Gina Mauro

Maintenance therapy with avelumab (Bavencio) plus best supportive care (BSC in the frontline setting of metastatic urothelial cancer showed continued improvement in overall survival (OS) compared with BSC alone in patients who receive first-line chemotherapy, according to updated findings from an exploratory analysis of the phase 3 JAVELIN Bladder 100 trial (NCT02603432).

With an additional 19 months of follow-up, the median OS with avelumab plus BSC was 23.8 months (95% CI, 19.9-28.8) compared with 15.0 months (95% CI, 13.5-18.2) with BSC alone (hazard ratio [HR], 0.76; 95% CI, 0.631-0.915; 

 = .0036). The 2- and 3-year OS rates with avelumab/BSC were 49.8% and 36.0%, respectively; these rates were 38.4% and 29.8%, respectively, in the BSC-alone arm.

Additional data, which were presented during the 2022 Genitourinary Cancers Symposium, showed that the investigator-assessed progression-free survival (PFS) was 5.5 months (95% CI, 4.2-7.2) with avelumab/BSC and 2.1 months (95% CI, 1.9-3.0) with BSC alone, translating to a 46% reduction in the risk of disease progression or death (HR, 0.54; 95% CI, 0.457-0.645; 

 <.0001). The 2- and 3-year PFS rates were 23.4% and 15.9%, respectively, with avelumab/BSC, and 7.1% and 5.3%, respectively, with BSC alone.

Lead study author Thomas Powles, MBBS, MRCP, MD, explained in a poster presentation during the meeting that no new safety signals were identified with the combination.

“In summary, these data show this consistent survival signal, a HR of 0.76 remains clinically meaningful, and this remains the standard of care for those patients with metastatic urothelial cancer who receive first-line chemotherapy, sequencing maintenance avelumab remains attractive for these patients, across broad subgroups of patients, with no new safety signals,” Powles, who is director of Barts Cancer Institute, said.

Earlier data from JAVELIN Bladder 100 led to the FDA approval of frontline maintenance avelumab plus BSC in June 2020 for use in patients with advanced urothelial cancer that did not progress on frontline platinum-based chemotherapy. At the earlier analysis, the median OS was 21.4 months (95% CI, 18.9-26.1) with the addition of avelumab and 14.3 months (95% CI, 12.9-17.9) with BSC alone, leading to a 31% reduction in the risk of death (HR, 0.69; 95% CI; 0.56-0.86; 1-sided 

In the phase 3 JAVELIN Bladder 100 trial, 700 patients with unresectable locally advanced or metastatic urothelial cancer were randomized 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350) until disease progression, unacceptable toxicity, or withdrawal. A total of 358 patients had PD-L1–positive disease.

To be eligible for participation, patients must have had a complete response (CR), partial response (PR), or stable disease (SD) with standard frontline chemotherapy with either cisplatin/gemcitabine or carboplatin/gemcitabine for 4 to 6 cycles.

Stratification factors included best response to frontline chemotherapy (CR or PR vs SD) and metastatic site (visceral vs nonvisceral) when initiating frontline chemotherapy.

The primary end point of the trial was OS in all randomized patients and in the PD-L1–positive population; secondary end points included PFS, objective response per RECIST v1.1 criteria, and safety.

The updated analysis includes at least 2 years of follow-up in all patients, bringing it to a median follow-up of 38 months. The data cutoff date was June 4, 2021.

Further findings showed that the OS benefit was observed across most prespecified subgroups and was found irrespective of site of metastases (visceral: HR, 0.91; 95% CI, 0.713-1.163; non-visceral: HR, 0.60; 95% CI, 0.451-0.798) and type of chemotherapy used (gemcitabine/cisplatin: HR, 0.78; 95% CI, 0.607-1.008; gemcitabine/carboplatin: HR, 0.70; 95% CI, 0.523-0.929; gemcitabine/carboplatin/cisplatin: HR, 0.69; 95% CI, 0.294-1.639). The benefit was not seen in those from Australia (HR, 1.29; 95% CI, 0.697-2.398) and those with liver lesions at baseline (HR, 0.95; 95% CI, 0.585-1.541).

