations of patients with cancer to continue optimizing the program. Symptom alert enhancements will also seek to strengthen patient engagement and discourage staff fatigue.

A presentation at the 2021 American Society of Clinical Oncology Meeting demonstrated that the use of electronic patient-reported outcomes in community oncology centers improved symptom-management. 

Texas Study Demonstrates Need for Electronic Patient-Report Outcomes in Oncology Centers

Patients with recurrent or metastatic nasopharyngeal carcinoma reported superior progression-free survival (PFS) with addition of immunotherapy agent toripalimab to gemcitabine plus cisplatin (GP) compared to patients undergoing chemotherapy alone.

The toripalimab regimen resulted in a median PFS of 11.7 months (95% CI, 11.0–not evaluable [NE]) via blinded independent review committee (BIRC) per RECIST v1.1 criteria vs 8.0 months (95% CI, 7.0-9.5) with chemotherapy alone (stratified HR, 0.52; 95% CI, 0.36-0.74; 

= .0003) in this population, according to data presented during a press briefing ahead of the 

 Additionally, the median overall survival (OS) was NE in both arms (stratified HR, 0.603; 95% CI, 0.364-0.997; 

“From this first international trial, we can see that the addition of toripalimab to GP as a first-line treatment for nasopharyngeal carcinoma showed better PFS and OS than GP alone. The combination was safe, and no new safety signals were found,” Rui-Hua Xu, MD, PhD, of Sun Yat-Sen University Cancer Center, China, said in a virtual presentation on the data. “These results support the use of the toripalimab combination as a new standard of care in the first-line treatment of patients with recurrent or metastatic [disease].”

Nasopharyngeal carcinoma is endemic in Southern China and Southeast Asia, according to Xu, who explained that the incidence of this cancer is 1.2 per 100,000 globally, while it is 3.0 per 100,000 in China. Moreover, patients with recurrent or metastatic disease have limited therapeutic options available to them, and the current standard-of-care frontline treatment worldwide for this population is GP.

The anti–PD-1 monoclonal antibody toripalimab was designed to block PD-1 interactions with its ligands PD-L1 and PD-L2 and strengthen receptor endocytosis function.2 The tumor checkpoint proteins PD-L1 and PD-L2 recognize the PD-1 receptor on T cells and deplete their antitumor activity. It is hypothesized that blocking PD-1 interactions with the proteins will result in a recharged immune system, boosting its ability to attack and eliminate cancer cells.

In February 2021, toripalimab was granted a conditional approval by the National Medical Products Administration of China for the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma in whom at least 2 prior lines of systemic treatment has failed.3

The regulatory decision was supported by data from the phase 2 POLARIS-02 trial (NCT02915432), where the agent elicited an objective response rate (ORR) of 20.5% (95% CI, 15.0%-27.0%), a median duration of response (DOR) of 12.8 months (95% CI, 9.4-NE), a median PFS of 1.9 months (95% CI, 1.8-3.5), and a median OS of 17.4 months (95% CI, 11.7-22.9) in the intent-to-treat population.4

In the global, double-blind, placebo-controlled phase 3 JUPITER-02 trial, investigators sought to examine toripalimab in combination with GP vs GP with placebo in the frontline treatment of patients with recurrent or metastatic nasopharyngeal carcinoma.

To be eligible for enrollment, patients needed to be between 18 and 75 years of age and have primary or metastatic nasopharyngeal carcinoma or recurrent disease following curative-intent treatment. Patients also needed to be treatment naïve for recurrent or metastatic disease, have an ECOG performance status of 0 or 1, and have measurable disease per RECIST v1.1 criteria.

A total of 289 participants from mainland China, Taiwan, and Singapore were randomized 1:1 to receive toripalimab at 240 mg plus GP every 3 weeks for 6 treatment cycles followed by toripalimab maintenance at 240 mg every 3 weeks, (n = 146) or GP plus placebo every 3 weeks for 6 cycles followed by placebo maintenance every 3 weeks (n = 143).

Patients were stratified based on disease (recurrent vs primary metastatic) and ECOG performance status (0 vs 1). Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, or a maximum of 2 years.

The primary end point of the trial was PFS per BIRC and RECIST v1.1 criteria, while secondary end points include PFS per investigator assessment, ORR, DOR, disease control rate, and OS, as well as 1- and 2-year PFS and OS rates.

Additional data from the trial showed that the 1-year PFS rates in the investigative and control arms were 49.4% (95% CI, 36.4%-61.1%) and 27.9% (95% CI, 18.0%-38.8%), respectively.

