Gina Mauro

In the phase 2 JACCRO GC-07 trial, patients with stage III gastric cancer who received the combination of S-1 and docetaxel in the adjuvant setting had a 29% reduction in the risk of relapse, according to updated study results presented during the 2021 Gastrointestinal Cancers Symposium.

At a median follow-up of 42.5 months (range, 0.3-85.16), the 3-year relapse-free survival (RFS) rate was 67.74% (95% CI, 63.19-71.84) in the combination arm versus 57.40% in the S-1–alone arm in the intent-to-treat (ITT) population (HR, 0.715; 95% CI, 0.587-0.871; 

 = .0008), meeting the primary end point of the study.

“The 3-year relapse-free survival and overall survival in the S-1 plus docetaxel group were significantly superior to those in the S-1 group,” lead study author Kazuhiro Yoshida, MD, PhD, FACS, who is director of Gifu University Hospital, and professor and chairman, Department of Surgical Oncology at Gifu University, Graduate School of Medicine, in Gifu, Japan, said in a virtual presentation during the meeting. “Adjuvant S-1 plus docetaxel is recommended for patients with stage III gastric cancer who underwent D2 gastrectomy without neoadjuvant chemotherapy.”

In Asia, S-1 is a standard adjuvant chemotherapy regimen for patients with stage II/III gastric cancer; however, outcomes of those with stage III disease are suboptimal.

The randomized, controlled JACCRO GC-07 trial evaluated adjuvant treatment with S-1/docetaxel compared with S-1 alone after D2 gastrectomy for patients with stage III gastric cancer. Patients received either S-1 alone (n = 459) at 80 mg/m2 on days 1 to 28 in every-6-week cycles, or plus docetaxel (n = 453) at 40 mg/m

 on days 1 to 14 every 3 weeks in cycles 2 to 7 followed by S-1 at 80 mg/m

 on days 1 to 28 in cycles 8 and higher, which was every 6 weeks. Treatment was continued in both arms up to 1 year following surgery. Stratification factors included stage (IIIA/IIIB/IIIC), histological type (differentiated/undifferentiated), and institution.

The primary end point was 3-year RFS rate; secondary end points included 3- and 5-year overall survival (OS) rates, 5-year RFS rates, time to treatment failure, and safety.

Patients on the study were aged 20 years to 80 years, had histologically proven gastric cancer that was stage IIIA, stage IIIB, or stage IIIC, had R0 resection with D2 lymph-node dissection, was negative for peritoneal washing cytology, did not receive prior treatment except for initial gastric resection of the primary lesion, had an ECOG performance status of 0 or 1, and were able to start chemotherapy within 42 days of gastrectomy. Patients also needed to have adequate major organ function.

Across both arms, most patients were male (70%), and the median age was 66 years; about one-third of patients in each arm had stage IIIA (32%) stage IIIB (35%), or stage IIIC disease (33%). Five percent of patients had T2 disease, followed by 37.5% and 57.5% with T3 and T4 disease, respectively. One percent of patients in each arm had N0, 10.5% had N1, and 32.5% had N2 disease. More than half (59.5%) of patients had undifferentiated histology, 86.5% had and ECOG performance status of 0, and 59% had a distal gastrectomy. The tumor location varied among patients overall: upper (23.5%), middle (36.5%), lower (37%), and other (3%).

The relative dose intensity was 71.4% in the S-1 alone; in the combination arm, these rates were 61.6% for S-1 and 77.5% for docetaxel.

Prior findings of the trial, which were from a second interim analysis, showed that there was a significant improvement in RFS with the addition of docetaxel, and a recommendation by a Data and Safety Monitoring Committee determined that the study be terminated in September 2017.2

The earlier results showed that the combination led to an estimated 36% reduction in the risk of relapse or death (HR, 0.632; 99.99% CI, 0.400-0.998; 

 = .0007). The median 3-year RFS rate was 65.9% with the combination versus 49.5% with S-1 alone.

When stratified by disease stage, the RFS benefits were observed in patients with stage IIIA (HR, 0.524; 95% CI, 0.285-0.966; 

 = .0351), stage IIIB (HR, 0.614; 95% CI, 0.382-0.989; 

 = .0427) and stage IIIC disease (HR, 0.693; 95% CI, 0.466-1.03; P = .0677). At the time, OS data was immature (

 = .1268). The preplanned analysis, set to take place at 3 years following completion of study enrollment, was performed with updated information of the patients.