It was also reported that more patients in the BSC-alone arm received subsequent anticancer therapy. Of all patients (n = 700), 52.9% of patients in the avelumab/BSC arm discontinued and received subsequent therapy with a PD-1/PD-L1 inhibitor (11.4%), FGFR inhibitor (2.9%), or another drug (50.6%). In the BSC-alone arm, 72.0% of patients discontinued treatment and went onto a PD-1/PD-L1 inhibitor (53.1%), FGFR inhibitor (3.7%), or another drug (44.6%). Moreover, 12.3% and 2.9% of patients in the investigative and control arms, respectively, were still receiving study treatment.

Of the subgroups who received subsequent therapy (n = 437), 21.6% of those on the avelumab arm (n = 185) were treated with a PD-1/PD-L1 inhibitor, 5.4% a FGFR inhibitor, and 95.7% another drug; these rates were 73.8%, 5.2%, and 61.9%, respectively, in the BSC-alone arm (n = 252).

For patients who discontinued study treatment due to progressive disease (n = 484), 75.6% of those on avelumab/BSC (n = 209) discontinued and received subsequent treatment with a PD-1/PD-L1 inhibitor (12.9%), FGFR inhibitor (4.8%), or another drug (72.2%). Of those in this subgroup who were treated with BSC alone (n = 275), 81.8% of patients discontinued and received subsequent therapy with a PD-1/PD-L1 inhibitor (60.4%), FGFR inhibitor (4.0%), or another drug (50.5%).

Regarding safety, Powles noted that the long-term safety profile with avelumab, which was analyzed in patients receiving the combination for at least 12 months, was consistent with prior studies of the single-agent checkpoint inhibitor. All-grade and grade 3 or higher treatment-emergent adverse effects (TEAEs) that occurred after at least 12 months of treatment were reported in 86.4% of patients who received avelumab/BSC (n = 118) and 47.5% were grade 3 or higher; these effects occurred with onset at any time (n = 344) in 98.3% of patients; 53.8% of patients had grade 3 or higher TEAEs with onset at any time.

Additionally, any-grade and grade 3 or higher treatment-related AEs (TRAEs) occurring after at least 12 months of treatment occurred in 50.0% and 11.9% of patients; these rates were 78.2% and 19.5%, respectively, at any time.

Also, as onset after at least 12 months of treatment, serious TEAEs occurred in 23.7% of patients and serious TRAEs were reported in 5.1% of patients; 36.4% experienced TEAEs that led to interruption of avelumab and 11.0% had TEAEs that led to discontinuation. TEAEs and TRAEs that led to death occurred in 2.5% and 0.8% of patients, respectively. All-grade infusion-related reactions were reported in 3.4% of patients.

For onset of AEs that occurred at any time, serious TEAEs occurred in 30.5% and serious TRAEs were reported in 10.2% of patients; 45.3% of patients had TEAEs that led to avelumab interruption and 14.2% had TEAEs that led to discontinuation. TEAEs and TRAEs that led to death occurred in 2.0% and 0.6% of patients, respectively. All-grade infusion-related reactions were reported in 21.8% of patients.

The most common TEAEs with onset at this time point was urinary tract infection and diarrhea (n = 15; 12.7% each). One patient did experience a TRAE of immune-mediated nephritis after at least 1 year of the combination that led to death.

1. Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. J Clin Oncol. 2022;40(suppl 6):487. doi:10.1200/JCO.2022.40.6_suppl.487

2. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Eng J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788

Articles

An exploratory analysis of the phase 3 JAVELIN Bladder 100 trial shows that the overall survival benefit of frontline maintenance avelumab is sustained in patients with advanced urothelial cancer. 

Upfront Avelumab Maintenance Demonstrates Continued OS Benefit in Advanced UC

Concurrent treatment with ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who were receiving lisocabtagene maraleucel (liso-cel; Breyanzi) led to measurable effects in both chimeric antigen receptor–positive (CAR+) and endogenous T cells, both of which were linked with improved efficacy, according to translational analyses of the ongoing TRANSCEND CLL 004 study (NCT03331198) that were presented during the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting.

Data within a gene set enrichment analysis showed that there was positive enrichment of gene sets linked with cell proliferation, metabolism, and interferon response, as well as a negative enrichment of inflammationassociated gene sets. “These results suggest that ibrutinib may potentiate the efficacy of liso-cel therapy in patients with relapsed/ refractory CLL,” lead study author Jerill Thorpe, a senior scientist at Bristol Myers Squibb, said in a virtual presentation during the meeting.

