Caroline Seymour

In the phase 3 SWOG S1207 trial (NCT01674140), adding 1 year of everolimus (Afinitor) to adjuvant endocrine therapy did not show statistically significant improvement in invasive disease-free survival (iDFS) or overall survival (OS), findings presented at the 2022 San Antonio Breast Cancer Symposium show.

With a median follow-up of 55.2 months among alive patients, neither the primary end point of iDFS (HR, 0.94; 95% CI, 0.77-1.14; 

 = .52) or secondary end point of OS were met (HR, 0.97; 95% CI, 0.75-1.26; 

 = .84). However, in an exploratory analysis, premenopausal patients were shown to derive a statistically significant improvement in iDFS (HR, 0.64; 95% CI, 0.44-0.94; 

 = .02) and OS (HR, 0.49; 95% CI, 0.28-0.86; 

 = .012). Postmenopausal patients did not experience a benefit in either iDFS (HR, 1.08; 95% CI, 0.86-1.36; 

 = .52) or OS (HR, 1.19; 95% CI, 0.89-1.60; 

“Among premenopausal patients, the addition of everolimus to endocrine therapy improved iDFS and OS, which is hypothesis generating. Future translational studies will evaluate potential predictors of everolimus benefit and drug toxicity,” lead study author Mariana Chavez-MacGregor, MD, of the Department of Health Services Research and Division of Cancer Prevention and Population Sciences at The University of Texas MD Anderson Cancer Center in Houston, Texas, said in a presentation of the data.

Dysregulation in the PI3K/AKT/mTOR signaling pathway is associated with endocrine therapy resistance. The addition of the mTOR inhibitor everolimus to endocrine therapy improved progression-free survival vs endocrine therapy alone in patients with metastatic hormone receptor–positive, HER2-negative breast cancer.

In the randomized, placebo-controlled S1207 trial, investigators evaluated the role of everolimus in the adjuvant setting in patients with hormone receptor–positive, HER2-negative breast cancer.

To be eligible for enrollment, patients at least 18 years of age needed to have histologically confirmed, invasive, high-risk hormone receptor–positive, HER2-negative breast cancer and have received prior chemotherapy.

Patients were stratified into 1 of 4 risk groups:

Tumor at least 2 cm; node-negative (or pN1mi); and Oncotype DX Recurrence Score (RS) of at least 25 or MammaPrint high-risk category (MP high; n = 158; 9%)

Between 1 and 3 positive nodes and either RS above 25, MP high or a pathological grade 3 tumor (n = 213; 12%)

At least 4 positive lymph nodes (n = 710; 40%)

Neoadjuvant chemotherapy and residual disease with at least 1 lymph node involvement (n = 711; 40%)

Per the study design, patients underwent either surgery or neoadjuvant chemotherapy first. Patients who underwent surgery first (risk groups 1-3) and those who received neoadjuvant chemotherapy first (risk group 4) proceeded to standard adjuvant chemotherapy and radiation afterward.

Following adjuvant chemotherapy and radiation, patients were randomly assigned 1:1 to receive physician’s choice of adjuvant endocrine therapy plus 1 year of everolimus 10 mg orally once daily (n = 971), or endocrine therapy plus placebo for 1 year (n = 968). A total of 896 patients from each arm were included in the analysis.

The primary end point of iDFS had 80% power to detect a hazard ratio (HR) of 0.75 in a sample size of 1900 patients, using a two-sided 5% level stratified log-rank test. The statistical power was changed from 90% in a sample size of 3500 patients to 80% in April 2016 to reflect the actual risk distribution of the enrolled population. No results were used to change the study design.

Secondary end points included OS, safety, and efficacy assessment by risk group.

Regarding baseline characteristics among all enrolled patients, the median age was 54 years (range, 22-86), and most patients were White (n = 1529; 85%) and postmenopausal (n = 1221; 68%). According to the study, menopause was defined as previous history of bilateral oophorectomy or last menstrual period greater than 12 months without any history of hysterectomy, MacGregor said.