The OS data were not mature at the interim analysis, according to Xu. “Nine months after the interim analysis we observed a 40% reduction in risk of death in the toripalimab arm vs the placebo arm,” Xu said.

The 1-year OS rate achieved with the toripalimab regimen was 91.6% (95% CI, 85.6%-95.1%) vs 87.1% (95% CI, 80.4%-91.7%) with chemotherapy alone; the 2-year OS rates were 77.8% (95% CI, 68.0%-85.0%) and 63.3% (95% CI, 49.8%-74.1%), respectively.

Regarding safety, a similar incidence of any-grade adverse effects (AEs; 100% in both), grade 3 or higher toxicities (89.0% vs 89.5%), infusion reactions (any-grade, 4.1% vs 4.2%), and fatal AEs (2.7% vs 2.8%) was observed between the investigative and control arms, respectively. The most frequently reported grade 3 or higher AEs included leukopenia (61.6% vs 58.0%), neutropenia (57.5% vs 63.6%), and anemia (47.3% vs 39.9%).

“The most common AEs were hematologic toxicity, which were mainly attributed to the GP chemotherapy regimen,” Xu noted. “The incidence of immune-related AEs, such as hypothyroidism, were higher in the toripalimab arm; this was expected [with immunotherapy] and [proved to be] manageable.”

All-grade immune-related AEs were reported in 39.7% of patients who received the toripalimab regimen vs 18.9% of those who received chemotherapy alone; grade 3 or higher immune-related toxicities were experienced by 7.5% and 0.7% of patients, respectively.5

Additionally, more patients on the investigative arm discontinued treatment due to AEs compared with the control arm, at 7.5% and 4.9%, respectively.5

Study participants will continue to be followed for OS and other secondary end points.

“Treatment advances for late-stage nasopharyngeal carcinoma have lagged behind those of other cancers,” Julie R Gralow, MD, FACP, FASCO, chief medical officer and executive vice president of ASCO, commented in a press release about the trial.5 “Findings from the JUPITER-02 study offer new hope for patients with advanced disease, changing how we care for them.”

Xu R-H, Mai H-Q, Chen Q-Y, et al. JUPITER-02: the randomized, double-blind phase 3 study of toripalimab or placebo plus cisplatin and gemcitabine as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC). 

Anti-PD-1 monoclonal antibody candidate toripalimab. Coherus Biosciences website. Accessed June 2, 2021. 

NMPA approves toripalimab in patients with recurrent or metastatic nasopharyngeal carcinoma after failure of at least two lines of prior systemic therapy. News release. Junshi Biosciences. February 22, 2021. Accessed June 2, 2021. 

Wang F-H, Wei X-L, Feng J, et al. Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase II clinical trial (POLARIS-02). 

. 2021;39(7):704-712. doi:10.1200/JCO.20.02712

Addition of immunotherapy to standard of care first-line regimen delays disease progression in advanced nasopharyngeal carcinoma. News release. ASCO. June 3, 2021. Accessed June 3, 2021. 

This article was originally published on OncLive as 

“Frontline Toripalimab Plus Gemcitabine/Cisplatin Significantly Improves PFS in Recurrent or Metastatic Nasopharyngeal Carcinoma.”

Data from the phase 3 JUPITER-02 trial (NCT03581786) suggests that frontline toripalimab plus gemcitabine/cisplatin improves progression-free survival (PFS).

Patients with Recurrent or Metastatic Nasopharyngeal Carcinoma Report Improved PFS with Frontline Toripalimab Plus Gemcitabine/Cisplatin

Updated data from the phase 3 CheckMate-648 trial (NCT03143153) revealed that the addition of nivolumab (Opdivo) to either ipilimumab (Yervoy) or chemotherapy was associated with improved survival outcomes in the frontline treatment of patients with unreselectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) in comparison to chemotherapy alone, according to a presscast presentation ahead of the 2021 ASCO Annual Meeting.

“Advanced esophageal squamous cell carcinoma carries a poor prognosis, with a median survival of around 10 months,” said Ian Chau, MD, FRCP, consultant medical oncologist at the Royal Mardsen Hospital in the United Kingdom, while presenting the findings during the presscast.

CheckMate-648 is a randomized phase III trial that was presented at a presscast ahead of the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting evaluating the efficacy of the following treatment regimens in adult patients with histologically confirmed squamous cell carcinoma or adenosquamous cell carcinoma of the esophagus that is deemed inoperable and cannot be treated with chemoradiation with curative intent:

: nivolumab 240 mg on day 1 and day 15; fluorouracil 800 mg/m2 per day on day 1 through day 5, for 5 days; and cisplatin 80 mg/m2 on day 1 of the 4-week cycle (n = 321).