CAR T-cell therapies have demonstrated potential in CLL. However, Thorpe noted that T-cell dysfunction that is inherent to CLL, including reduced proliferative and cytotoxic capacities, limits the efficacy of this approach. Preclinical data have shown that ibrutinib improves the function of liso-cel that is independent of its antitumor effects.

The phase 1 TRANSCEND CLL 004 trial is evaluating the efficacy and safety of liso-cel monotherapy or with concurrent ibrutinib in patients with relapsed/refractory CLL. Most recently, in data presented at the International Workshop on CLL, the combination was associated with a manageable safety profile for patients with relapsed/refractory CLL or small lymphocytic lymphoma.

At a median follow-up of 17 months, no grade 5 adverse events or grade 4/5 cytokine release syndrome (CRS) or neurological events were reported. Of the 23 evaluable patients, all-grade CRS events occurred in 18 patients (78%), with only 1 (4%) having grade 3 CRS. All-grade neurologic events were reported for 7 patients (30%), and 4 of these (17%) had grade 3 events. Eleven of these patients (48%) required tocilizumab (Actemra) and/or corticosteroids.

Efficacy findings showed that the overall response rate was 95%, which included a 59% complete response (CR) rate and a 36% partial response (PR) rate. Moreover, patients who received liso-cel at 100 × 10

 CAR T cells had a more pronounced CR (61%) and a 29% PR rate, compared with 50% and 25%, respectively, for those who received 50×106 CAR T cells.

At the 2021 SITC Annual Meeting, investigators presented the data from translational analyses from those who received liso-cel alone (n=16) or plus ibrutinib (n=19) from the trial. Liso-cel pharmacokinetics were assessed via flow cytometry.

Further data showed that gene set enrichment analyses through hallmark gene sets demonstrated that CAR+ and endogenous T cells had similar expression profiles in response to ibrutinib in patients on this study. Data showed that at peak CAR+ T-cell expansion, increased expression of pathways were associated with T-cell proliferation and metabolism as well as decreased expression of pathways linked with inflammatory signaling. Additionally, Thorpe noted that treatment with ibrutinib led to increased liso-cel expansion and reduced serum IL-6.

An independently derived CLL ibrutinibresponse gene signature score was increased and sustained over time in CAR+ and endogenous T cells following the liso-cel/ibrutinib combination, but this was not the case with liso-cel alone. Also, a higher ibrutinib gene signature score in CAR+ T cells at time to maximum concentration was linked with increased probability of undetectable minimal residual disease in the bone marrow and in the peripheral blood regardless of treatment arm. When the ibrutinib score was higher in endogenous T cells at 2 months, posttreatment was linked with longer progression-free survival (PFS) (

Additional findings showed that a T-cell exhaustion gene signature was significantly reduced and associated with improved PFS with both liso-cel alone and in combination with ibrutinib. However, Thorpe cautioned that the small sample size of the analysis should be taken into consideration when interpreting the ibrutinib gene expression score and T-cell exhaustion–related gene signature data. “Work is under way to extend this analysis to a larger cohort,” Thorpe said. Also, a lower CAR+ T-cell exhaustion score after 1 month of treatment (≤0.8 vs >0.8) was linked with a longer PFS (

1. Thorpe J, Rytlewski JA, Gillenwater HH, et al. Concurrent ibrutinib enhances T cell function in patients with chronic lymphocytic leukemia (CLL) treated with lisocabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T cell therapy. Presented at: 2021 Society for Immunotherapy of Cancer Annual Meeting; November 10-14, 2021; Washington, DC. 

2. Qin JS, Johnstone TG, Baturevych A, et al. Antitumor potency of an anti-CD19 chimeric antigen receptor t-cell therapy, lisocabtagene maraleucel in combination with ibrutinib or acalabrutinib. J Immunother. 2020;43(4):107-120. doi:10.1097/CJI.0000000000000307 3. Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory CLL/SLL. Presented at: 2021 International Workshop on Chronic Lymphocytic Leukemia; September 17-20, 2021; virtual.

Chimeric antigen receptor T-cell therapies have demonstrated potential in chronic lymphocytic leukemia. However, T-cell dysfunction that is inherent to the disease, including reduced proliferative and cytotoxic capacities, limits the efficacy of this approach, according to an expert.

