Brittany Lovely

With addition 16-month follow-up, the benefit of fam-trastuzumab deruxtecan-nxki (Enhertu) as treatment of patients with HER2-overexpressing metastatic colorectal cancer (mCRC) showed results that were consistent with the primary analysis of the DESTINY-CRC01 trial (NCT03384940) study, according to a presentation given during the 2021 ASCO Annual Meeting.

Data from a cohort of 53 patients with HER2-positive mCRC (cohort A) showed that treatment with trastuzumab deruxtecan elicited a confirmed objective response rate (ORR) of 45.3% (95% CI, 31.6%-59.6%). All responses were partial response (PR), and stable disease was observed in 37.7% of patients. The disease control rate (DCR) was 83.0% (95% CI, 70.2%-91.9%). The median duration of response (DOR) of 7.0 months (95% CI, 5.8-9.5).

Patients included in cohort A had HER2-overexpressing disease defined by investigators as immunohistochemistry (IHC) score 3+ or IHC 2+/in situ hybridization (ISH)+. The ORR for these patients served as the primary end point of the study.

“In the primary analysis of cohort A, results yielded promising primary antitumor activity and a manageable safety profile,” Takayuki Yoshino, MD, said in a presentation of the data. “These [continued] promising results support continued exploration of [trastuzumab deruxtecan] in patients with HER2-positive mCRC.” Yohshino is the director of gastroenterology and gastrointestinal oncology and the head of the Clinical Research Coordinating Division at the National Cancer Center Hospital Japan in Tokyo.

Trastuzumab deruxtecan has demonstrated efficacy across cancers with HER2 expression, including breast and lung cancers. Approximately 25% of patients with CRC have metastatic disease and 2% to 3% of those patients have HER2-amplified tumors. Median overall survival (OS) with available options does not surpass 8 months, representing an unmet clinical need for approved targeted therapies in this patient population.

The phase 2 DESTINY-CRC01 trial enrolled patients with unresectable and/or mCRC with 

 expression via central confirmation whose disease is also 

 V600E wild type. Patients must have received at least 2 prior therapies and prior treatment with anti-HER2 therapy was allowed. Patients were stratified into one of 3 cohorts based on 

 expression: IHC 3+, IHC 2+/ISH+ (cohort A; n = 53), ICH2+/ISH- (cohort B; n = 15), or IHC 1+ (cohort C; n = 18). All patients received trastuzumab deruxtecan 6.4 mg/kg administered once every 3 weeks.

Median follow up at the time of final analysis was 62.4 weeks for cohort A, 27.0 weeks for cohort B, and 16.9 weeks for cohort C. No patients remained on treatment at data cutoff of December 28, 2020. The secondary end points of the study included ORR for cohorts B and C, progression-free survival (PFS), overall survival (OS), DOR, DCR, and safety.

The baseline patient characteristics were consistent across groups (N = 86) with a median age of 58.5 years (range, 27-79), more than half of patients in each cohort were from Europe (53.5%) and left-sided primary tumors were dominant (90.7%). Further, a majority of patients were microsatellite stable (80.2%).

In cohort A, 75.5% of patients had a HER2 status of IHC 3+, 24.5% had IHC 2+, and 98.1% reported ISH+. Because of the overexpression of HER2 in this cohort, 30.2% of patients had prior anti-HER2 treatment which accounted for the total number of patients in the study with prior HER2-targeted therapy.

The median number of prior regimens for metastatic disease was 4 (range, 2-11) and all patients received prior irinotecan.

Additional efficacy results for all cohorts were presented by Yoshino; no patients in cohort B or cohort C had a confirmed response. Stable disease was reported in 60% and 22.2% of patients, respectively, and corresponded with a 60% (95% CI, 32.3%-83.7%) and a 22.2% (95% CI, 6.4%-47.6%) DCR in each cohort, respectively.

The median treatment duration across cohorts A, B, and C was 5.1 months (95% CI, 3.9-7.6), 2.1 months (95% CI, 1.4-2.6), and 1.4 (95% CI, 1.3-1.5), respectively.