Among patients who received everolimus, 48% (n = 428) completed treatment as planned, and 37% (n = 335) discontinued treatment due to an adverse effect (AE). Twenty-one patients (2%) experienced progression or relapse, and one (0.1%) death was reported. In the placebo arm, 73% (n = 651) of patients completed treatment as planned, and 10% (n = 86) stopped treatment due to an AE. A total of 43 patients (5%) had progressed or relapsed, and one death occurred. Refusal to complete treatment for reasons other than toxicity occurred in 9% (n = 84) of patients in both arms.

Additional results showed that the estimated 5-year iDFS rate was 74.9% with everolimus vs 74.4% with placebo. The estimated 5-year OS rates were 88.1% and 85.8%, respectively. “In the forest plot of the iDFS subgroup analysis, we did not observe any differences according to high-risk group category, or according to endocrine therapy received initially according to treatment arm. Similar to the iDFS subgroup analysis, the OS subgroup analysis demonstrated no differences according to treatment arm based on high-risk group category or based on treatment assigned,” MacGregor said.

Within the exploratory analysis by menopausal status, the estimated 5-year iDFS rate in the postmenopausal population was 72.0% with everolimus vs 74.3% with placebo. The estimated 5-year OS rates were 84.6% and 85.7%, respectively. In the premenopausal population, the estimated 5-year iDFS rate was 81.0% with everolimus vs 74.7% with placebo. The estimated 5-year OS rates were 95.7% and 86.0%, respectively.

A Cox regression model indicated that the treatment arm and menopausal status interaction had a hazard ratio of 1.67 for iDFS (95% CI, 1.07-2.60; 

 = .0241) and 2.41 for OS (95% CI, 1.27-4.57; 

Regarding safety, grade 3/4 treatment-related AEs occurred in 35% of patients (n = 303) in the everolimus arm vs 7% (n = 59) in the placebo arm. These AEs included oral mucositis (7% vs 0%), lymphopenia (4% vs 1%), hypertriglyceridemia (4% vs 0%), hyperglycemia (4% vs 0%), fatigue (3% vs 1%), neutropenia (3% vs 0%), leukopenia (2% vs 0%), hypertension (2% vs 1%), diarrhea (1% vs 0%), anemia (1% vs 0%), hypercholesterolemia (1% vs 0%), and skin infection (1% vs 0%).

Chavez-MacGregor M, Miao J, Pusztai L, et al. Results from a phase III randomized, placebo-controlled clinical trial evaluating adjuvant endocrine therapy +/- 1 year of everolimus in patients with high-risk hormone receptor-positive, HER2-negative breast cancer: SWOG S1207. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2021. San Antonio, TX. Abstract GS1-07.

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Among premenopausal patients, the addition of everolimus to endocrine therapy improved iDFS and OS, which is hypothesis generating, said Mariana Chavez-MacGregor, MD.

Everolimus Plus Adjuvant ET in Shows No Significant iDFS or OS Advantage in HR+/HER2- Breast Cancer

Results from a post hoc exploratory analysis of the phase 3 CheckMate 214 trial (NCT02231749) show that nivolumab (Opdivo) and ipilimumab (Yervoy) achieved significant improvements in survival vs sunitinib (Sutent) in patients with intermediate- and poor-risk renal cell carcinoma (RCC) with sarcomatoid features.

At 5 years of minimum follow-up, the median overall survival (OS)n was 48.6 months (95% CI, 25.2-not evaluable [NE]) with the combination (n = 74) vs 14.2 months (95% CI, 9.3-22.9) with sunitinib (n = 65; HR, 0.46; 95% CI, 0.29-0.71; 

 = .0004). The median progression-free survival (PFS) was 26.5 months (95% CI, 7.2-NE) and 5.5 months (95% CI, 4.1-6.9), respectively (HR, 0.50; 95% CI, 0.32-0.80; 

“These results extend those previously reported and add further support to the preferred use of nivolumab and ipilimumab as first-line therapy in patients with intermediate- and poor-risk sarcomatoid RCC, a population with a historically high unmet medical need for safe and effective treatment options,” Nizar M. Tannir, MD, lead study author and professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said.