The updated data also included all stage III disease subsets. In patients with stage IIIA disease, the 3-year RFS rates were 81.46% and 71.25% with S-1/docetaxel and S-1 alone, respectively (HR; 0.617; 95% CI, 0.403-0.944; 

 = .025). In stage IIIB disease, these rates were 66.14% and 61.61% (HR, 0.881; 95% CI, 0.629-0.234; 

 = .46); in stage IIIC disease, the 3-year RFS rates were 55.85% with S-1/docetaxel and 39.25% with S-1 alone (HR, 0.640; 95% CI, 0.475-0.863; 

The RFS benefit was also observed in the S-1/docetaxel group across most prespecified subgroups, except for N0 stage (HR, 1.291) and N1 stage (HR, 1.154), and those with “other” listed as their extent of gastrectomy (HR, 1.964).

RFS was evaluated by pT and pN stages. In the T2 population (n = 44), the 3-year RFS rates were 100% with S-1/docetaxel and 64.96% with S-1 alone (

 = .0079); in the T3 group (n = 342), these rates were 67.62% and 60.88%. respectively (

 = .19). In the T4 population (n = 526), the 3-year RFS rates were 65.61% and 54.32% with S-1/docetaxel and S-1 alone, respectively (

For pN stage, however, the 3-year RFS rates were 50.00% and 66.67% with the combination and S-1 alone, respectively, in the N0 population (n = 9; 

 = .82). In the N1 group (n = 97), these rates were 80.00% and 85.26%, respectively (

 = .74); the rates were 77.24% and 67.63% in the N2 subgroup (n = 296). In those with N3 disease (n = 510), the 3-year RFS rates were 60.09% with S-1/docetaxel and 46.82% with S-1 alone.

At a median follow-up of 48.25 months (range, 3.25-85.16) and a data cutoff date of September 9, 2020, the 3-year OS rate was 77.68% with S-1/docetaxel compared with 71.17% with S-1 alone (HR, 0.742; 95% CI, 0.596-0.925; 

OS was analyzed across each subset of stage III disease as well. In the stage IIIA subset, the 3-year OS rates were 90.33% and 78.65% with the S-1/docetaxel arm and S-1–alone arm, respectively (HR, 0.523; 95% CI, 0.313-0.873; 

 = .012). The benefit was least prominent in the stage IIIB subset at 73.09% and 77.23%, respectively (HR, 0.988; 95% CI, 0.681-0.434; 

 = .095). In the stage IIIC population, the 3-year OS rates were 70.07% with the combination and 57.24% with S-1 monotherapy (HR, 0.682; 95% CI, 0.493-0.943; 

Similarly, patients with N0 stage disease did not have an OS benefit from S-1/docetaxel (HR, 1.141), and neither did those with “other” extent of gastrectomy (HR, 3.311; 95% CI, 0.299-36.696).

The sites of first relapse varied between arms: local (4.4% with S-1 vs 2.9% with S-1/docetaxel), lymph nodes (15.0% vs 6.4%, respectively), peritoneum (21.4% vs 18.8%), and hematogenous (15.5% vs 9.7%) said Yoshida, noting that some patients relapsed at more than 1 site.


Regarding safety, grade 3/4 adverse events (AEs) occurred in both arms, the most common being neutropenia (39.2% with the combination vs 16.4% with S-1 alone), leukopenia (22.4% vs 2.7%, respectively), febrile neutropenia (5.7% vs 0.4%), and anorexia (13.6% vs 12.0%). There was 1 case of TRD due to respiratory failure in the S-1–alone arm.

When measuring time to treatment failure, Yoshida said treatment compliance was consistent between the 2 groups (

1. Yoshida K, Kodera Y, Kochi M, et al. Confirmed 3-year RFS and OS of the randomized trial of adjuvant S-1 versus S-1 plus docetaxel after curative resection of pStage III gastric cancer (JACCRO GC-07). 

2. Yoshida K. Addition of docetaxel to oral fluoropyrimidine improves efficacy in patients with stage III gastric cancer: interim analysis of JACCRO GC-07, a randomized controlled trial. 

.2019;37(15):1296-1304. doi:10.1200/JCO.18.01138

Articles

In the phase 2 JACCRO GC-07 trial, patients with stage III gastric cancer who received the combination of S-1 and docetaxel in the adjuvant setting had a 29% reduction in the risk of relapse.