The median PFS for cohort A was 6.9 months (95% CI, 4.1-8.7) and the median OS was 15.5 months (95% CI, 8.8-20.8), which Yoshino noted was “very impressive for heavily pretreated patients.” The median PFS for cohorts B and C was 2.1 months (95% CI, 1.4-4.1) and 1.4 months (95% CI, 1.3-2.1), respectively; median OS was 7.3 months (95% CI, 3.0-not estimable) and 7.7 months (95% CI, 2.2-13.9), respectively.

In a subgroup analysis of ORR in cohort A, Yoshino said that no difference exists stratified by age, gender, region, or prior anti-HER2 treatment. However, he highlighted that “some difference exists when stratified by ECOG performance status and HER2 status, with ECOG [performance status] of 0 and [IHC 3+] as good indicators of response.” Specifically, the ORR in patients with ECOG performance status of 0 (n = 37) was 54.1% (95% CI, 36.9%-70.5%) compared with 25.0% (95% CI, 7.3%-52.4%) in those with ECOG performance status of 1 (n = 16). Patients with IHC 3+ (n = 40) had an ORR of 57.5% (95% CI, 40.9%-73.0%) compared with only 7.7% in patients with ICH 2+/ISH+ disease (n = 13).

Finally, the best change in tumor size was reported for cohort A and Yoshino noted that “most patients had tumor reduction regardless of prior HER2-treatment [and] IHC 3+ seemed to be a good indicator of treatment response compared [with] IHC 2+/ISH+.”

The safety profile of trastuzumab deruxtecan was consistent with low grade gastrointestinal and hematologic treatment-emergent adverse effects (TEAEs) being the most common in the overall population (N = 86). The most common TEAEs included nausea (61.6%), anemia (36.0%), fatigue (36.0%), and decreased appetite (34.9%). The most common grade 3 or higher TEAEs were neutropenia (22.1%), anemia (14.0%), decreased platelet count (9.3%), and nausea (5.8%).

TEAEs associated with death were reported in 10.5% of the overall patient population. Drug-related TEAEs associated with death were reported in 3 patients overall (3.5%); 2 patients in cohort A and 1 in cohort B. TEAEs led to drug discontinuation, dose reduction, drug and drug interruption in 15.1%, 17.4%, 39.5% of the overall population, respectively.

Interstitial lung disease (ILD), an AE of special interest, was observed in 8 patients (9.3%); ILD grade 2 was reported in 4 patients, grade 3 was reported in 1 patient, and grade 5 ILD occurred in 3 patients. In the 3 fatal cases, median onset of ILD was 22 days (range, 9-120) and death occurred a median of 6 days after diagnosis (range, 6-19).

For all instances of adjudicated drug-related ILS, the median time to onset was 61 days (range, 9-165) and all 8 patients were treated with corticosteroids; all 4 patients with grade 2 ILD recovered.

Yoshino noted that updated ILD guidelines should be followed which recommend interruption or discontinuation of trastuzumab deruxtecan as soon as ILD is suspected. “[ILD] is an important risk and required careful monitoring and prompt intervention,” he said.

Yoshino T, Di Bartolomeo M, Singh Raghav KP, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). 

. 2021;39(suppl 15):3505.doi:10.1200/JCO.2021.39.15_suppl.3505

Articles

With addition 16-month follow-up, the benefit of fam-trastuzumab deruxtecan-nxki as treatment of patients with HER2-overexpressing metastatic colorectal cancer showed results that were consistent with the primary analysis of the DESTINY-CRC01 trial study.

Trastuzumab Deruxtecan Sustains Efficacy Benefit in HER2-Positive mCRC

Data from the phase 2 NIFTY trial (NCT03524508) demonstrated that liposomal irinotecan (Onivyde) in combination with 5-fluorouracil/leucovorin (5-FU/LV) significantly improved progression-free survival (PFS) and overall survival (OS) for patients with metastatic biliary tract cancer, according to data presented during the 

Patient’s disease had progressed following first-line line gemcitabine/cisplatin. In the study, at a median follow-up of 11.8 months, the median PFS for patients treated with liposomal irinotecan plus 5-FU/LV (n = 88) was 7.1 months (95% CI, 3.6-8.8) compared with 1.4 months (95% CI, 1.2-1.5) for patients treated with 5-FU/LV alone (n = 86). These data correspond with a 44% reduction in the risk of progression (HR, 0.56; 95% CI, 0.39-0.81; 