In the trial, patients with previously untreated clear cell advanced RCC were randomly assigned to 3 mg/kg of intravenous nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg of nivolumab, or 50 mg of oral sunitinib once daily every 4 weeks of the 6-week cycle. In this exploratory analysis, patients with advanced RCC with sarcomatoid features were identified through an independent central pathology review of archival tumor tissue or histological classification per local pathology.

Individual tumor samples were collected from nephrectomy and metastatic biopsy in CheckMate 214, and tumors with any percent sarcomatoid component were deemed sarcomatoid positive.

Additional results indicated that the combination led to improved survival regardless of tumor PD-L1 expression level. In patients with PD-L1–positive tumors (≥1%), the median OS was not reached (NR) with the combination (n = 36; 95% CI, 29.9-NE) vs 20.9 months (n = 33; 95% CI, 9.3-41.2) with sunitinib (HR, 0.40; 95% CI, 0.19-0.84; 

 = .0143). The median PFS was NR (95% CI, 9.1-NE) vs 5.6 months (95% CI, 2.8-6.9), respectively (HR, 0.29; 95% CI, 0.14-0.57; 

Patients with PD-L1–negative tumors (<1%) experienced a median OS of 40.4 months (n = 35; 95% CI, 18.5-NE) with the combination vs 13.8 months (n = 29; 95% CI, 5.5-20.3) with sunitinib (HR, 0.42; 95% CI, 0.22-0.78; 

 = .0049). The median PFS was 9.0 months (95% CI, 3.3-47.0) vs 5.4 months (95% CI, 4.0-17.0), respectively (HR, 0.65; 95% CI, 0.34-1.24; 

The objective response rate (ORR) was significantly higher with the combination, 60.8% (95% CI, 48.8%-72.0%) vs 23.1% (95% CI, 13.5%-35.2%) with sunitinib (

 < .0001). The complete response (CR) rates were 23.0% and 6.2%, respectively.

Notably, the ORR and CR rates improved with the combination compared with sunitinib regardless of baseline tumor PD-L1 expression. Moreover, the median duration of response was not reached ([NR] 95% CI, 22.5-NE) with the combination vs 25.1 months (95% CI, 7.2-60.4) with sunitinib.

The median treatment-free interval was 2.9 months (range, 0.0-68.2) with the combination vs 1.4 months (range, 0.1-65.8) with sunitinib. In patients who discontinued therapy because of treatment-related adverse events (TRAEs), the median treatment-free interval was 12.3 months (range, 1.0-66.0) and 3.1 months (range, 0.7-65.8), respectively.

Among responders who discontinued treatment and never received subsequent therapy, 49% (n = 22/45) in the combination arm and 40% (n = 6/15) in the sunitinib arm experienced a treatment-free interval. Among responders who discontinued treatment and did receive subsequent therapy, 82% (n = 37/45) and 100% (n = 15/15) of patients experienced a treatment-free interval, respectively.

Regarding toxicity, investigators identified no new signals with either regimen in the sarcomatoid population. The safety profiles were comparable with the overall trial population.

Any-grade TRAEs occurred in 97.3% of patients who received the combination vs 96.9% of patients who received sunitinib; grade 3 or 4 TRAEs were reported in 49.3% and 44.6% of patients, respectively. TRAEs leading to discontinuation occurred more often in the combination arm (any grade, 21.9%; grade 3/4, 19.2%) vs the sunitinib arm (any grade, 12.3%; grade 3/4, 9.2%).

One treatment-related death, previously reported, occurred in a patient who received the combination. There were no deaths with sunitinib.

Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib for first-line treatment of patients with advanced sarcomatoid renal cell carcinoma (sRCC) in the phase 3 CheckMate 214 trial with extended 5-year minimum follow-up. Presented at: International Kidney Cancer Symposium; November 4-5, 2022. Austin, Texas. Abstract 32.

Post hoc CheckMate 214 results show that nivolumab plus ipilimumab extend progression and overall survival in patient with advanced sarcomatoid renal cell carcinoma who have not be previously treated.