Adjuvant S-1 Plus Docetaxel Improves Survival in Stage III Gastric Cancer 

The final overall survival analysis of the phase 3 ClarIDHy trial demonstrated that treatment with ivosidenib tablets (Tibsovo) achieved a 21% reduction in the risk of death in patients with 

-mutant cholangiocarcinoma compared with placebo, according to results presented during the American Society of Clinical Oncology (ASCO) 2021 Gastrointestinal Cancers Symposium.

Findings showed that the median OS was 10.3 months in patients who received ivosidenib compared with 7.5 months for those who received placebo (HR, 0.79; 95% CI, 0.56-1.12; 1-sided 

 = .093). The 6-month OS rates were 69% and 57%, respectively, and were not adjusted for crossover. The 1-year OS rates were 43% and 36% for ivosidenib and placebo, respectively, and also not adjusted for crossover.

Furthermore, results of a prespecified analysis to adjust for crossover to ivosidenib, based on a rank-preserving structural failure time model, showed that the median OS for patients in the placebo arm was 5.1 months (HR, 0.49; 95% CI 0.34-0.70, 1-sided 

Based on these data, Agios Pharmaceuticals, Inc, the developer of ivosidenib, has planned to submit a supplemental new drug application for use of ivosidenib in this setting in the first quarter of 2021.

“The ClarIDHy study represents the first phase 3 study of a targeted, oral therapeutic with a noncytotoxic mechanism of action in advanced 

-mutant cholangiocarcinoma,” lead study author Andrew X. Zhu, MD, director of Liver Cancer Research at Massachusetts General Hospital, and professor of medicine at Harvard Medical School, said in a virtual presentation during the meeting. “Along with a tolerable safety profile and supportive quality of life, these final efficacy results demonstrate the clinical benefit of ivosidenib in this patient population, for which there is an urgent need for new therapies.”

Cholangiocarcinoma is a rare, aggressive cancer of the bile ducts in and outside the liver. 

 mutations are found in an estimated 20% of intrahepatic cholangiocarcinoma cases. Although current therapeutics for localized disease include surgery, radiation, and/or other ablative treatments, no FDA-approved systemic treatments are available for patients with 

-mutated disease, and gemcitabine-based regimens are often used in those with newly diagnosed or advanced disease.

Ivosidenib is an oral, first-in class, oral small molecule IDH1 inhibitor. In May 2019, the FDA approved ivosidenib for the treatment of patients with IDH1-mutant acute myeloid leukemia (AML), specifically for those with newly diagnosed disease who are at least 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy; as well as for patients with relapsed/refractory AML.

In the international, randomized, phase 3 ClarIDHy study, 187 previously treated patients with IDH1-mutant cholangiocarcinoma were randomized 2:1 to receive oral ivosidenib at 500 mg daily (n= 126) or placebo (n = 61). Crossover from the placebo arm to ivosidenib was permitted following signs of radiographic progression.

Prior to study entry, patients aged 18 years or older with 

-mutant cholangiocarcinoma had received 1 to 2 prior therapies, including 1 gemcitabine- or 5-fluorouracil–containing regimen. The median age of patients was 62 years, 92.4% had intrahepatic disease, and 92.3% had metastatic disease. Nearly half of patients (46.7%) had received 2 prior therapies, and the remainder received 1. All patients had confirmed 

 mutations by next-generation sequencing in R132C (71.05%) and the rest were in R132L/G/S/H. Also, 35.4% of patients had an ECOG performance status of 0, while 63.3% had a status of 1.

The primary end point of the trial was progression-free survival (PFS) by blinded independent review; key secondary end points were OS, objective response rate, PFS by local review, safety and tolerability, pharmacokinetics and pharmacodynamics, as well as health-related quality-of-life (QoL).

ClarIDHy data showed that ivosidenib led to a 63% reduction in the risk of disease progression or death

 versus placebo in previously treated patients with IDH1-mutant advanced cholangiocarcinoma.3 The median PFS was 2.7 months versus 1.4 months for ivosidenib and placebo, respectively (HR, 0.37; 95% CI, 0.25-0.54; 1-sided P <.0001). Six- and 12-month PFS rates were 32% and 22% with ivosidenib, no patients on placebo were progression free at either of these time points. Moreover, the disease control rates were 53% and 28%, respectively.