: nivolumab 3 mg/kg every 2 weeks, followed by ipilimumab 1mg/kg every 6 weeks until unacceptable toxicity or disease progression (n = 325).

Eligible patients had an ECOG PS score of 0 to 1, measurable disease, and no prior systemic treatment for advanced disease. The primary end points in the trial were overall survival (OS) and progression-free survival (PFS) in patients whose tumors had PD-L1 expression ≥ 1%. Secondary end points were OS and PFS in all patients, as well as objective response rate (ORR), both in patients with PD-L1 ≥ 1% and all patients.

At a minimum follow-up of 12.9 months, median OS in patients with PD-L1 ≥ 1% in the nivolumab plus chemotherapy arm (n = 158) was 15.4 months (95% CI, 11.9-19.5), and was 13.7 months (95% CI, 11.2-17.0) in the nivolumab plus ipilimumab arm (n = 158). In the PD-L1-positive patients in the chemotherapy alone arm (n = 157) median OS was 9.1 months (95% CI, 7.7-10.0; 

“This translates into over 6 months [of] improvement in median overall survival [when comparing nivolumab plus chemotherapy to chemotherapy alone],” Chau said. “But importantly, if you look at the latter parts of the overall survival curve, they’re widely separated in favor of nivolumab plus chemo, meaning that there were more patients with prolonged overall survival.”

In the overall study population–regardless of PD-L1 expression–the median OS in the nivolumab plus chemotherapy arm was 13.2 months (95% CI, 11.1-15.7); 12.8 months in the nivolumab plus ipilimumab arm (95% CI, 11.3-15.5 months); and 10.7 months in the chemotherapy arm (95% CI, 9.4-11.9; 

The primary end point of PFS per blind independent committee review (BICR) was not met in patients whose tumors were PD-L1 positive (HR, 1.02; 95% CI, 0.73-1.43).

The ORR in patients with PD-L1-positive tumors given nivolumab plus ipilimumab was 35% (95% CI, 28-43). In the chemotherapy arm it was 20% (95% CI, 14-27). In all patients, ORR was 28% (95% CI, 23-33) and 27% (95% CI, 22-32) in the nivolumab plus ipilimumab and nivolumab plus chemotherapy arms, respectively.

Regarding safety, the most common (occurring in 10% or more) treatment-related adverse events (TRAEs) for the chemotherapy-containing arms were nausea, decreased appetite, and stomatitis. For the nivolumab/ipilimumab arm, common TRAEs were rash, pruitis, and hypothyroidism. Notably, incidence of TRAEs was consistent with all treated patients across all arms for patients whose tumor cell had PD-L1 expression ≥ 1%.

Ultimately, nivolumab-containing regimens have the potential to drastically improve outcomes in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma–a group that tends to have poor prognoses.

“Nivolumab plus chemotherapy [and] nivolumab plus ipilimumab each represents a new potential first-line standard of care for patients with advanced esophageal squamous cell carcinoma, based on the results of CheckMate-648, the largest randomized control trial conducted in this setting to date,” Chau said.

Chau I. First results from the CheckMate 648 study evaluating nivolumab plus ipilimumab or nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma. Presented at: 2021 ASCO Annual Meeting Press Program, May 28, 2021.

A study to evaluate efficacy in subjects with esophageal cancer treated with nivolumab and ipilimumab or nivolumab combined with fluoraucil plus cisplatin versus fluorouracil plus cisplatin (CheckMate648). Clinicaltrials.gov. Updated May 7, 2021. Accessed June 1, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03143153

This article was originally published on OncLive as “Frontline Nivolumab Plus Ipilimumab or Chemo Improves Survival Outcomes in Advanced ESCC"

Survival outcomes in the frontline treatment of patients with unresectable advanced or metastatic esophageal squamous cell carcinoma were improved when nivolumab was added alongside either ipilimumab or chemotherapy.

Patients With Advanced ESCC Experience Improved Survival Outcomes With Addition of Nivolumab to Ipilimumab or Chemotherapy 

The implementation of electronic patient management solutions at a community oncology practice was associated with an 8% hospital avoidance for symptom-related incidents, according to a collaborative research effort between Texas Oncology and Navigating Cancer presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Through the use of Navigating Cancer’s triage care management tool, call-back times, particularly for symptom-related calls, were markedly reduced.