Nivolumab Plus Ipilimumab Prolongs Survival in Treatment-Naïve Advanced Sarcomatoid RCC

Patients with metastatic renal cell carcinoma (RCC) who had more than 2 tertiary lymphoid structures (TLSs), an increased density of Ki-67 and PD-1 positivity elicited increased response rates and prolonged progression-free survival (PFS) with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in the frontline, according to findings from the phase 2 BIONIKK trial (NCT02960906) that were presented at the 2022 ESMO Congress.

Several treatment cohorts were evaluated in the trial. Within 15 days of screening, patients were grouped into 1 of 4 molecular subsets. Patients in subsets 1 and 4 were randomly assigned to 3 mg/kg of intravenous (IV) nivolumab every 2 weeks or 3 mg/kg of IV nivolumab plus 1 mg/kg of IV ipilimumab every 3 weeks for 4 cycles followed by 240 mg of nivolumab every 2 weeks. Those in subsets 2 and 3 were randomly assigned to the combination or 50 of oral sunitinib for 4 weeks on, 2 weeks off, or 800 mg of oral pazopanib once daily.

With nivolumab alone (n = 38), patients with more than 2 TLSs achieved an objective response rate (ORR) of 73% (n = 8) vs 15% (n = 4) in those with fewer than 2 TLSs (chi-square 

 = .00195; HR for PFS, 0.31; 95% CI, 0.12-0.83; 

 = .015). With the combination (n = 76), 69% (n = 20) and 40% (n = 19) of patients experienced response with more than 2 and fewer than 2 TLSs, respectively (chi-square 

 = .0291; HR for PFS, 0.81; 95% CI, 0.44-1.46; 

“TLS >2 identify responders to nivolumab and nivolumab plus ipilimumab, and Ki-67- and PD-1–positive cell density identifies patients with longer PFS,” lead study author Maxime Meylan, PhD, research fellow at Dana-Farber Cancer Institute, said. “Patients with TLS >2 and high Ki-67 and PD-1 positivity have high response rates to nivolumab plus ipilimumab and longer PFS.”

BIONIKK is a hypothesis-generating, noncomparative, per-molecular group randomized phase 2 trial.

The trial enrolled patients at least 18 years of age with treatment-naïve, metastatic clear cell RCC with an ECOG performance status between 0 and 2 and frozen tumor tissue. Patients with active brain metastases were excluded from enrollment.

Treatment was continued until disease progression, death, or end of study.

A total of 160 samples underwent immunohistochemical and immunofluorescence staining to assess TLS, PD-1, and Ki-67 level.

The primary end point was investigator-assessed objective response per RECIST v1.1 criteria. Key secondary end points were PFS, overall survival, time to subsequent therapy, time to objective response, and duration of response. 

Additional results showed that higher density of PD-L1– and Ki-67–positive cells was associated with improved ORR and PFS with nivolumab. The ORR was 40% (n = 6) with nivolumab in patients with high expression vs 26% (n = 5) in those with low expression (chi-square 

 = .633); with the combination, these rates were 56% (n = 25) and 45% (n = 14), respectively (chi-square 

However, the median PFS was not different between cohorts of high or low expression with nivolumab alone (HR, 0.73; 95% CI, 0.32-1.65; 

 = .44). Only with the combination, did patients with high expression level outperform those with low expression (HR, 0.49; 95% CI, 0.28-0.88; 

Finally, the investigators showed that the presence of both high TLS and PD-1/Ki-67 positivity enhanced response rates and PFS for the combination. In this population, the ORR was 81% (n = 17) vs 40% (n = 21) in those without both markers (chi-square test 

 = .00319). Moreover, the PFS was favorable in the population with more than 2 TLSs and Ki-67 positivity vs those without (HR, 0.53; 95% CI, 0.26-1.07; 

Notably, 95% of patients enriched with both markers (n = 20) who received treatment with the combination did not experience early progression within the first 6 months of therapy vs only 64% (n = 34) of those without both markers.

Meylan added that preliminary peripheral blood mononuclear cell analysis indicated that select circulating CD4 T-cell populations were also associated with response.

“Validation of these markers on immunotherapy and TKI/immunotherapy [combinations] is ongoing,” the study authors concluded.

Meylan M, Sun CM, Elaidi RT, et al. In-situ and circulating immune markers predict nivolumab +/- ipilimumab efficacy in frontline metastatic clear cell renal cell carcinoma: key ancillary analyses from the BIONIKK randomized trial. 