The median OS at the time of publication was 10.8 months with ivosidenib and 9.7 months for placebo (HR, 0.69; 95% CI, 0.44-1.10; 

 = .06). At 6 months, 67% of patients in the ivosidenib arm remained alive versus 59% on placebo. At 1 year, the OS rate was 48% with ivosidenib and 38% for placebo.

With the longer follow-up, in which the data cutoff was May 31, 2020, investigators reported that 70.5% of patients had crossed over to received ivosidenib. Eighteen patients on placebo did not cross over because of death (n = 12), withdrawal of consent (n = 2), were on placebo but never dosed (n = 2), took the incorrect drug (n = 1), or received another therapy (n = 1). Disease progression was the most common reason for treatment discontinuation in both the ivosidenib (74.8%) and placebo arms (86.4%). Nineteen percent and 14.8% of patients on ivosidenib and placebo, respectively, remain on study.

The median duration of treatment of patients on ivosidenib was 2.8 months versus 1.6 months for those on placebo; patients who crossed over to receive ivosidenib had a median treatment duration of 2.7 months. Twenty-five patients (15.1%) remained on ivosidenib treatment for at least 1 year; this includes 6 patients who crossed over from the placebo group.

When assessed for QoL through the EORTC QLQ-C30 questionnaire, ivosidenib was found to preserve patients’ physical functioning from baseline, while those on placebo had a reported decline from baseline at day 1 of cycle 2 (2-sided 

 = .004). Moreover, ivosidenib improved patients’ pain at day 1 of cycle 2 compared with placebo, which was assessed by the EORTC QLQ-BIL21 questionnaire (2-sided 

 = .039). On day 1 of cycle 3, there was no difference observed.

On other prespecified QoL subscales, such as QLQ-C30 Appetite Loss and QLQ-BIL21 Pain and Eating, neither arm was favored.

Regarding safety, updated results showed that the most common treatment-emergent adverse effects (AEs) in the total ivosidenib and placebo groups, comprised of nausea (38.0% vs 28.8%), diarrhea (33.1% vs 16.9%), fatigue (28.9% vs 16.9%), abdominal pain (22.3% vs 15.3%), cough (21.7% vs 8.5%), decreased appetite (21.7% vs 18.6%), ascites (19.9% vs 15.3%), vomiting (19.9% vs 18.6%), and anemia (18.1% vs 5.1%).

Grade 3 or higher treatment-emergent AEs (TEAEs) were seen in 53% of ivosidenib-treated patients, which includes those who also crossed over from placebo, compared with 37.3% for placebo-treated patients. The most common grade 3 or higher TEAEs reported in the ivosidenib and placebo groups, respectively, were ascites (9.0% vs 6.8%, respectively), blood bilirubin increase (5.4% vs 1.7%), and anemia (7.2% vs 0%).

Treatment-emergent AEs led to discontinuation for 8.5% of those in the placebo arm compared with 6.6% of those in the ivosidenib group; dose reductions occurred in 3.0% of those on ivosidenib compared with 0% of patients on placebo. Additionally, dose interruptions were reported in 30.1% and 18.6% of patients on ivosidenib and placebo, respectively.

1. Zhu AX, Macarulla T, Javle MM, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. 

. 2021;39(suppl 3):266. http://bit.ly/2KobGOh.

2. Agios presents final data from phase 3 ClarIDHy study of Tibsovo (ivosidenib tablets) in patients with previously treated IDH1-mutant cholangiocarcinoma. News release. Agios Pharmaceuticals. January 17, 2021. Accessed January 17, 2021. https://bit.ly/2LWKg2r.

3. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. 

. 2020;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1

The final overall survival analysis of the phase 3 ClarIDHy trial demonstrated that treatment with ivosidenib tablets achieved a 21% reduction in the risk of death in patients with IDH1-mutant cholangiocarcinoma compared with placebo.

Ivosidenib Improves Overall Survival in Advanced IDH1+ Cholangiocarcinoma

-positive advanced gastric or gastroesophageal junction adenocarcinoma, the combination of bemarituzumab combined with mFOLFOX6 achieved a 56% reduction in the risk of disease progression or death compared with placebo, according to results of the phase 2 FIGHT study (NCT03694522) that were presented during the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

 overexpression via immunohistochemistry (IHC) 2+/3+ at 10% or more of the sample (n = 96), the median progression-free survival (PFS) was 14.1 months and 7.3 months, respectively (HR, 0.44; 95% CI, 0.25-0.77). The 1-year PFS rates were 57.0% and 26.4% in the combination and placebo arms, respectively.

 overexpression via IHC 2+/3+ in at least 5% of the sample (n = 118), the median PFS was 10.2 months in the bemarituzumab arm versus 7.3 months with the placebo arm (HR, 0.54; 95% CI, 0.33-0.87). The 1-year PFS rates were 56.3% and 28.6%, respectively.