Researchers hope that the utilization of this technology can result in a meaningful reduction in hospitalization and emergency department (ED) visits by allowing nurses and health care professionals to communicate with patients in a timelier manner.

The study, which started in the fourth quarter of 2019 and continued until December 2020, showed that the electronic dashboard had a positive impact in reducing call back times. Pre-implementation call-back times started at 3.2 hours for all incidents and 2.3 hours for symptom-related incidents. By December 2020, resolution times had improved to 2.2 hours for all incidents and 1.5 hours for symptom-related incidents.

These findings are important because the preliminary data suggests that managing symptoms in a timely fashion will lower overall ED visits and hospitalizations. “Patients routinely complained that, if they called our clinics, their calls were not answered quickly,” explained lead study author Lalan Wilfong, MD, Texas Oncology, at the virtual conference. “We hypothesized that we needed a better system of managing patient phone calls so that we could get them in our offices and take care of them, rather than them having to go to the emergency room.”

The Care Management Tool allowed documentation of all inbound patient calls and incidents, which were then made visible to the entire care team. Patients could easily input answers to questions regarding their symptoms and medication compliance. Calls with high risk-symptoms, such as fevers of 102 degrees, were flagged as needing to be prioritized.

Automated task assignments helped to streamline care coordination so that nurses were able to reach patients in an appropriate and timely fashion. After a nurse has called a patient back, they then resolve the call with documentation. Furthermore, the symptom management pathways established consistency across clinics and their systems of triaging, managing, and documenting symptoms and adverse events. 

By the conclusion of 2020, the research team was successfully able to not only return all calls but resolve them within a 2-hour time frame. Return times for symptom-related calls improved to under 90 minutes, at 1.4 hours, and 60% of symptom-related calls were managed within the hour. The majority of symptom-related incidents were therefore being taken care of in less than an hour.

“We hope that this has significant effects on reducing our hospitalization and ED visits for our patient population by simply taking care of them quickly, and answering the phone, and resolving their calls in a timely fashion,” said Wilfong.

Future efforts will include finding ways to continue improving the reduction in call-back times with the intention of having all symptom-related calls attended to under an hour. Team research objectives will involve evaluating whether the implementation of the electronic patient management technology successfully lowers hospitalization and ED visits as well as conducting surveys to determine whether the use of such technology results in higher patient satisfaction.

Wilfong L, Patel A, Ortega L, et al. Improvement in incident resolution time with implementation of electronic patient management solution at a community oncology practice. 

A Texas study revealed that the implementation of electronic patient management solutions resulted in reduced call back times for symptom-related calls as well as reduced hospitalizations. 

Triage Care Management Tool Associated with 8% Hospital Avoidance 

While cabozantinib (Cabometyx) exposure was not a predictor of progression-free survival, it was related to high rate of palmar-plantar plantar erythrodysesthesia (PPE) and diarrhea in patients with advanced renal cell carcinoma (RCC) who are given frontline cabozantinib plus nivolumab (Opdivo). These findings, which were a part of an exposure-response analysis of the phase 3 CheckMate 9ER trial, were presented during the 2021 ASCO Annual Meeting.

“ER modeling predicts that appropriate dose modification of the 40-mg cabozantinib starting dose to manage AEs [adverse effects] will not adversely affect the efficacy of nivolumab plus cabozantinib in first-line advanced RCC,” lead study author Amishi Y. Shah, MD, an assistant professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, and co-authors wrote in a poster of the data.

The CheckMate 9ER trial revealed that the frontline combination of nivolumab plus cabozantinib significantly improved PFS (HR, 0.51; 95% CI, 0.41-0.64; 

 < .001), overall survival (OS; HR, 0.60; 95% CI, 0.40-0.89; 

 < .001) compared with sunitinib (Sutent) in patients with advanced RCC.

In the study, patients with previously untreated RCC received 40 mg of cabozantinib daily in combination with 240 mg of nivolumab every 2 weeks.

The regimen was generally well tolerated among patients, with low rates of treatment-related discontinuations. Dose modifications appeared to successfully manage AEs and allow patients to tolerate the regimen.

Patients (n = 320) received a median average daily dose of 29.4 mg of cabozantinib in the CheckMate 9ER trial. First-level dose reductions of cabozantinib to 20 mg daily because of AEs were observed in 50% (n = 161) of patients after a median time of 98 days (range, 9-506). Second-level dose reductions of cabozantinib to 20 mg every 2 days were observed in 8.1% of patients (n = 26) after a median time of 173 days (range, 65-613).