. 2022;33(suppl 7):S660-S680. doi:10.1016/annonc/annonc1072

Patients with more than 2 tertiary lymphoid structures, high Ki-67, and PD-1 positivity had high response rates to nivolumab plus ipilimumab.

Frontline Nivolumab Plus Ipilimumab Improves Efficacy in Metastatic RCC

Treatment with atezolizumab (Tecentriq) led to an almost doubled rate of 2-year overall survival (OS) vs vinorelbine or gemcitabine in patients with advanced platinum-ineligible non–small cell lung cancer (NSCLC), meeting the primary end point of the phase 3 IPSOS trial (NCT03191786).

Findings from the study, which were presented at the 2022 ESMO Congress with a median follow-up of 41.0 months, demonstrated that the median OS was 10.3 months (95% CI, 9.4-11.9) with atezolizumab (n = 302) vs 9.2 months (95% CI, 5.9-11.2) with chemotherapy (n = 151), resulting in a 22% reduction in the risk of death with the PD-L1 inhibitor (HR, 0.78; 95% CI, 0.63-0.97; 

 = .028). The 12-month OS rate was 43.7% with atezolizumab vs 38.6% with chemotherapy. Moreover, the 24-month OS rate with atezolizumab was approximately double that with chemotherapy, at 24.3% and 12.4%, respectively.

“Many patients with advanced stage lung cancer cannot tolerate standard platinum-based chemotherapy. IPSOS is a randomized phase 3 trial to examine the role of immunotherapy with first-line atezolizumab for advanced stage NSCLC patients deemed not eligible to receive platinum-based chemotherapy treatments because of poor performance status [PS] or elderly with significant contraindications,” said lead study author Siow Ming Lee, MD, PhD, FRCP, professor of medical oncology at University College London Hospitals.

Approximately 40% of patients with advanced NSCLC have an ECOG PS of at least 2 and/or significant comorbidities rendering them ineligible for platinum-doublet chemotherapy. As such, IPSOS was designed to evaluate the efficacy of immune monotherapy in a population that has been historically excluded from clinical trials with first-line immunotherapy.

Eligible patients had treatment-naïve, stage IIIB/IV, squamous or nonsquamous NSCLC per the AJCC 7th edition. Reasons for platinum ineligibility included an ECOG PS of 2 or 3 or age of at least 70 years and substantial comorbidities or contraindications to platinum in the context of a PS of 0 or 1. Patients with treated, asymptomatic brain metastases were permitted. Those with 

 alterations were excluded. Patients were stratified by PD-L1 status but it was not an inclusion criteria.

Patients were randomly assigned 2:1 to 1200 mg of intravenous (IV) atezolizumab every 3 weeks until progressive disease (PD) or loss of clinical benefit; or either oral or IV vinorelbine or IV gemcitabine, both dosed by the local primary investigator until PD. Median age was 75 years and 31% were 80 or older. Eighty-three percent had ECOG PS of 2 or more.

The primary end point was OS, with secondary end points of 6-, 12-, 18-, and 24-month OS rates, progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and OS and PFS in the PD-L1–positive subgroups.

Additional findings demonstrated that the ORR was 16.9% (95% CI, 12.8%-21.6%)with atezolizumab vs 7.9% (95% CI, 4.2%-13.5%) with chemotherapy, reflecting an absolute difference of 8.9% (95% CI, 2.4-15.5). The median DOR was 14.0 months (95% CI, 8.1-20.3) with atezolizumab vs 7.8 months (95% CI, 4.8-9.7) with chemotherapy.

QOL as assessed by the EORTC QLQ-C30 and QLQ-LC13 functioning scales and symptoms questionnaires indicated that role function, cognitive function, and social function remained stable or were improved from baseline to week 48 of treatment with atezolizumab. Notably, the median time to confirmed deterioration of chest pain was not estimable in either arm but favored the use of atezolizumab (HR, 0.51; 95% CI, 0.27-0.97).