 = .0019). The median OS was 8.6 months (95% CI, 5.4-10.5) and 5.5 months (95% CI, 4.7-7.2), respectively (HR, 0.68; 95% CI, 0.48-0.98; 

“[Liposomal irinotecan] plus 5-FU/LV should be considered as one of the standard treatments for patients with advanced biliary tract cancer [whose disease has progressed] on gemcitabine/cisplatin,” Changhoon Yoo, MD, PhD, said in a presentation of the data. Yoo added that benefit was observed in the “preplanned subgroup analysis for blind independent central review–assessed PFS, investigator review–assessed PFS, and OS, all [of which] favored the liposomal irinotecan plus 5-FU/LV reporting group and there was no significant interaction.”

Yoo is an assistant professor of oncology at the University of Ulsan College of Medicine and Asan Medical Center in Seoul, Korea.

Liposomal irinotecan is a topoisomerase inhibitor that contains SN-38, an active metabolite of irinotecan that binds reversibly to the topoisomerase 1-DNA complex and prevents religation of the single strand breaks.2 The agent is approved for the treatment of patients with gemcitabine -refractory metastatic pancreatic cancer based on data from the phase 3 NAPOLI-1 trial (NCT01494506).2

Investigators hypothesized that liposomal irinotecan would elicit similar response in patients with biliary tract cancer because of biologic similarities in the tumor stroma. The randomized phase 2 NIFTY trial enrolled patients with metastatic biliary tract cancer with a least 1 measurable lesion per RECIST v1.1. Patients also had to have confirmed radiological progression following first-line gemcitabine/cisplatin, no prior treatment with second-line chemotherapy, adequate organ function, and an ECOG performance status of 0 to 1.1.

Patients were stratified by tumor site—intrahepatic vs extrahepatic/gallbladder—prior surgery with curative intent, and by their participating treatment center. In total 174 patients were randomized to receive liposomal irinotecan 70 mg/m2 on day 1 plus 5-FU (2400 mg/m2) on days 1-2 plus LV (400 mg/m2 on day 1 every 2 weeks or 5-FU/LV every 2 weeks until disease progression per investigator review or intolerable toxicities.

The primary endpoint is PFS by blind independent review committee (BICR). Secondary end points include investigator-assessed PFS, OS, overall response rate (ORR), quality of life assessed by EORTC QLQ-C30 and safety. Radiological tumor assessment by CT or MRI was completed every 6 weeks from day 1 of cycle 1.

The treatment arms were well balanced; the median age in the liposomal irinotecan plus 5-FU/LV arm was 63 years (range, 38-84) and 65 years (range, 37-80) in the 5-FU/LV alone arm. Intrahepatic carcinoma was most common across the groups (39.8% vs 45.3%, respectively), followed by gallbladder (35.2% vs 25.6%) and extrahepatic carcinoma (25.0% vs 29.1%). The median duration of first-line gemcitabine was 5.1 months and most patients had not undergone prior curative-intent surgery, 70.5% and 66.3%, respectively.

Additional PFS data from the BICR–assessed review showed a 6-month PFS rate of 55.7% (95% CI, 44.7%-66.6%) for those in the liposomal irinotecan plus 5-FU/LV arm compared with 26.2% (95% CI, 16.6%-35.8%) in the 5-FU/LV arm.

Investigator-assessed PFS data demonstrated similar efficacy outcomes favoring the addition of liposomal irinotecan. The median PFS in the combination arm was 3.9 months (95% CI, 2.7-5.2) compared with 1.6 months (95% CI, 1.3-2.2) in the 5-FU/LV arm (HR, 0.48; 95% CI, 0.34-0.69; 

 < .0001). The 6-month PFS rates were 30.6% (95% CI, 20.6%-40.5%) and 11.6% (4.9%-18.4%), respectively.

OS rates were also reported for both regimens. The 6-month OS rate for the liposomal irinotecan arm was 60.7% (95% CI, 50.3%-71.2%) compared with 45.9% (35.3%-56.5%) in the 5-FU/LV arm. The 1-year OS rates were 35.4% (95% CI, 24.9%-45.9%) and 22.4% (95% CI, 13.1%-31.7%), respectively.