Because of AEs, 7.5% of patients (n = 24) discontinued cabozantinib, 6.6% of patients (n = 21) discontinued nivolumab, and 5.6% of patients (n = 18) discontinued both agents.

With a database lock date of March 30, 2020, investigators sought to understand the relationship between cabozantinib exposure, and the efficacy and safety outcomes observed in the CheckMate 9ER trial utilizing time-to-event Cox proportional hazard ER models.

The models evaluated specified end points, including PFS, dose modifications (holds or reductions), and select AEs, such as grade 1 or greater PPE, grade 3 or greater diarrhea, grade 3 or greater hypertension, grade 3 or greater fatigue/asthenia, and grade 3 or greater alanine aminotransferase (ALT)/aspartate aminotransferase (AST) increase.

“Cabozantinib exposure was defined as the overall average concentration from time zero to time of event or censoring [CAVG0T] for each end point and estimated by population pharmacokinetic modeling,” Shah and co-authors wrote.

As of the database lock date, survival data were immature, so the relationship between OS and cabozantinib exposure was not assessed.

Regarding end points, the number of patients at risk receiving 1 or more doses of cabozantinib were 311 for PFS, 318 for dose modification, 320 each for PPE, diarrhea, hypertension, and fatigue/asthenia, and 317 for ALT/AST elevation. Of these, the number of patients with 1 or more measurable cabozantinib concentration was 303 for PFS, 306 for dose modification, 308 each for PPE, diarrhea, hypertension, and fatigue/asthenia, and 307 for ALT/AST elevation.

Regarding the number of events by end point, the number of patients receiving at least 1 dose of cabozantinib was 144 for PFS, 285 for dose modification, 128 for PPE, 22 for diarrhea, 44 for hypertension, 24 for fatigue/asthenia, and 35 for ALT/AST elevation. Of these, patients with at least 1 measurable cabozantinib concentration included 139 for PFS, 279 for dose modification, 128 for PPE, 21 for diarrhea, 44 for hypertension, 23 for fatigue/asthenia, and 34 for ALT/AST elevation.

In evaluable populations, patients were a median age of 62 years (range, 29-90), with a median body weight of 80.3 kg (range, 36.0-159.3), and the majority of patients (77%) were male with high Karnofsky Performance Statuses (≥90, 79%) and low lactase dehydrogenase (≤1.5 x upper limit of normal, 94%). The median nivolumab clearance was 0.009 L/h (range, 16.0-53.4).

The target lesions were a median of 69 mm (range, 10-330). Most patients did not have prior radiotherapy (86%) but underwent prior nephrectomy (69%).

Most patients (65%) were randomized to treatment in the CheckMate 9ER trial less than 1 year from initial diagnosis.

The majority of patients (74%) had a baseline PD-L1 status of less than 1% or an indeterminate status and International Metastatic RCC Database Consortium (IMDC) scores of 1 or 2 (58%).

In the PFS analysis population (n = 303), more favorable IMDC scores were observed in patients in higher exposure quartiles. However, baseline characteristics were generally similar otherwise.

Further results revealed that cabozantinib exhibited higher interpatient variability in apparent clearance (n = 306; median 1.93 L/h; range, 0.64-10.3) and average exposure (n = 303; median 564.6 ng/mL; range, 29.3-1995).

With regard to PFS, the median exposure in quartile 4 was 848.1 ng/mL (HR relative to CAVG0T, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 302.3 ng/mL (HR, 0.99; 95% CI, 0.71-1.40) in quartile 1, 485 ng/mL (HR, 1.00; 95% CI, 0.79-1.25) in quartile 2, and 641.2 ng/mL (HR, 1.00; 95% CI, 0.88-1.14) in quartile 3. Overall, this suggested that PFS was not different between cabozantinib exposure quartiles.

Regarding the development of grade 1 or greater PPE, the median exposure in quartile 4 was 872.1 ng/mL (HR relative to CAVG0T, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 318.9 ng/mL (HR, 0.51; 95% CI, 0.37-0.70) in quartile 1, 512.5 ng/mL (HR, 0.65; 95% CI, 0.53-0.80) in quartile 2, and 658.6 ng/mL (HR, 0.77; 95% CI, 0.68-0.87) in quartile 3.

Regarding the development of grade 3 or higher diarrhea, the median exposure in quartile 4 was 825.1 ng/mL (HR relative to CAVG0T, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 312.2 ng/mL (HR, 0.38; 95% CI, 0.19-0.75) in quartile 1, 471.2 ng/mL (HR, 0.51; 95% CI, 0.32-0.82) in quartile 2, and 606.9 ng/mL (HR, 0.66; 95% CI, 0.49-0.88) in quartile 3.

