Adavosertib plus irinotecan showed early activity in a cohort of pediatric patients with neuroblastoma, thus meeting the protocol-defined efficacy end point of the 1/2 ADVL1312 trial (NCT02095132), which was presented virtually during the AACR Annual Meeting 2021.

Moreover, adavosertib plus irinotecan also showed the potential to benefit patients with 

-mutant tumors, with further validation required for this effect.

“In order to look for an early signal of activity and to obtain more information regarding toxicity of the recommended phase 2 dose, the ADVL1312 trial proceeded with a phase 2 expansion in 3 pediatric disease-specific cohorts,” presenting author Kristina A. Cole, MD, PhD, of Children’s Hospital of Philadelphia and Perelman School of Medicine of the University of Pennsylvania, said in the presentation of the data.

The 3 pediatric cohorts analyzed in the expansion phase of this trial included neuroblastoma (n = 20), medulloblastoma with central nervous system (CNS) embryonal tumors (n = 10), and rhabdomyosarcoma (n = 10).

Overall, 3 objective responses were recorded from 16 eligible patients in the neuroblastoma cohort, which met the protocol-defined efficacy end point. Meanwhile, there was 1 recorded objective response in the group with medulloblastoma and CNS embryonal tumors and no responses with rhabdomyosarcoma, respectively.

The investigative team also sought to determine factors correlated with clinical response, focusing on the 

 chromatin remodeler gene. Twelve of the archival ADVL1312 tumors were evaluated.

Ultrabright telomeric foci (UBTF) were present in tumors from 2 of the 3 patients who experienced an objective response. More, ATRX deficiency was present in 4 of the 9 patients with clinical response or stable disease.

Common grade 3 or higher adverse events included neutropenia (5 events in the neuroblastoma cohort; 4 events in medulloblastoma; and 3 events in rhabdomyosarcoma), lymphopenia (4 events; 2 events; and 1 event, respectively), and leukopenia (2 events vs 2 events vs 0 events).

More, the toxicity profile of ADVL1312 featured no dose-limiting toxicities at cycle 1 or later at the maximum-tolerated dose. Regardless of this finding, and although the combination was well tolerated, the investigative team notes that oral irinotecan is not palatable.

The investigative team utilized the phase 2 data from irinotecan to inform the efficacy end point for the combination therapy analyzed in the expansion portion of ADVL1312. In order to define the therapy as effective in the neuroblastoma and rhabdomyosarcoma cohorts, 3 objective responses out of 20 eligible patients were required. More, 6 response out of 19 eligible patients were required for efficacy in the medulloblastoma with CNS embryonal tumors cohort.

“Several of the limitations of this study relate to the fact that it was a phase 2 expansion,” explained Cole. “For example, patients were eligible for response regardless of if they completed a cycle of therapy or had their disease reevaluated. One-third of patients discontinued therapy with stable disease or better.”

Median age for patients in the neuroblastoma cohort was 9 years (range, 6-19), with a majority of patients being male (65%) and White (60%). In the medulloblastoma cohort, the median age was 13.5 years (range, 6-20), with a majority of patients female (60%) and White (70%). Lastly, the rhabdomyosarcoma cohort reported a median age of 11 years (range, 4-16) with 80% of patients reporting as male and 90% of patients reporting as White.

Looking ahead, because of the satisfaction with the preliminary findings in this expansion trial, Cole noted that an adavosertib pediatric development plan is being discussed.

Cole KA, et al. Pediatric phase 2 trial of the WEE1 inhibitor adavosertib (AZD1775) and irinotecan; A Children’s Oncology Group Study (ADVL1312). Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT029.

This article was originally published on OncLive as, "

Adavosertib/Irinotecan Shows Early Activity in Pediatric Neuroblastoma

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Overall, 3 objective responses were recorded from 16 eligible patients in the neuroblastoma cohort, which met the protocol-defined efficacy end point.

Drug Combo Shows Early Activity in Pediatric Neuroblastoma Treatment

The implementation of nurse breast navigators resulted in trends towards less frequent refusal of care by patients diagnosed or receiving treatment, according to a poster published at the 2020 San Antonio Breast Cancer Symposium (SABCS).

Researchers found that lower refusal rates of chemotherapy and hormonal therapy were the areas of treatment most effected by the implementation of nurse breast navigation.

The team of researchers compiled a tumor registry comprised of patients diagnosed or treated at a minimum of 1 time at the Grady Cancer Center for Excellence. Then, they conducted a tumor registry audit of refusal of care as coded by “patient or patient guardian refused care” for 2-time intervals of pre- (2016-2017) and post-nurse navigation (2018-2019).

Patients who were diagnosed at the Grady Cancer Center for Excellence but were treated elsewhere (out-migration of breast cancer patients) was also an audited group for the same time intervals.

In the pre-nurse navigation period, a total of 325 patients with breast cancer were analyzed with 58 (17.8%) refusing care. During the post-nurse navigation period, 376 patients were seen with 50 (13.2%) refusing care (P = 0.128).