Liposomal irinotecan plus 5-FU/LV elicited an ORR of 14.8% compared with 5.8% with 5-FU/LV alone as assessed by BICR (

 = .0684). Half of patient in the liposomal irinotecan arm had stable disease and 14.8% had a partial response vs 29.1% and 5.8%, respectively, in the 5-FU/LV arm. More than half of patients in the 5-FU/LV arm had progressive disease (64.0%) vs 29.5% in the liposomal irinotecan arm. No complete responses were reported in either arm. Investigator-assessed review reported similar results.

“The safety profile for liposomal irinotecan plus 5-FU/LV was consistent with that seen in the previous NAPOLI-1 trial for pancreatic cancer,” Yoo explained. “Neutropenia and fatigue were the most commonly observed any-grade and grade 3 and 4 adverse events for the liposomal irinotecan plus 5-FU/LV group,” he said.

Specifically, neutropenia of any grade was reported in 33.0% of patients in the liposomal irinotecan plus 5-FU/LV arm vs 3.5% in the 5-FU/LV arm. Incidence rates of grade 3 or 4 neutropenia were 23.9% and 1.2% in the arms, respectively. Incidence of any grade fatigue was reported in 30.7% of patients in the liposomal irinotecan arm compared with 19.8% in the 5-FU/LV arm; grade 3 or 4 incidence rates were 12.5% vs 3.5%, respectively.

“We assessed patient-reported quality of life using the EORTC QLQ-C30 questionnaire measured over 8 cycles of the study treatment,” Yoo said. “Overall quality of life was well-preserved in both arms and there were no clinically meaningful differences in global health–related quality of life in the arms.”

Finally, 34.9% of patients in the liposomal irinotecan plus 5-FU/LV arm went on to receive post study treatment and the most common therapy was fluoropyrimidine plus cisplatin or oxaliplatin (17.4%). In the 5-FU/LV arm, 31.8% of patients went on to receive post treatment therapy, the most common of which was pembrolizumab (Keytruda; 11.8%).

Yoo concluded by noting that despite the fact that the study was conducted in Korea only, the study was appropriately powered to compare 2 treatment groups and was designed for meticulous tumor response evaluation and that the combination should be considered as a treatment option for patients with biliary tract cancer in the second line.

Yoo C, Kim KP, Kim I, et al. Liposomal irinotecan (nal-IRI) in combination with fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic biliary tract cancer (BTC) after progression on gemcitabine plus cisplatin (GemCis): multicenter comparative randomized phase 2b study (NIFTY). 

. 2021;39(suppl 15):4006. doi:10.1200/JCO.2021.39.15_suppl.4006

Onivyde. Prescribing information. Merrimack Pharmaceuticals Inc. Accessed June 5, 2021. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207793lbl.pdf

Data from the phase 2 NIFTY trial demonstrated that a combination with liposomal irinotecan significantly improved survival in patients with metastatic biliary tract cancer.

Liposomal Irinotecan Combo Improves Outcomes for Patients with Biliary Tract Cancer Who Progressed on Previous Treatment

Early relapse in patients with completely resected 

-mutant non–small cell lung cancer (NSCLC) was delayed with the adjuvant treatment of gefitinib (Iressa). Despite this outcome, the EGFR inhibitor did not significantly improve disease-free survival (DFS) or overall survival (OS) compared with cisplatin/vinorelbine, according to data from the phase 3 Japanese IMPACT trial (UMIN000006252) presented at the 

The median DFS patients treated with gefitinib was 35.9 months (95% CI, 30.0-47.7) compared with 25.0 months (95% CI, 17.7-41.8) in those who received cisplatin/vinorelbine (HR, 0.92; 95% CI, 0.67-1.28; 

 = .63). At a median follow-up of 70.1 months, the 5-year OS rate was 78.0% for 116 patients treated with gefitinib and 74.6% for 116 patients treated with cisplatin/vinorelbine (HR, 1.03; 95% CI, 0.65-1.65; 

“The IMPACT trial failed to demonstrate the superiority of DFS [with] gefitinib compared with cisplatin/vinorelbine for completely unresected NSCLC harboring 

 mutations,” said Hirohito Tada, MD, principal investigator of the trial and member of the Suita Tokushukai Hospital Cancer Center in Japan.