“The risk of developing PPE or diarrhea was greater at higher cabozantinib exposure quartiles; there was not association for hypertension, fatigue/asthenia, or AST/ALT elevation,” wrote Shah and co-authors.

Regarding dose modifications, the median exposure was 2.96 L/h in clearance quartile 4 (HR relative to CL/F, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 1.32 L/h (HR, 1.20; 95% CI, 0.91-1.57) in quartile 1, 1.74 L/h (HR, 1.13; 95% CI, 0.94-1.35) in quartile 2, and 2.19 L/h (HR, 1.07; 95% CI, 0.97-1.18) in quartile 3.

“The risk of cabozantinib dose modification increased with decreasing cabozantinib clearance but was not significantly different between cabozantinib clearance quartiles,” Shah and co-authors wrote.

Additionally, cabozantinib exposure was not found to be a statistically significant predictor of PFS, and the rate of progression or death was not significantly associated with daily cabozantinib exposure (20 mg vs 40 mg). CAVG0T was 386 ng/mL at the 20 mg daily dose vs 772 ng/mL at the 40 mg daily dose (HR, 1.00; 95% CI, 0.78-1.27).

Increased cabozantinib exposure was significantly associated with an increased risk of PPE (HR, 0.63; 95% CI, 0.50-0.78) and diarrhea (HR, 0.48; 95% CI, 0.29-0.80), but no significant exposure-response relationships were identified for hypertension, fatigue/asthenia, or ALT/AST elevation.

Although not statistically significant, higher cabozantinib clearance was associated with a lower rate of cabozantinib dose modification (2.2 L/h vs 1.2 L/h; HR, 0.87; 95% CI, 0.71-1.07; 3.2 L/h vs 1.2 L/h; HR, 0.80; 95% CI, 0.57-1.12).

A multivariable analysis with backward elimination showed that certain baseline patient characteristics, including sex, nivolumab clearance, and baseline albumin, were significant covariates. Patients with higher baseline nivolumab clearance or lower baseline albumin levels were predicted to have higher rates of disease progression or death.

Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib exposure-response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma. 

 2021;39(suppl 15):4561. doi:10.1200/JCO.2021.39.15_suppl.4561

While cabozantinib exposure was not a predictor of progression-free survival, it was related to high rate of palmar-plantar plantar erythrodysesthesia  and diarrhea in patients with advanced renal cell carcinoma who are given frontline cabozantinib plus nivolumab. 

Cabozantinib Associated With Higher Rates of Certain AEs in Advanced Kidney Cancer

Each year at the American Society of Clinical Oncology Annual (ASCO) Congress, researchers from around the globe present on the latest updates in cancer care. Here’s a list of some of the key takeaways for oncology nurses.This year, there were many takeaways from the American Society of Clinical Oncology Annual Meeting that oncology nurses can incorporate into their practice

ASCO 2021: Top Takeaways for Oncology Nurses

For comprehensive and ongoing coverage of the ASCO Annual Meeting, visit 

https://www.oncnursingnews.com/conference/asco

This year, there were many takeaways from the American Society of Clinical Oncology Annual Meeting that oncology nurses can incorporate into their practice.

ASCO 2021: Top Nursing Takeaways

The use of integrative palliative care can improve coping skills, thus bettering quality of life in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy. That said, it is essential that oncology nurses advocate for palliative care for patients who could benefit from it.

“Often what we have found in our practice – and certainly in our studies – is that nurses and nurse clinicians are begging for palliative care specialists to be invited to see these patients, and it’s often the attending physicians who are saying, ‘we don’t really need that’ or ‘the patient isn’t ready for that yet,” said Thomas W. LeBlanc, MD, associate professor of medicine at the Duke University School of Medicine, noting that some people still believe the misconception that palliative care is synonymous with end-of-life care (hospice).

LeBlanc recently presented his research on palliative care in patients with AML at the 2021 ASCO Annual Meeting.

The study analyzed quality of life, depression, and anxiety symptoms for patients with AML who are in their second week of treatment with induction therapy. Researchers chose the second week of treatment because that is when patients tend to feel the worst. Two groups were compared: the integrated palliative and oncology care (IPC) cohort that saw palliative care clinicians at least twice a week while hospitalized (n=86) versus usual care (n=74).

Findings showed that the patients randomized to IPC had more approach-oriented coping skills and less avoidant-oriented coping skills. The interventions effects on those given IPC who had approach-oriented coping were sustained all the way up until week 24.

