Patients with persistent, recurrent, or metastatic cervical cancer experienced favorable outcomes with pembrolizumab (Keytruda), with or without bevacizumab (Avastin), with manageable levels of toxicity, according to patient-reported outcome (PRO) data collected as part of the phase 3 KEYNOTE-826 trial (NCT03635567).

The PRO findings were presented as part of the 2022 SGO Annual Meeting on Women’s Cancer and demonstrated that these pembrolizumab yielded a -0.3 global geometric least square mean change from baseline (95% CI, -3.1 to 2.6) compared with -1.3 (95% CI, -4.2 to 1.7) with placebo (difference in least squares mean, 1.01; 95% CI, –2.7 to 4.7).

The global geometric least square change metrics were measured in accordance with the European Organisation for Research and Treatment of Cancer (EORTC): Quality of Life Questionnaire-Core 30 (QLQ-C30) for global health status (GHS)/quality of life (QOL) scores. Placebo was determined to have a numeric improvement over placebo in terms of QOL although its impact was not statistically significant.

“Overall findings from KEYNOTE-826 support pembrolizumab plus chemotherapy with or without bevacizumab as the new standard of care for women with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 [combined positive score] of 1 or more,” Bradley Monk, MD, FACOG, FACS, professor in the department of obstetrics and gynecology, University of Arizona College of Medicine, said in his presentation of the data.

Eligible patients were randomized 1:1 to receive 200 mg of intravenous pembrolizumab or placebo every 3 weeks for 35 cycles plus intravenous paclitaxel, cisplatin, or carboplatin for up to 6 cycles with or without 15 mg/kg of intravenous bevacizumab every 3 weeks.

Co-primary end points of the KEYNOTE-826 trial were progression-free survival (PFS) and overall survival (OS). Key secondary end points included overall response rate, duration of response, 12-month PFS rate, safety, and changes from baseline in QOL questionnaire scores. Changes in PROs was an exploratory end point of the research.

To be eligible for enrollment, patients needed a diagnosis of persistent, recurrent, or metastatic cervical cancer not amenable to curative treatment. In addition, they were required to have an ECOG performance score of 0 or 1, and could not have received prior chemotherapy.

The KEYNOTE-826 trial’s co-primary end points were previously reported, showing that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab significantly improved PFS and OS over placebo while maintaining a tolerable safety profile.

“KEYNOTE-826 improved progression-free survival and overall survival, but it’s all about the patient experience,” Monk explained in his presentation of the data. “We have to contextual this clinical benefit to see if it satisfies the risk-benefit ratio in the clinic.”

To measure PROs, the investigative team used the EORTC: QLQ-C30, EuroQol 5-Dimension 5-Level visual analog scale questionnaire (EQ-5D-5L VAS), and the EORTC QLQ-CX24 Cervical Cancer questionnaire which were administered before every cycle of treatment through cycle 14, and then after every subsequent cycle, end of treatment, and at safety follow up visit.

All PRO end points were prespecified, with the change in EORTC QLQ-C30 global health status labeled as a key secondary end point. To ensure the data were reliable, 60% and 80% compliance rates were required in the pembrolizumab and placebo groups, respectively.

At 30 weeks, completion and compliance rates were sufficient among the pembrolizumab and placebo groups to create the study’s focal end point.

When looking at the EORTC QLQ-C30 scale, physical, role, cognitive, and social functioning were slightly worse in the pembrolizumab group compared with the placebo group. By the QLQ-CX24 scale, peripheral neuropathy was worse in the placebo group than the pembrolizumab group.

In the time to true deterioration (TTD) analysis, with deterioration defined as a 10-point decrease in PRO scores, the pembrolizumab arm performed numerically better than the placebo arm across most measures. For the GHS/QOL by EORTC QLQ-C30, median TTD in the pembrolizumab arm was not reached (NR; 95% CI, 13.4-NR) compared with 12.9 months (95% CI, 6.6-NR) in the placebo arm (HR, 0.84; 95% CI, 0.65-1.09; 

 = .1851). For EQ-5D-5L VAS, median TTD in the pembrolizumab arm was NR (95% CI, 17.2-NR) vs 7.7 months (95% CI, 6.0-NR) in the placebo arm (HR, 0.75; 95% CI, 0.58-0.97; 

For physical functioning by EORTC QLQ-C30, the proportion of patients with improved PROs was 42.1% compared with 26.8% in the placebo arm. For the EQ-5D-5L VAS, the proportion of patients with improved PROs was 42.8% and 36.4% in the pembrolizumab and placebo groups, respectively.