Similar to the OS rates, no significant difference in DFS was seen for patients treated with gefitinib at 2 and 5 years. Specifically, the 2-year DFS rate with gefitinib was 63.7% compared with 52.3% with cisplatin/vinorelbine; 5-year DFS rates were 31.8% vs 34.1%, respectively.

Results of an exploratory subgroup analysis of DFS demonstrated a slight division in elderly patients (age ≥ 70 years) with an HR of 0.589 favoring gefitinib (95% CI, 0.284-1.222). Similarly, in the exploratory analysis of OS, patients age 70 years or more demonstrated better survival with gefitinib compared with cisplatin/vinorelbine (HR, 0.314; 95% CI, 0.101-0.981).

“The apparent noninferiority of DFS and OS may justify the use of adjuvant gefitinib in selected subset of patients, especially those deemed unsuitable for adjuvant chemotherapy with cisplatin/vinorelbine,” Tada said.

Investigators enrolled patients with completely resected 

 mutation–positive (exon 19 deletion or L858R) stage II-III NSCLC. Patients were randomized 1:1 to receive gefitinib 250 mg once daily for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8) every 3 weeks for 4 cycles. Patients who went on to receive gefitinib remained on treatment for the full 24 months or until disease progression or unacceptable toxicity.

The primary end point was DFS in the intention-to-treat population. Secondary end points included OS, safety, and relapse pattern. Efficacy was assessed every 6 months via contrast chest/abdominal CT and every 12 months via brain MRI, PET/CT, or bone scan.

In total, 116 patients were randomized to each arm with safety data reported for 115 in each arm. The baseline characteristics between the gefitinib and cisplatin/vinorelbine cohorts were well balanced, with a majority of patients being female (62.1% and 61.2%, respectively) and reporting an ECOG score of 0 at baseline (81.0% and 78.4%). The median age for both arms was 64 years (range, 34-74).

In an analysis of the mutational profiles, nearly half of patients in each had either an exon 19 deletion (55.2% and 50.9%, respectively) or an exon 21 L858R mutation (44.8% and 48.3%). One patient (0.9%) in the cisplatin/vinorelbine arm had both mutations.

In total, 61.2% of patients completed 24-month treatment cycle of gefitinib and 77.6% of patients complete up to 4 courses of cisplatin/vinorelbine. The discontinuation rates were 38.8% and 22.4%, respectively. the leading cause of discontinuation in the gefitinib arm was relapse or second cancer (16.4%) and patient request (8.6%) in the cisplatin/vinorelbine arm. Of note, 3 treatment-related deaths occurred in the cisplatin/vinorelbine arm.

For patients who experienced local relapse, a majority of patients had local lymph node disease and comprised 15 and 17 patients with gefitinib and cisplatin/vinorelbine, respectively. The most common site of distant metastasis was the brain occurring in 26 and 14 patients, respectively.

The data also included an analysis of subsequent treatments pursued following relapse. In 76 patients with relapse following gefitinib, 67% proceeded to treatment with a tyrosine kinase inhibitor (TKI), including 14 patients who went on to receive osimertinib (Tagrisso). Tada noted that of the 98% of patients in the cisplatin/vinorelbine arm who experienced relapse went on to treatment with a TKI; 7 patients were enrolled in clinical trials including 1 patient to the RELAY trial (NCT02411448) and 2 patients to the FLAURA trial (NCT02296125).

“Eleven patients in the gefitinib arm and 6 patients in the cisplatin arm were not treated a drug, most of them were treated with radiation therapy,” Tada said.

In terms of safety, more patients reported grade 3 and 4 neutropenia and leucopenia compared with gefitinib. Specifically, grade 3 and 4 neutropenia incidence rates were 26.1% and 60.9%, respectively, with cisplatin/vinorelbine compared with 0.9% and 0% with gefitinib. Grade 3 and 4 leucopenia incidence rates were 47.0% and 10.4% with cisplatin/vinorelbine; no incidences of grade 3 or 4 leucopenia were reported with gefitinib.