An improvement in coping skills was correlated with improved quality of life and decreased depression and anxiety symptoms.

Nurses treating this patient population can understand how life-changing improved quality of life can be for patients with AML.

“Nurses are often the ones who are seeing and witnessing the suffering of these patients and their families because they’re in the room 11 out of the 12 hours of their shift,” LeBlanc said. “The nurses have an incredible opportunity and really also (a) responsibility to be the voice of the patient, who maybe doesn’t know how to articulate that they’re really suffering with something that we’re not doing a good job managing.”

Not only do nurses have to advocate for palliative care to the clinicians and other members of the treatment team, but they must also ensure that patients and their families understand the benefit of receiving palliative services as well.

“The mistake that often is made is that we kind of go in with our tail between our legs, because we’re afraid that patients are going to get freaked out when they hear the P-word. Even though most [patients] have heard it, they don’t know what it means,” LeBlanc said.

LeBlanc recommends clinicians approach the conversation with a script similar to this:

“We’re going to call another group of specialists to come and see you. They’re called palliative care specialists, and they’re experts in helping patients and families deal with the stresses and symptoms that go along with having a serious illness like AML. I have found that they often can really help people feel better with symptom management and help improve or maintain quality of life or help you cope with anxieties that can come along with having this diagnosis and getting treatment.”

Laying down the basics for what palliative care actually is – and what it is not – can greatly sway patients’ opinions.

“We know from other studies that when patients and families hear an explanation of what palliative care is, and how it might be helpful to them, they just about universally want it,” LeBlanc said.

LeBlanc TW, Kavanaugh A, Webb J, et al. Palliative care and coping in patients with acute myeloid leukemia receiving intensive induction therapy: A Mediation analysis of data from a randomized trail. Presented at: 2021 ASCO Annual Meeting. June 4-8, 2021. Virtual

Learn how to approach palliative care discussions with both physicians and patients. 

Nurses Have the Responsibility to be the ‘Voice of the Patient’ in Palliative Care Advocacy

Treatment with the second-generation 4-1BB bi-specific chimeric antigen receptor (CAR) T-cell therapy C-CAR039 led to improved response rates – as well as a favorable safety profile – in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL), according to phase 1 data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

“C-CAR039 has demonstrated a favorable safety profile and highly promising efficacy in patients with relapsed/refractory B-NHL,” Aibin Liang, MD, Tongji Hospital of Tongji University, Shanghai, China, said during an oral presentation of the data.

According to the safety data, 100% of patients experienced at least 1 adverse event (AE) of any grade.

In total, 92.9% of patients reported cytokine release syndrome (CRS); however, Liang noted, that most were grade 1 or 2 and all events were reversible. Only 1 patient, who was treated in the 2.5x106 CAR T cells/kg, experienced grade 3 CRS. The most common symptoms were pyrexia (100%) and hypotension (23.1%).

The median time to onset of CRS events was 2.5 days (range, 0-10), with a median time to resolution of 4 days (range, 1-25). CRS cases were treated with tocilizumab (14.3%), corticosteroids (3.6%), or a combination of the 2 (3.6%).

Two cases of neurologic events – both in the 5.0x106 CAR T cells/kg group – occurred at a median time of onset of 16 days (range, 4-28). The median time to resolution was 31.5 days (range, 11-52).

“CRS in higher dose groups showed shorter time to onset and longer resolution time,” Liang said.

Cytopenias were common, “mostly related to Cy/Flu lymphodepletion and are reversible,” he added, noting that infection was also common, occurring in 53.6% of patients, with only 1 grade 3 event.

The most common grade 3 or higher AEs included lymphopenia (96.$%), leukopenia (89.3%), neutropenia (89.3%), anemia (32.1%), and thrombocytopenia (25%).

For efficacy, median follow-up was 7 months (range, 1.9-17.2).

The overall response rate (ORR) was 92.6% for the entire population, including an 85.2% complete response (CR) rate, 7.4% partial response (PR) rate, 3.7% with stable disease (SD), and 3.7% with progressive disease (PD). Broken down by disease subtype, ORR in those with diffuse large B-Cell Lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), follicular lymphoma (FL), and tFL were 91.7% (CR, 83.3%; PR, 8.3%), 100% (CR, 100%), 100% (CR, 100%), and 100% (CR, 100%), respectively. Liang noted that the CR rate was consistent among key subgroups, including dose level, disease type, cell or origin of cancer, age, sex, stage, IPI, double expressors, extranodal disease, prior lines of therapy, previous response status, previous ASCT, and bridging treatment.