Monk BJ, Tewari KS, Hasegawa CK, et al. Patient-reported outcomes from the phase 3 randomized, double-blind, KEYNOTE-826 trial of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for the first-line treatment of persistent, recurrent, or metastatic cervical cancer. Presented at: 2022 SGO Annual Meeting on Women’s Cancer; March 18-21, 2022; Phoenix, AZ.

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Data collected with patient-reported outcomes show that pembrolizumab, with or without bevacizumab, is associated with a favorable toxicity profile in effectively treating women with persistent, recurrent, or metastatic cervical cancer.

Patient-Reported Outcomes Demonstrate Satisfaction With Pembrolizumab in Advanced Cervical Cancer

Patients with muscle-invasive bladder cancer (MIBC) who were not eligible for cisplatin experienced promising antitumor responses after receiving neoadjuvant enfortumab vedotin (Padcev), according to preliminary findings from cohort H of the phase 1b/2 EV-103 trial (NCT03288545) presented during the 2022 Genitourinary Cancers Symposium.

Investigators reported a pathological complete response (pCR) rate of 36.4% (95% CI, 17.2%-59.3%) among those treated with enfortumab vedotin (n = 22), as well as a pathological downstaging (pDS) rate of 50.0% (95% CI, 28.2%-71.8%).

“This first disclosure of data supports the ongoing phase 2 and 3 programs evaluating enfortumab vedotin alone or in combination with pembrolizumab in MIBC,” Daniel Petrylak, MD, professor of medical oncology and urology at the Yale Cancer Center, said in his presentation of the data.

Eligibility required patients to be ineligible for cisplatin, have clinical T2-T4N0M0 disease, and no upper tract or urethral tumors. Additionally, a urothelial carcinoma histology of greater than 50% was required. Patients also needed to have an ECOG performance status of 0 to 2, be medically fit for radical cystectomy plus pelvic lymph node dissection and have undergone transurethral resection of bladder tumor within 90 days of the first day of cycle 1.

Patients received 1.25 mg/kg of neoadjuvant enfortumab vedotin monotherapy on days 1 and 8 per 21-day cycle for 3 cycles. Within 4 weeks of treatment, patients underwent radical cystectomy plus pelvic lymph node dissection followed by imaging every 12 weeks for the first 2 years and then every 24 weeks after.

The primary end point was pCR by central pathology review. Secondary end points included pDS by central review, event-free survival, disease-free survival, overall survival, safety, patient-reported outcomes, and biomarkers.

The median age of the study population was 74.5 years. All patients were White, and most patients were male (90.9%) and a current or former smoker (95.5%). Most patients had an ECOG performance status of 0 (59.1%) followed by 1 (36.4%) and 2 (4.5%).

The most common reason for cisplatin-ineligibility was creatine clearance between less than 60 to 30 or more mL per minute (50.0%), followed by grade 2 or greater hearing loss (40.9%). A total of 86% of patients completed all 3 cycles of neoadjuvant therapy.

Any grade enfortumab vedotin–related treatment emergent adverse effects (TEAEs) were seen in all patients, with common TEAEs including fatigue (45.5%), alopecia (36.4%), dysgeusia (36.4%), diarrhea (27.3%), nausea (27.3%), peripheral sensory neuropathy (27.3%), dry eye (22.7%), and maculopapular rash (22.7%). Four patients experienced grade 3 or higher TEAEs, and no grade 4 TEAEs or deaths were reported. Grade 3 TEAEs related to treatment with enfortumab vedotin included asthenia, dehydration, erythema multiforme, and hyperglycemia.

Three enfortumab vedotin–related TEAEs leading to dose interruptions, 2 TEAEs leading to dose reductions, and 3 TEAEs leading to discontinuations were observed in the safety analysis. Most AEs of special interest were grade 1 and 2. Any grade AEs of interest included peripheral neuropathy (36.4%), skin reaction (63.6%), hyperglycemia (22.7%), ocular disorder (40.9%), and infusion-related reactions (9.1%). Grade 3 or greater AEs of special interest were skin reactions (9.1%) and hyperglycemia (13.6%).