“On the other hand, [treatment with] gefitinib showed frequent hepatotoxicity and skin events,” Tada noted. Alanine transaminase and aspartate transaminase levels were increased in patients treated with gefitinib with grade 3 and 4 events reported in 22.6%/4.3% and 14.8%/0.9% of patients, respectively. Events of any grade were reported for 68.7% and 65.2% of patients treated with gefitinib, respectively.

No incidences of grade 3 or 4 skin-related events were reported with cisplatin/vinorelbine compared with 4.3% of patients experiencing grade 3 dermatitis acneiform and 4.3% with grade 3 rash. Over half of patients treated with gefitinib had dermatitis acneiform of any grade (58.3%) and 46.1% of patients treated cisplatin/vinorelbine had alopecia of any grade.

Tada H, Mitsudomi T, Yamanaka T, et al; West Japan Oncology Group.Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): a randomized phase 3 trial. 

. 2021;39(suppl 15):8501. doi:10.1200/JCO.2021.39.15_suppl.8501

New data from the phase 3 IMPACT trial shows the advantages and shortcomings of gefitinib in patients with EGFR-mutant non-small cell lung cancer. 

Gefitnib Delays Early Relapse, Fails to Improve DFS or OS Compared to Chemotherapy in EGFR-mutant NSCLC

Durable response rate were observed with afamitresgene autoleucel (afami-cel) as treatment of patients with advanced synovial sarcoma or myxoid/round cell liposarcoma (MRCLS), according to data from the phase 2 SPEARHEAD-1 trial (NCT04044768) presented during the 2021 ASCO Annual Meeting.

As of the March 29, 2021, the evaluable population included 33 patients with synovial sarcoma and 4 with MRCLS. The overall response rate (ORR) for the intention-to-treat population was 39.4% with a disease control rate of 84.8%. Broken down by histology the ORR for patients with synovial sarcoma was 41.4% (n = 12) and 25.0% (n = 1) for patients with MRCLS. Of note, 2 complete responses were observed in patients with synovial sarcoma. Additionally, 1 partial response and stable disease in 2 other patients were reported for patients with MRCLS.

The median duration of response has not yet been reached (range, 4.3+–38.0+).

“The responses [with afami-cel] appear to be protracted, deep, and durable,” Sandra P. D’Angelo, MD, explained in a presentation of the data adding that the data is “encouraging.” D’Angelo is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.

Afami-cel is a specific peptide enhanced affinity receptor (SPEAR) T-cell therapy that is engineered to target MAGE-A4 peptide expressed on tumor cells. In the context of HLA-A*02, MAGE-A4 is highly expressed in synovial sarcoma and MRCLS.

 The T-cell therapy previously demonstrated clinical activity in in various tumors in a phase 1 study (NCT03132922). At the time of data cutoff all partial responses reported for the trial were in patients with synovial carcinoma.

SPEARHEAD-1 is designed to further evaluate the safety and efficacy of afami-cel in HLA-A*02 eligible and MAGE-A4-positive patients with metastatic or advanced synovial sarcoma or MRCLS. Patients must have previously received either an anthracycline- or ifosfamide-containing regimen. The primary end point is ORR. Disease is assessed using CT/MRI every 4 weeks for 6 months and then every 2 months after that via independent review per RECIST v1.1.2 Secondary outcomes include duration of response, time to response, progression-free and overall survival.

Prior to afami-cel infusion, patients received lymphodepleting chemotherapy consisting of fludarabine (30 mg/m

 daily for 4 days) and cyclophosphamide (600 mg/m

 daily for 3 days). Patients then received a single infusion of autologous genetically modified afami-cel at a dose of 1 to 10 × 10

At the time of presentation, 330 patients were screened for HLA-A*02 and of those 176 were determined to have positive disease.

 From these patients, 106 were determined to have MAGE-A4 expression in at least 30% of tumor cells that were at least 2+ as determined by immunohistochemistry.

 In total, 59 patients were enrolled and underwent leukapheresis across the 2 cohorts of the study and 37 were treated with afami-cel. Sixteen patients are awaiting treatment and 5 discontinued prior to T-cell therapy.