The median time to first response was 1 month (range, 0.9-1.6), as was median time to CR (range, 0.9-6.0). Four patients relapsed at 3, 6, 8, and 9 months, respectively, after achieving CR. Median duration of response (DOR) has not been reached. The 6-month progression-free survival (PFS) was 83.2% (95% CI, 69.1-100).

“C-CAR039 proliferation and expansion in the peripheral blood correlated with B cell depletion,” Liang added.

C-CAR039 – a novel second generation 4-1BB bi-specific CAR T-cell therapy that targets both CD19 and cd20 antigens – has demonstrated in vitro anti-tumor activity against both single- and double-positive CD20/CD19-expressing tumors, as well as superior anti-tumor activity in both in vitro and in vivo to the bi-specific CAR T-cell therapy with the tandem linked scFvs of Leu16 and FMC63, Liang explained.

“This data strongly support moving this CAR design to clinic use as the lead asset,” he added.

Manufacturing the CAR T-cell therapy was carried out in a functionally closed, highly automated serum free system within a median of 6 days (range, 5-11). Median vein-to-vein time was 19 days (range, 12-67).

Dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen.

The phase 1 study is an open-label, dose escalation and expansion study conducted across 4 sites in China – designed to evaluate the safety and efficacy of this approach in patients with relapsed/refractory B-NHL.

Investigators administered C-CAR039 as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen.

Eligibility criteria included patients aged 18 to 75 years; relapsed/refractory B-NHL, including DLBCL, FL, and mantle cell lymphoma (MCL); either CD19- or CD20-positive disease; no active central nervous system (CNS) involvement; and have received anti-CD20 monoclonal antibodies.

The safety assessment included the incidence and severity of treatment-emergent adverse events (TRAEs), while the efficacy assessment was comprised of ORR, DOR, PFS, and OS.

In the trial, patients were treated across 3 doses: 1.0x106 CAR T cells/kg (DL1), 2.5x106 CAR T cells/kg (DL2), and 5.0x106 CAR T cells/kg (DL3).

As of April 20, 2021, 34 patients were infused with C-CAR039. In total, 28 were evaluable for safety, including 4 in the DL1 arm, 15 in the DL2 arm, and 9 in the DL3 arm; while 27 were evaluable for efficacy, including 4 in the DL1 arm, 15 in the DL2 arm, and 8 in the DL3 arm.

Median age was 55.5 years (range, 28-71). The majority of patients were male (89.3%), had diffuse large B-cell lymphoma (89.3%), an ECOG performance score of 0 (64.3%), and were Ann Arbor stage III/IV (75%). Moreover, 8 patients (28.6%) had double-expressor lymphoma.

The median number of prior lines of therapy was 3 (range, 1-5), including ASCT (17.9%), a BTK inhibitor (28.6%), and lenalidomide (Revlimid; 32.1%). Eight patients (28.6%) had never experienced a CR to prior therapies and 5 patients (17.9%) received bridging therapy.

“The early clinical efficacy signal is encouraging and compares favorably to anti-CD19 CAR T and peer therapies,” the study authors concluded. “These findings will be evaluated in more patients with longer follow-up to confirm safety, efficacy and duration of response.”

Liang A, Zhou L, Li P, et al. Safety and efficacy of a novel anti-CD20/CD19 bi-specific CAR T-cell therapy (C-CAR039) in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). 

. 2021;39:suppl 15; abstr 2507. doi: 10.1200/JCO.2021.39.15_suppl.2507.

The second-generation 4-1BB bi-specific CAR T-cell therapy was efficacious and safe in treating patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Second-Generation CAR T-Cell Therapy Is ‘Highly Promising’ in Relapsed/Refractory B-NHL

In previously treated patients with chronic lymphocytic leukemia (CLL) that harbors del(17p) or del(11q), acalabrutinib (Calquence) had similar survival rates but fewer adverse events than ibrutinib (Imbruvica), according to findings presented at the 2021 ASCO Annual Meeting.

“Acalabrutinib is a more selective inhibitor of [Bruton tyrosine kinase (BTK)] and has been known to have less adverse events (AEs) when compared across trials. [Until] today, no clinical trial has directly compared ibrutinib to acalabrutinib in previously treated CLL. Our trial presented here does this,” said John C. Byrd, MD, professor of hematology at The Ohio State University.

Byrd presented findings from an open-label, randomized, noninferiority, phase 3 trial that compared acalabrutinib and ibrutinib in 533 patients.

Survival rates were similar between the 2 drugs, but acalabrutinib had fewer adverse events.

ASCO Annual Meeting