In the intent-to-treat (ITT) population (n = 155), the median PFS was 9.5 months and 7.4 months for the combination and placebo arms, respectively (HR, 0.68; 95% CI, 0.44-1.04; 

 = .0727). The 1-year PFS rates were 52.5% and 33.8%, respectively.

“The FIGHT trial is the first study to evaluate targeting the overexpression of 

 in any cancer, and is the first randomized dataset of any FGFR inhibitor in any malignancy,” lead study author Zev A. Wainberg, MD, co-director of the University of California, Los Angeles (UCLA) Gastrointestinal Oncology Program, director of the Early Phase Clinical Research Program, Jonsson Comprehensive Cancer Center, and associate professor of medicine and surgery at the David Geffen School of Medicine at UCLA, in a virtual presentation during the meeting. “Bemarituzumab when added to mFOLFOX6 chemotherapy led to clinically meaningful and statistically significant improvements in PFS, OS, and ORR.”

Bemarituzumab is an IgG1 antibody that is specific for FGFR2b isoform, which blocks growth factor signaling and works through an antibody-dependent cellular cytotoxicity mechanism, said Wainberg. Prior single-agent activity with bemarituzumab in later-line 

-positive gastric cancer elicited an 18% objective response rate (ORR) with no dose-limiting toxicities.2

In the double-blind, placebo-controlled, 

phase 2 FIGHT trial, patients with unresectable locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma

were randomized 1:1 to receive bemarituzumab with mFOLFOX6 (n = 77) or placebo/mFOLFOX6 (n = 76), every 2 weeks. The primary end point was investigator-assessed PFS; secondary end points included overall survival (OS) and ORR.

To be eligible for enrollment, patients could not have received prior therapy, had RECIST v1.1 evaluable disease, harbored 

 amplification by circulating tumor DNA (ctDNA), an ECOG performance status of 0 or 1, did not harbor HER2 positivity, and could have received 1 dose of mFOLFOX6. Patients were stratified by geographic region, single dose of mFOLFOX6 during screening, and prior adjuvant or neoadjuvant chemotherapy.

Initially, the trial was designed as a registrational phase 3 trial with a planned 548 patients; however, the design was amended after enrolling 155 patients to a proof-of-concept phase 2 study with prespecified statistical assumptions.

Baseline demographics were similar between the 2 arms; overall, the median age was 59.7 years, more than half of patients were male, and about 45 patients in each arm were Asian. Patients were from the United States/European Union (42.6%), China (17.4%), or rest of Asia (40.0%). In the bemarituzumab arm, 94.8% and 15.6% of patients had 

 overexpression and amplification, respectively, compared with 97.4% and 17.9% in the placebo arm. Additionally, 83.2% of patients were IHC positive and ctDNA negative; 12.9% of patients were IHC positive and ctDNA positive, and 3.9% of patients were IHC negative and ctDNA positive.

Additionally, in the ITT population, data showed that the median OS was not reached in the bemarituzumab arm versus 12.9 months in the placebo arm (HR, 0.58; 95% CI, 0.35-0.95; 

 = .0268). The 1-year OS rates were 65.3% and 56.9%, respectively.

Similar to the PFS trends, the OS benefit with bemarituzumab increased with higher levels of 

 overexpression. In the IHC 2+/3+ in at least 5% of the sample, the median OS was not reached with bemarituzumab versus 12.5 months with the placebo arm (HR, 0.52; 95% CI, 0.30-0.91). The 1-year OS rates were 67.9% and 55.5%, respectively.

In the IHC 2+/3+ in at least 10% of the sample, the median OS was not reached compared with 11.1 months with bemarituzumab and the placebo arms, respectively (HR, 0.41; 95% CI, 0.22-0.79).

The ORR in the ITT population was 47% with the combination and 33% with placebo/mFOLFOX6. For patients who had measurable disease at baseline, the ORRs were 53% and 40%, respectively, with a best change in tumor size at –41.7% and –29.9%, respectively. The median time to response was 1.84 months with bemarituzumab and 1.67 months with placebo/mFOLFOX6, and the median duration of response was 12.2 months and 7.1 months, respectively.