Adding Ibrutinib Improves the Efficacy of Liso-Cel in R/R CLL

phase 2 DESTINY-Gastric01 trial (NCT03329690), treatment with 

am-trastuzumab deruxtecan-nxki (Enhertu) acheived a 40% reduction in the risk of death compared with standard chemotherapy in patients with HER2-positive gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma, according to updated survival results o presented during the 2022 Gastrointestinal Cancers Symposium.

The updated median overall survival (OS) with trastuzumab deruxtecan remained at 12.5 months (95% CI, 10.3-15.2) compared with 8.9 months (95% CI, 6.4-10.4) with chemotherapy (HR, 0.60; 95% CI, 0.42-0.86).

“With continued follow-up after the primary analysis, trastuzumab deruxtecan demonstrated a clinically meaningful OS benefit and clinically relevant improvement in [objective response rate] compared with standard chemotherapy in HER2-positive advanced gastric or GEJ cancer,” lead study author Kensei Yamaguchi, of The Cancer Institute Hospital of the Japanese Foundation for Cancer Research in Tokyo, Japan, said in a presentation during the meeting.

In January 2021, the FDA approved trastuzumab deruxtecan for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a previous trastuzumab (Herceptin)-based regimen.

The regulatory decision was based on primary findings from the phase 2 DESTINY-Gastric01 study, which showed that the median OS with trastuzumab deruxtecan was 12.5 months (95% CI, 9.6-14.3) compared with 8.4 months (95% CI, 6.9-10.7) with irinotecan or paclitaxel in patients with advanced, HER2-positive gastric or GEJ adenocarcinoma who had progressed following a trastuzumab-based treatment (HR, 0.59; 95% CI, 0.39-0.88; 

DESTINY-Gastric01 is an open-label, multicenter, randomized, phase 2 study. Investigators evaluated trastuzumab deruxtecan versus physician’s choice of standard chemotherapy in patients with HER2-expressing advanced gastric or GEJ adenocarcinoma who had received at least 2 prior regimens, including fluoropyrimidine, a platinum-based agent, and trastuzumab or approved biosimilar.

Patients who had or were suspected to have interstitial lung disease (ILD) or pneumonitis, or a history of noninfectious ILD or pneumonitis that had been treated with steroids, were excluded from enrollment.

A total 188 patients were randomized 2:1 to receive either trastuzumab deruxtecan at 6.4 mg/kg every 3 weeks (n = 126) or chemotherapy with irinotecan or paclitaxel (n = 62). Eighty-six percent of participants received a prior taxane, 71% had ramucirumab (Cyramza), and 31% received prior PD-1/PD-L1 inhibitors.

Stratification factors included by country, ECOG performance status, and HER2 status.

The primary end point of the trial was objective response rate (ORR) per independent central review (ICR), while secondary end points comprised OS, duration of response (DOR), progression-free survival, confirmed ORR, and safety.

The data cutoff date for OS was June 3, 2020, after a median follow-up of 18.5 months.

The median age was 65.5 years (range, 28.0-82.0), 24.1% of patients were female, and most patients were from Japan (79.9%). Forty-nine percent of patients had an ECOG performance of 0, and patients either had intestinal histology (66.3%), diffuse (25.7%), or other (8.1%). Three-fourths of patients (76.3%) had HER2 expression and 87.6% had gastric/GEJ as their primary site. Patients had tumors measuring at less than 5 cm (46.2%), between 5 and 10 cm (31.8%), at least 10 cm (14.9%), or missing (12.1%).

Patients had received either 2 (57.1%), 3 (28.1%), or at least 4 (14.9%) prior systemic therapies, which consisted of trastuzumab (100%), ramucirumab (70.7%), taxane (86.4%), irinotecan or another topoisomerase I inhibitor (7.3%), or an immune checkpoint inhibitor (31.3%). Patients in the trastuzumab deruxtecan group were more than twice as likely to have received 4 or more prior therapies (20.0% vs 9.7%).

Additional data with the longer follow-up showed that the ORR by ICR was 51.3% (95% CI, 41.9%-60.5%) and 14.3% (95% CI, 6.4%-26.2%) with trastuzumab deruxtecan and chemotherapy, respectively, which Yamaguchi said was a statistically significant difference. In the trastuzumab deruxtecan arm, this consisted of a 9.2% complete response (CR) rate and a 42.0% partial response (PR) rate; the stable disease (SD) rate was 35.3% and the progressive disease (PD) rate was 11.8%. Two patients (1.7%) were not evaluable for response.