Additionally, meaningful changes were reported across several disease- and treatment-related symptoms, including an improvement in appetite loss and cough with atezolizumab, an improvement in insomnia with chemotherapy, and a worsening of appetite loss, peripheral neuropathy, and alopecia with chemotherapy.

Lee noted that no new or unexpected safety concerns occurred with atezolizumab. The median treatment duration (3.5 months vs 2.3 months and 1.8 months) and number of cycles started (6 vs 4 and 3) was higher in the atezolizumab arm vs the gemcitabine and vinorelbine arms, respectively.

Treatment-related adverse effects (TRAEs) occurred in 57.0% (n = 171) of patients in the atezolizumab arm vs 80.3% (n = 118) of those in the chemotherapy arm. Grade 3/4 TRAEs occurred in 16.3% (n = 49) and 33.3% (n = 49) of patients in the atezolizumab and chemotherapy arms, respectively. Serious TRAEs were experienced by 11.7% (n = 35) and 15.6% (n = 23) of patients, respectively. Three treatment-related fatalities occurred in the atezolizumab arm vs 4 in the chemotherapy arm.

AEs leading to drug discontinuation were comparable between arms, at 13.0% (n = 39) and 13.6% (n = 20) with atezolizumab and chemotherapy, respectively. AEs leading to drug modification or interruption occurred less frequently with atezolizumab at 32.0% (n = 96) vs 48.3% (n = 71) with chemotherapy.

“For over two decades, clinical trials have not brought significant improvement for this population. IPSOS is the first randomized trial to show that first-line atezolizumab treatment significantly improves OS compared with single-agent chemotherapy for these poor prognosis patients with no 

 alterations,” said Lee. “Twice as many patients remained alive at 2 years when treated with atezolizumab. OS benefit was seen regardless of patients’ age, histology, PD-L1 status and ECOG PS. Atezolizumab also stabilized and/or improved some HRQOL measures with no new safety signals identified.”

Lee SM, Schulz C, Prabhash K, et al. IPSOS: results from a phase 3 study of first-line (1L) atezolizumab vs single-agent chemotherapy in patients with NSCLC not eligible for a platinum-containing regimen. 

. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089

The rate of 2-year overall survival was nearly doubled with atezolizumab vs vinorelbine or gemcitabine in advanced platinum-ineligible non–small cell lung cancer.

Atezolizumab Improves Overall Survival in Platinum-Ineligible NSCLC

Results from the phase 3 KEYNOTE-412 trial (NCT03040999) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) showed pembrolizumab (Keytruda) plus chemoradiation failed to provide a statistically significant improvement in event-free survival (EFS) vs chemoradiation alone, according to data presented at the 2022 ESMO Congress.

The results showed that the median EFS was not reached (NR; 95% CI, 44.7-NR) with pembrolizumab plus chemoradiation vs 46.6 months (95% CI, 27.5-NR) with chemoradiation alone, failing to meet the superiority threshold of a 1-sided alpha of 0.0242 (HR, 0.83; 95% CI, 0.68-1.03; 

 = .0429). The 24-month EFS rate was 63.2% with pembrolizumab/chemoradiation vs 56.2% with chemoradiation alone; the 36-month EFS rates were 57.4% and 52.1%, respectively.

“Pembrolizumab plus chemoradiation was associated with a favorable trend toward improved EFS vs placebo plus chemoradiation in patients with locally advanced HNSCC, and PD-L1 expression may be an informative predictive biomarker” lead study author Jean-Pascal Machiels, MD, PhD, head of the Department of Medical Oncology at the Cliniques Universitaires Sain-Luc in Brussels, Belgium, said.

HNSCC originates from the mucosa of the oral cavity, hypopharynx, larynx, and oropharynx. Owing primarily to alcohol and tobacco exposure or human papilloma virus, the disease represents the seventh most common cancer, with an annual global incidence of 600,000 cases.

The standard of care for locally advanced unresected HNSCC, concurrent chemoradiation with high-dose cisplatin, is associated with less than a 50% disease-free survival rate and a 5-year overall survival (OS) rate of approximately 50%.

Pembrolizumab monotherapy in patients with a PD-L1 combined positive score (CPS) of at least 1 or in combination with chemotherapy improves survival as first-line therapy in recurrent or metastatic HNSCC, serving in part as the rationale for the study.