The overall refusal of care rates decreased from 17.8% during the pre-nurse navigation period to 13.2% during the post-nurse navigation period. The out-migration rates of patients with breast cancer during both time periods was 3.6%.

“While there was no difference in “out-migration” to other cancer centers identified during this time interval, the number of patients leaving the system remains low,” wrote the researchers in their study’s presentation poster for SABCS 2020.

During the pre-nurse navigation period, when breaking down the data according to treatment refusal by the type of recommended care, 29 patients refused chemotherapy, 18 refused hormonal therapy, 0 refused immunotherapy, 22 refused radiation therapy, and 10 refused surgery.

For the post-nurse navigation period, 18 patients refused chemotherapy, 12 refused hormonal therapy, 2 refused immunotherapy, 24 refused radiation therapy, and 12 refused surgery. It’s noted in the poster that the rates of refusal for different treatment types varied between the 2 different time periods analyzed.

The researchers used Grady Memorial Hospital in Atlanta, Georgia as their safety net hospital, and the Georgia Cancer Center for Excellence at Grady received a Merck Foundation grant in which it introduced a nurse navigator to the breast cancer program on January 1, 2018.

Grady Memorial Hospital treats a diverse and medically underserved population, with a reported 28% of patients who are uninsured. The grant was awarded to “improving care for vulnerable cancer patients.”

The nurse navigators meet with all of the newly diagnosed breast cancer patients during clinic. More, they track the progression of care for these patients, occasionally intervening for timeliness of work-up and for treatment.

“We plan to continue to track our navigated patients and collect patient satisfaction information with navigation as a future initiative,” wrote the researchers.

Rehr C, Coples S, Wang Z, et al. The Impact of Nurse Navigation on Adherence to Care for Patients Treated for Breast Cancer in a Safety Net Hospital. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Poster PS7-58.

A poster presented at the 2020 San Antonio Breast Cancer Symposium found a trend towards less frequent care refusal when a safety net hospital introduced nurse breast navigators.
 

Nurse Navigation in Safety Net Hospital Resulted in Less Frequent Care Refusal for Patients with Breast Cancer

The FDA recently granted priority review designation to Bristol Myers Squibb’s supplemental Biologics License Application (sBLA) for nivolumab (Opdivo) plus ipilimumab (Yervoy) as a first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), according to a Bristol Myers Squibb press release.

The nivolumab and ipilimumab will be administered in combination with limited chemotherapy for patients with MSCLC with no EGFR or ALK genomic tumor aberrations. The FDA set a PDUFA date of August 6, 2020 for the priority review, while also granting fast track designation to the combination.

“Despite treatment advances, there remains a serious unmet need for additional innovative treatment options for lung cancer patients globally,” Sabine Maier, MD, development lead, thoracic cancers, Bristol Myers Squibb, said in a press release. “The FDA’s acceptance and EMA’s validation of our applications represent important milestones for patients with lung cancer, and we look forward to working with regulatory authorities to bring the first and only dual immunotherapy plus limited chemotherapy regimen to patients as soon as possible.”

Moreover, the European Medicines Agency (EMA) validated a type 2 variation application for nivolumab plus ipilimumab in combination with chemotherapy for the same indication. This validation allows the EMA to begin the centralized review process.

These applications came on the heels of the results from the phase III CheckMate -9LA trial, which met its primary end point of superior overall survival. The open-label, multi-center, randomized trial evaluated the efficacy of nivolumab plus ipilimumab in combination with 2 cycles of chemotherapy, compared to chemotherapy alone as a first-line treatment for NSCLC.

Patients included in the experimental arm were treated for up to 2 years, while patients in the control arm were treated with up to 4 cycles of chemotherapy. The secondary endpoints of the trial included progression-free survival (PFS), overall response rate (ORR) and efficacy measures according to biomarkers.

Lung cancer is the leading cause of death in the United States, with NSCLC being the most common type of lung cancer, accounting for about 84% of all diagnoses. The 5-year survival rate for patients diagnosed with metastatic lung cancer is approximately 5%.

Bristol Myers Squibb Announces Acceptance of U.S. and EU Regulatory Filings for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Combined with Limited Chemotherapy in First-Line Lung Cancer [news release]. Princeton, New Jersey. Published April 8, 2020. 

https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-announces-acceptance-us-and-eu-regulatory

Bristol Myers Squibb recently announced that the FDA granted priority review to nivolumab plus ipilimumab in combination with chemotherapy as a first-line treatment for metastatic NSCLC.
 

Matthew Fowler

Articles

Drug Combo Shows Early Activity in Pediatric Neuroblastoma Treatment

Nurse Navigation in Safety Net Hospital Resulted in Less Frequent Care Refusal for Patients with Breast Cancer

FDA Grants Priority Review to Nivolumab Plus Ipilimumab to Treat NSCLC