The confirmed ORR was 42.0% (95% CI, 33.0%-51.4%) with trastuzumab deruxtecan and 12.5% (95% CI, 5.2%-24.1%) with chemotherapy. In the trastuzumab deruxtecan arm, the CR and PR rates were 8.4% and 33.6%, respectively; the SD and PD rates were 43.7% and 11.8%, respectively. Three patients (2.5%) were not evaluable for response.

The confirmed disease control rate was 85.7% (95% CI, 78.1%-91.5%) with trastuzumab deruxtecan compared with 62.5% (95% CI, 48.5%-75.1%) with chemotherapy. The confirmed median DOR was 12.5 months (95% CI, 5.6–not evaluable) and 3.9 months (95% CI, 3.0-4.9), respectively. The median time to response was similar between arms, at 1.5 months (95% CI, 1.4-1.7) with trastuzumab deruxtecan and 1.6 months (95% CI, 1.3-1.7) with chemotherapy.

“This presentation shows that most patients received [trastuzumab deruxtecan had a reduction in tumor size compared with approximately half of patients receiving [chemotherapy],” Yamaguchi said.

Regarding safety, grade 3 or higher adverse events (AEs) occurred in 85.6% of patients on trastuzumab deruxtecan compared with 56.5% of those on chemotherapy. The most common grade or higher AE was decreased neutrophil count (51.2% with trastuzumab deruxtecan vs 24.2% with chemotherapy), followed by anemia (38.4% vs 22.6%, respectively) and decreased white blood cell count (20.8% vs 11.3%).

Sixteen patients (12.8%) experienced ILD/pneumonitis related to trastuzumab deruxtecan as determined by an independent adjudication committee. These occurred at levels of grade 1/2 (n = 13), grade 3 (n = 2), and grade 4 (n = 1). Four ILD/pneumonitis events occurred since the primary analysis; 1 was a grade 1 event and the remaining 3 were grade 2.

The median time to first onset among the 16 overall ILD/pneumonitis events was 102.5 days (range, 36-638).

One treatment-related death from pneumonia occurred on the trastuzumab deruxtecan arm, which had been reported in the primary analysis. No ILD/pneumonitis events nor AE-related deaths occurred on the chemotherapy arm.

“This additional follow-up provides further evidence that trastuzumab deruxtecan is an effective treatment option for patients with HER2-positive advanced gastric cancer or GEJ adenocarcinoma who have progressed after 2 or more previous lines of therapy, including trastuzumab, fluoropyrimidine, and a platinum agent,” Yamaguchi concluded.

DESTINY-Gastric01 trial also has 2 exploratory cohorts focused on the HER2-low population: HER2 (immunohistochemistry [IHC] 2+/in situ hybridization —; n = 21) and HER2 (IHC 1+; n = 24).

1. Yamaguchi K, Bang Y-J, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2–positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: Final overall survival (OS) results from a randomized, multicenter, open-label, phase 2 study (DESTINY-Gastric01). 

. 2022;40(suppl;242). doi:10.1200/JCO.2022.40.4_suppl.242

2. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA. January 15, 2021. Accessed January 15, 2021. http://bit.ly/35KBZ8T.

3. Shitara K, Bang Y-J, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: a randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). 

. 2020;38(suppl 15):4513). doi:10.1200/JCO.2020.38.15_suppl.4513

Updated survival results from the phase 2 DESTINY-Gastric01 trial reveal the survival benefit of trastuzumab deruxtecan HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.

Trastuzumab Deruxtecan Extends Overall Survival in HER2+ Advanced Gastric/GEJ Cancer

Treatment options for endometrial cancer have evolved over recent years, with significant progress seen in 2021 for treating the distinct molecularly-driven subtypes of endometrial cancer. In a presentation during the 39th Annual Chemotherapy Foundation Symposium (CFS®), Bhavana Pothuri, MD, MS, explained the recent advances in subtypes and treatment options for patients with endometrial cancer.

Moreover, Pothuri added that phase 3 trials of other immune-based combinations with chemotherapy, PARP inhibitors, and other novel agents are on the horizon for 2022 and beyond to target some of these select subsets.