At the time of data cutoff, 4 patients who received afami-cel were still awaiting their first efficacy assessment and were not included in the initial analysis.

Of the 37 evaluable patients, the median age was 42 years (range, 24-73) and has a median of 3 prior lines of systemic therapy (range, 1-12). The median cell dose was 8.8 × 10

In terms of safety, treatment-emergent adverse effects (TEAEs) were consistent with those observed for patients who undergo cytotoxic chemotherapy, D’Angelo noted. “The most common TEAEs were likely related to the lymphodepleting regimens [with the] incidence of cytopenia in a majority of patients, with a majority being grade 3 or greater in severity,” she said.

Specifically, the most common TEAEs of any grade were lymphopenia (84%), neutropenia (73%), nausea (65%), and pyrexia (51%). Two AEs were of special interest: cytokine release syndrome and grade 3 or higher prolonged cytopenia at 4 weeks post infusion.

Cytokine release syndrome of any grade was observed in 22 patients (59%) and was grade 3 or higher in 1 patient (3%). The median time to onset was 3 days (range, 1-9) and the median time to resolution was 3 days (range, 1-34). D’Angelo highlighted that more than half (55%) of patients with cytokine release syndrome required treatment with tocilizumab (Actemra).

“Patients often experience cytopenia on these clinical trial for several weeks following lymphodepletion and T-cell infusion. We have seen neutropenia, thrombocytopenia, and anemia of grade 3 or greater in less than 10% of patients,” D’Angelo said. Of the 37 patients treated, 2 experienced grade 3 or higher neutropenia, 1 had thrombocytopenia, and 3 had anemia at the 4-week post infusion analysis.

Additionally, D’Angelo highlighted early analysis of responses that demonstrated clinical activity across a wide range of MAGE-A4 H-scores and cell doses. “Translational data from this trial are continuing to be evaluated and early results from 13 patients with clinical responses [are available] to date,” D’Angelo said.

The median H-score via immunohistochemistry was 225 (range, 134-300) and the median cell dose in the responders was 6.45 × 10

Primary efficacy analysis will be for cohort 1 of the trial and enrollment is complete, according to the agent’s developer Adaptimmune Therapeutics.

“SPEARHEAD-1 is ongoing and data from this trial will be used to support Adaptimmune’s BLA [biologic license application] submission next year [2022],” D’Angelo said.

1. D'Angelo SP, Van Tine BA, Attia S, et al. SPEARHEAD-1: a phase 2 trial of afamitresgene autoleucel (Formerly ADP-A2M4) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma. 

. 2021;39(suppl 15):11504. doi:10.1200/JCO.2021.39.15_suppl.11504

2. Araujo DM, Druta M, Agulnik M, et al. SPEARHEAD-1: a phase II trial of ADP-A2M4 SPEAR T cells in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma. 

. 2021;38(suppl 15):TPS11569. doi:10.1200/JCO.2020.38.15_suppl.TPS11569

3. Hong DS, Van Tine BA, Olszanski AJ, et al. Phase I dose escalation and expansion trial to assess the safety and efficacy of ADP-A2M4 SPEAR T cells in advanced solid tumors. 

. 2021;38(suppl 15):102. doi:10.1200/JCO.2020.38.15_suppl.102

4. Two complete responses and response rate of 41% for people with synovial sarcoma reported at ASCO in Adaptimmune’s phase 2 SPEARHEAD-1 trial. News release. Adpatimmune Therapeutics. May 19, 2021. Accessed June 4, 2021. https://bit.ly/3z5QNvF 

New data from the phase 2 SPEARHEAD-1 trial showed that afami-cel can elicit encouraging responses in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma.

Brittany Lovely | Authors

Articles

Trastuzumab Deruxtecan Sustains Efficacy Benefit in HER2-Positive mCRC

Liposomal Irinotecan Combo Improves Outcomes for Patients with Biliary Tract Cancer Who Progressed on Previous Treatment

Gefitnib Delays Early Relapse, Fails to Improve DFS or OS Compared to Chemotherapy in EGFR-mutant NSCLC

Afami-cel Shows Encouraging Response Durability in Synovial Sarcoma or MRCLS