The study enrolled patients with newly diagnosed, treatment-naïve, unresected locally advanced HNSCC eligible for definitive high-dose cisplatin-based chemoradiation.

A total of 804 patients were randomly assigned 1:1 to 200 mg of intravenous (IV) pembrolizumab every 3 weeks plus chemoradiation followed by 14 cycles of maintenance pembrolizumab or IV placebo every 3 weeks plus chemoradiation followed by 14 cycles of maintenance placebo.

Treatment was continued until progressive disease or intolerable toxicity; 17 cycles of pembrolizumab or placebo had been administered; or the investigator or patient decided to withdraw.

The primary end point was EFS, with secondary end points including OS and safety/tolerability.

The median OS was NR in either arm (HR, 0.90; 95% CI, 0.71-1.15). The 24-month OS rates in the pembrolizumab/chemoradiation and chemoradiation alone arms, respectively, were 77.9% and 76.8%; the 36-month OS rates were 71.9% and 70.1%.

In a post-hoc analysis of EFS and OS in patients with a PD-L1 CPS of at least 20, the addition of pembrolizumab to chemoradiation appeared to result in greater benefit compared with chemoradiation alone. Here, the median EFS was NR in either arm but demonstrated a 24-month EFS rate of 71.2% with pembrolizumab/chemoradiation vs 62.6% with chemoradiation alone; the 36-month EFS rates were 66.7% and 57.2%, respectively (HR, 0.73; 95% CI, 0.49-1.06). The median OS was also NR in either arm, but indicated a 24-month OS rate of 83.3% with pembrolizumab/chemoradiation vs 79.9% with chemoradiation alone; the 36-month OS rates were 79.1% and 73.0%, respectively (HR, 0.67; 95% CI, 0.43-1.04).

Machiels stated that no new safety signals were reported with the combination of pembrolizumab and chemoradiation.

“In this study, pembrolizumab given as a lead-in dose, concomitantly with chemoradiotherapy and then adjuvantly for 1 year failed to deliver a statistically significant improvement in EFS as a primary end point when compared with placebo,” Kevin Harrington, PhD, head of the Division of Radiotherapy and team leader at The Institute for Cancer Research in London, said.

“Even though there was a trend in favor of the pembrolizumab arm in the intention-to-treat and PD-L1–positive populations, the current study cannot be interpreted as an indication for use of anti–PD-1 therapy in combination with chemoradiotherapy in any patient group. Indeed, in light of the recent presentations of negative findings from the JAVELIN Head and Neck 100 [NCT02952586], REACH [NCT02999087], and PembroRad [NCT02707588] studies, these data should signal the need for a change in thinking in how to design optimal combination regimens. Focus is now likely to shift to neoadjuvant and true adjuvant therapy approaches,” Harrington concluded.

Machiels JP, Tao Y, Burtness B, et al. Primary results of the phase 3 KEYNOTE-412 study: pembrolizumab plus chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced head and neck squamous cell carcinoma. Presented at: ESMO Congress 2022; September 9-13, 2022; Paris, France. Abstract LBA5.

Patients with locally advanced head and neck squamous cell carcinoma did not show statistically significant improvement in event-free survival with pembrolizumab plus chemoradiation vs chemoradiation alone. 

Only Numerical Improvement in Survival Seen in Locally Advanced HNSCC With Pembrolizumab Plus Chemoradiation

Findings from the phase 3 DeFi trial (NCT03785964) showed that nirogacestat led to a 71% reduction in the risk of disease progression or death vs placebo in patients with progressive desmoid tumors, according to data presented at the 

At a median follow-up of 19.2 months with nirogacestat (n = 70) and 10.9 months with placebo (n = 72), the median progression-free survival (PFS) was not estimable (NE; 95% CI, NE-NE) and was 15.1 months (95% CI, 8.4-NE) with placebo (HR, 0.29; 95% CI, 0.15-0.55; 

“Nirogacestat demonstrated rapid, sustained, and statistically significant improvements in all primary and secondary efficacy end points,” lead study author Bernd Kasper, MD, PhD, a professor at the Universitätsmedizin Mannheim in Germany, said.