“The observed safety profile of neoadjuvant enfortumab vedotin monotherapy in patients with cisplatin-ineligible MIBC is consistent with the known AE profile of enfortumab vedotin in other settings,” Petrylak concluded.

Petrylak DP, Flaig TW, Mar N, et al. Study EV-103 cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients (pts) with muscle invasive bladder cancer (MIBC) who are cisplatin-ineligible. 

. 2022;40(suppl 6):435. doi:10.1200/JCO.2022.40.6_suppl.435

Preliminary findings suggest that enfortumab vedotin may be an effective treatment option for cisplatin-ineligible patients with muscle-invasive bladder cancer.

Neoadjuvant Enfortumab Vedotin Shows Potential in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer

Patients with refractory microsatellite stable, 

 V600E–mutant metastatic colorectal cancer experienced high response rates and manageable adverse events (AEs) after receiving nivolumab (Opdivo) in addition to encorafenib (Braftovi) plus cetuximab (Erbitux), according to data from a phase 1/2 trial (NCT04017650) that were presented during the 2022 Gastrointestinal Cancers Symposium.

The results highlighted an overall response rate (ORR) of 50% (95% CI, 28%-72%) among those treated with the combination, with all patients achieving partial responses. The disease control rate (DCR) was 96% (95% CI, 77%-100%) among the 22 evaluable patients.

“Encorafenib, cetuximab, and nivolumab appears to be a safe and well-tolerated combination for patients with microsatellite stable 

-mutated metastatic CRC,” lead study author Van K. Morris, MD, an assistant professor of the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, explained in a presentation of the data. “The efficacy of this combination appears promising when considering the precedent of encorafenib and cetuximab alone from the previously reported BEACON study.”

V600E metastatic CRC were eligible to enroll on the study. Further eligibility criteria required patients to have received 1 to 2 prior lines of systemic therapy and have an ECOG performance status of 1 or less. Prior treatment with a BRAF, MEK, ERK, anti-EGFR, or immune-checkpoint therapy was not allowed.

The primary end points of the phase 1/2 study were radiographic response per RECIST 1.1 criteria and safety. Key secondary end points included progression-free survival (PFS), overall survival (OS), duration of response, DCR, and time to response.

The study regimen included a 300 mg dose of oral encorafenib that was administered daily daily, 500 mg/m2 of cetuximab intravenously every 14 days, and 480 mg of nivolumab intravenously every 28 days.

A total of 26 patients were treated on protocol, with all of whom were evaluable for safety and 22 were evaluable for response. The median age for the full population was 58 years (range, 32-85). Most patients were female (58%), Caucasian (85%), and had right primary tumor sidedness (62%). Moreover, most patients had received 1 prior line of therapy (62%). Investigators reported an even split between those who had an ECOG performance status of 0 and 1.

Common any grade adverse effects (AEs) included headache (65%), nausea (35%), maculopapular rash (31%), arthralgia (27%), acneiform rash (27%), chills (23%), and precancerous skin lesions (23%). Grade 3 AEs seen in 1 patient each included colitis, maculopapular rash, asymptomatic elevated amylase/lipase, and leukocytosis. The only grade 4 AE observed in 1 patient was myositis.

At a median follow-up time of 16.3 months (95% CI, 6.9–not applicable [NA]), the median PFS was 7.4 months (95% CI, 5.6-NA) and the median OS was 15.1 months (95% CI, 7.7-NA). Additionally, the median duration of response for patients treated with the combination was 7.7 months (95% CI, 3.8-NA). 

“For patients who are experiencing responses, there is continued reduction in tumor size across the period of treatment,” Morris explained in his presentation. “For the 11 patients who continue to remain on study, 2 of the patients remain on treatment with encorafenib, cetuximab, and nivolumab at 100 weeks.”

Morris VK, Parseghian CM, Escano M, et al. Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAFV600E metastatic colorectal cancer. 

. 2022;40(suppl; abstr 12). doi:10.1200/JCO.2022.40.4_suppl.012

Encouraging response rates were observed among patients with BRAF V600E–mutant metastatic colorectal cancer who received a triplet regimen of nivolumab, encorafenib, and cetuximab. 

 Adding Nivolumab to Encorafenib/Cetuximab Yields High Response Rates in MSS, BRAF V600E+ CRC 

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

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.
 