Regarding safety, grade 3 or higher adverse events (AEs) were observed in 82.9% of patients on bemarituzumab versus 74.0% of those on the placebo/mFOLFOX6 arm; the 2 most prominent increases in grade 3 or higher AEs with bemarituzumab included stomatitis (9.2% vs 1.3% with placebo) and dry eye (2.6% vs 0%, respectively). Grade 5 AEs occurred in 5 and 4 patients, respectively. Serious AEs occurred in 31.6% of bemarituzumab-treated patients and in 36.4% of patients on the placebo arm. AEs that led to mFOLFOX6 discontinuation occurred in 46.1% and 36.4% of patients on bemarituzumab/mFOLFOX6 and placebo/mFOLFOX6, respectively; these rates were 34.2% and 5.2% for bemarituzumab and placebo discontinuation, respectively. The duration of exposure to mFOLFOX6 was similar across the bemarituzumab (29.80 weeks) and placebo arms (26.47 weeks).

Corneal-related toxicities tend to be associated with FGFR inhibitors, Wainberg explained. All-grade and grade 3 or higher corneal-related AEs occurred in 67.1% and 23.7% of bemarituzumab-treated patients versus 10.4% and 0% of those on placebo/mFOLFOX6, respectively. The mean time to onset, of any grade, was 16.1 weeks on bemarituzumab/mFOLFOX6 and 11.6 weeks on placebo. Twenty patients discontinued bemarituzumab treatment due to corneal AEs, and 12 AEs did resolve with a median time to resolution of 27.0 weeks.

“The FIGHT trial results support a prospective randomized phase 3 study in gastric/gastroesophageal adenocarcinoma, and the evaluation of bemarituzumab in other 

-positive tumor types,” Wainberg concluded.

1. Wainberg ZA, Enzinge P, Kang Y, et al. A double-blind randomized study of bemarituzumab (bema) plus mFOLFOX6 versus placebo plus mFOLFOX6 as first-line treatment for advanced gastric/gastroesophageal junction cancer (FIGHT). 

2. Catenacci DVT, Rasco D, Lee J, et al. Phase I escalation and expansion study of bemarituzumab (FPA144) in patients with advanced solid tumors and FGFR2b-selected gastroesophageal adenocarcinoma. 

. 2020;38(21):2418-2426. doi:10.1200/JCO.19.01824

In the frontline setting of FGFR2b-positive advanced gastric or gastroesophageal junction adenocarcinoma, the combination of bemarituzumab combined with mFOLFOX6 achieved a 56% reduction in the risk of disease progression or death compared with placebo.

Frontline Bemarituzumab Doublet Prolongs Survival in Advanced FGFR2b+ Gastric/GEJ Cancer

In the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577), patient with breast cancer who received plinabulin and pegfilgrastim (Neulasta) experienced a reduction in the incidence of profound neutropenia (CIN) that was 53% more effective than that of chemotherapy, according to findings presented during the 2020 San Antonio Breast Cancer Symposium.

Results showed that the incidence of profound neutropenia was 21.6% with the combination vs 46.4% with pegfilgrastim alone (

 = .0001) in patients with breast cancer who were undergoing chemotherapy with docetaxel, doxorubicin, and cyclophosphamide (TAC). Moreover, plinabulin/pegfilgrastim also reduced the risk of febrile neutropenia by 41% compared with pegfilgrastim alone, based on a reduction of profound neutropenia.

There was also a 50% reduction in the mean duration of profound neutropenia with the combination at 0.3 days compared with 0.6 days with pegfilgrastim alone (

“It is clinically meaningful to reduce [febrile neutropenia] risk by 41% in the combination, compared to pegfilgrastim alone, which is the only major breakthrough advancement in CIN prevention in the last 30 years. The CIN protection from plinabulin added to pegfilgrastim, particularly in the first week of chemotherapy when 75% of CIN-related complications occur before the effect of pegfilgrastim kicks-in in week 2, fills the treatment gap in current standard of care,” said principal investigator Douglas Blayney, MD, professor of medicine at Stanford Cancer Center. “The combination of plinabulin with pegfilgrastim represents a major advancement in offering protection against CIN, with the potential to reduce [febrile neutropenia] risk, in the care of cancer patients.”