Desmoid tumors are rare, locally aggressive, invasive soft tissue tumors that are difficult to manage due to heterogeneous presentation, disease course, and absence of approved therapies. Nirogacestat is an investigational, oral, selective, small molecule gamma secretase inhibitor that has demonstrated efficacy in desmoid tumors in phase 1 and 2 trials. The Notch pathway, which is active in desmoid tumors, is blocked by gamma secretase inhibition, providing mechanistic rationale for the agent in this population.

DeFi is a global, randomized, double-blind, placebo-controlled phase 3 trial evaluating the activity and safety of nirogacestat in patients with progressive desmoid tumors. Eligible patients had histologically confirmed desmoid tumors with progressive disease (PD) per RECIST v.1.1 criteria. Patients either had to be previously untreated and unfit for surgery or have recurrent or refractory disease following 1 line of therapy.

Patients were randomly assigned 1:1 to 150 mg of nirogacestat twice daily or matched placebo in 28-day cycles until radiographic disease progression, at which point patients in the placebo arm could receive open-label nirogacestat. The primary end point was PFS, with secondary end points of objective response rate (ORR), QOL, and patient-reported outcomes (PROs) for pain, symptom burden, and physical and role function.

The cutoff for the primary analysis was April 7, 2022.

The ORR assessed by blinded independent central review was more than five times higher with nirogacestat compared with placebo, at 41% (n = 29; 95% CI, 30.2%-54.5%) vs 8% (n = 6; 95% CI, 3.1%-17.3%), respectively (

In the nirogacestat arm, best overall response consisted of 5 (7%) complete responses (CRs), 24 (34%) partial responses (PRs), and 35 (50%) cases of stable disease (SD). One patient developed PD, and 4 (6%) patients were not evaluable. In the placebo arm, best overall response included 6 (8%) PRs and 55 (76%) cases of SD. There were no CRs. Ten (14%) patients had PD, and one patient was not evaluable.

The median time to response with nirogacestat was 5.6 months (range, 2.6-19.4) vs 11.1 months for placebo (range, 2.8-16.4). The estimated Kaplan-Meier duration of objective response was not estimable in both arms.

Regarding PROs, nirogacestat led to a significant reduction in pain severity at cycle 10 of treatment compared with placebo, with least squares mean change from baseline of –1.5 vs –0.04, respectively (difference, –1.5; 

The median duration of nirogacestat and placebo exposure was 20.6 months (range, 0.3-33.6) and 11.4 months (range, 0.2-32.5), respectively. The median dose intensity was 288.3 mg/d (range, 169-300) with nirogacestat and 300.0 mg/d with placebo (range, 239-300). Dose reductions were common in the nirogacestat arm at 42% (n = 29), but few patients required discontinuation (n = 14; 20%). No dose reductions occurred in the placebo arm, and only one discontinuation was reported.

Regarding safety, Kasper noted that 95% of treatment-emergent adverse effects (TEAEs) were grade 1 or 2 and presented in most patients during cycle 1 of therapy. The most common grade 3 or greater TEAEs in the nirogacestat and placebo arms, respectively, included diarrhea (16% vs 1%), maculopapular rash (6% vs 0%), stomatitis (4% vs 0%), fatigue (3% vs 0%), hypophosphatemia (3% vs 0%), and nausea (1% vs 0%).

There were no TEAEs that led to death in the nirogacestat arm and one fatality due to sepsis in the placebo arm.

“DeFi represents the largest and most rigorous randomized controlled trial conducted to date in desmoid tumors and is also the first phase 3, randomized, controlled trial to demonstrate clinical benefit with a gamma secretase inhibitor in any indication. [As such,] nirogacestat has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment,” Kasper concluded.

Kasper B, Ratan R, Alcindor T, et al. DeFi: a phase 3, randomized controlled trial of nirogacestat versus placebo for progressing desmoid tumors (DT). 

. 2022;33(suppl 7)S808-S869. doi:10.1016/annonc/annonc1089

Data from the Defi trial shows that nirogacestat had a significant reduction in the risk of disease progression for patients with progressive desmoid tumors. 