In September 2020, the FDA granted a breakthrough therapy designation to the combination of plinabulin, which is a differentiated immune and stem cell modulator, in combination with pegfilgrastim for the treatment for patients with chemotherapy-induced neutropenia. The designation for plinabulin was based on clinical evidence from PROTECTIVE-2 trial and other CIN studies. China’s National Medical Products Administration also granted plinabulin breakthrough status in September 2020.

In the double-blind, active-controlled, international, phase 3 PROTECTIVE-2 study, 221 patients were randomized to receive docetaxel, doxorubicin, and cyclophosphamide (day 1 dose) in a 21-day cycle along with 40 mg of plinabulin (day 1 dose) and 6 mg pegfilgrastim (day 2 dose; n = 111) versus a single 6-mg dose of pegfilgrastim (day 2 dose; n = 110).

Prior reported results showed that pegfilgrastim also improved the following secondary end points: duration of severe neutropenia (DSN) cycle 1 on days 1 through 8 (absolute neutrophil count [ANC] <0.5 x 109 cells/L; 

 = .0002), and duration of profound neutropenia cycle 1 (ANC <0.1 x 109 cells/L; 

The full findings had reported that the improvement in preventing grade 4 chemotherapy-induced neutropenia (CIN) was statistically significant in cycle 1 at 31.5% with the combination versus 13.6% with pegfilgrastim alone (

 = .0015), and key secondary end points were also met, including DSN cycle 1 D1 to 8, DSN cycle 1, and mean ANC nadir cycle 1.

Moreover, there was a lower frequency of grade 4 adverse events with the combination versus pegfilgrastim alone, at 58.6% and 80.0%, respectively.

In the phase 2 portion of the trial, the combination resulted in a reduction in CIN compared with pegfilgrastim monotherapy in patients who received TAC chemotherapy.

 Here, rates of grade 3 neutropenia were 81% vs 50% in the control and investigational arms, respectively (

< .05). Lower rates of grade 4 neutropenia were also observed in the combination arm compared with the monotherapy arm, at 38% vs 57%, respectively.

Moreover, patients who received treatment with the plinabulin combination experienced less bone pain compared with those who received single-agent pegfilgrastim. Bone pain for day 1 or longer was reported in 6% of those on the combination versus 95% of those on the monotherapy (

< .001). Rates of bone pain that persisted for 4 days or longer were 0% vs 33% in the investigational and control arms, respectively (

The PROTECTIVE-2 results were further supported by other CIN studies that were conducted, data of which showed the early onset action of agent in week 1 with regard to neutrophil protection in various cancer types and several chemotherapies.

1. Blayney DW, Huang L, Mohanlal R. Superior and clinically meaningful protection against profound neutropenia with the plinabulin/pegfilgrastim (Plin/Peg) combination versus peg in breast cancer patients receiving TAC chemotherapy: phase 3 results from Protective-2 (BPI-2358-106). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PS13-53-01.

2. BeyondSpring announces positive topline results from its PROTECTIVE-2 phase 3 registrational trial of plinabulin in combination with pegfilgrastim for prevention of chemotherapy-induced neutropenia. News release. BeyondSpring Therapeutics. November 16, 2020. Accessed November 16, 2020. https://bit.ly/35BVosZ

3. BeyondSpring announces positive topline interim results from PROTECTIVE-2 (Study 106) phase 3 trial evaluating superiority of plinabulin in combination with Neulasta for chemotherapy-induced neutropenia prevention. News release. BeyondSpring Pharmaceuticals. June 15, 2020. Accessed September 10, 2020. https://bit.ly/3fval2d

In the phase 3 PROTECTIVE-2 trial, patient with breast cancer who received plinabulin and pegfilgrastim experienced a reduction in the incidence of profound neutropenia that was 53% more effective than that of chemotherapy, according to findings presented during the 2020 San Antonio Breast Cancer Symposium. 

Gina Mauro | Authors

Articles

Adjuvant S-1 Plus Docetaxel Improves Survival in Stage III Gastric Cancer

Ivosidenib Improves Overall Survival in Advanced IDH1+ Cholangiocarcinoma

Frontline Bemarituzumab Doublet Prolongs Survival in Advanced FGFR2b+ Gastric/GEJ Cancer

Plinabulin/Pegfilgrastim Shows Improved Prevention of Profound Neutropenia in Breast Cancer Versus Chemotherapy