“The endometrial cancer treatment paradigm has changed significantly and will continue to evolve,” said Pothuri, a professor in the Department of Obstetrics and Gynecology and Medicine at NYU Grossman School of Medicine, and director of Gynecologic Oncology Clinical Trials at NYU Langone Health’s Laura & Isaac Perlmutter Cancer Center.

Endometrial cancer is comprised of 4 distinct subtypes: POLE-mutant, microsatellite instability– high (MSI-H)/mismatch repair deficient (dMMR), copy number (CN) low, and CN high/

abnormal. Patients with POLE-mutant disease tend to have the best prognosis compared with CN-low and MSI/dMMR disease (intermediate outcomes), and CN-high/TP53 abnormal disease (worst prognosis).

Up until 2017, the sole FDA-approved therapy in the endometrial cancer armamentarium was megestrol acetate. Now, clinical practice has benefitted from 3 new regimens that are available based on patients’ molecular profiles: dostarlimab-gxly (Jemperli), pembrolizumab (Keytruda), and pembrolizumab plus lenvatinib (Lenvima).

Recent Regulatory Advances in Endometrial Cancer Treatment 

The multicenter, single-arm, multiple parallel-cohort, open-label, phase 1b GARNET trial (NCT02715284) evaluated single-agent dostarlimab, a PD-1 inhibitor, in expansion cohorts across multiple tumor types, including endometrial cancer. Patients were treated with dostarlimab at 500 mg of intravenous (IV) every 3 weeks for 4 cycles followed by 1000 mg IV every 6 weeks until disease progression.

The trial featured dose-finding (part 1), fixed-dose safety run-in (part 2A), and expansion cohorts (part 2B). In the expansion cohort, there were 5 groups: dMMR endometrial cancer, MMR proficient (pMMR) endometrial cancer, non–small cell lung cancer, nonendometrial dMMR/MSI-H cancer, and platinum-resistant ovarian cancer.

Dostarlimab elicited a 42.3% ORR in 71 patients with dMMR recurrent or advanced endometrial cancer, which included a 12.7% CR rate and a 29.6% PR rate.

 The DOR was at least 6 months for 93.3% of responders, and the median DOR was NR at a median follow-up of 14.1 months (range, 2.6-22.4+).

At a median follow-up of 16.5 months, the ORR via investigator-assessed irRECIST criteria was 45.5% in patients with dMMR endometrial cancer (n = 110).

Based on the GARNET findings, the FDA granted an accelerated approval in April 2021 to dostarlimab for the treatment of patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers are dMMR, as determined by an FDA-approved test.

The safety profile with dostarlimab was also found to be manageable. Any-grade treatment-emergent AEs (TEAEs) occurred in 69.9% of patients; grade 3 or higher irTRAEs had an incidence of 1.6% or lower. Additionally, increased alanine aminotransferase led to discontinuation in 1.4% of patients, but no TRAEs led to death.

The PD-1 inhibitor pembrolizumab was explored in the open-label, nonrandomized, phase 2 KEYNOTE-158 trial (NCT02628067), which comprised previously treated patients with advanced MSI-H/dMMR tumors, including endometrial cancer. Patients received either pembrolizumab at 200 mg every 3 weeks, or at 10 mg/kg every 2 weeks.

Preliminary findings from all-comers showed that the objective response rate (ORR) was 39.6% (95% CI, 31.7%-47.9%), and responses lasting at least 6 months occurred in 78% of responders.

The FDA granted a tissue-agnostic approval in May 2017 to pembrolizumab based on the preliminary KEYNOTE-158 data, making it the first regulatory approval based on a biomarker regardless of tumor type. 

Longer follow-up of the endometrial cancer cohort was presented at the 2021 European Society of Medical Oncology Congress, which had a data cutoff date of October 5, 2020.

 In the efficacy-evaluable population of the endometrial group (cohorts D and K; n = 79), the ORR was 48% (95% CI, 37%-60%), which included a 14% complete response (CR) rate and a 34% partial response rate; 18% of patients had stable disease.

The median time to response was 2.3 months (range, 1.3-10.6). Additionally, the median duration of response (DOR) had not been reached, but 68% of patients were still in response at 3 years. The median progression-free survival (PFS) and overall survival (OS) was 13.1 months (95% CI, 4.3-34.4) and not reached (NR; 95% CI, 27.2-NR), respectively.

Safety with pembrolizumab was consistent with that of other checkpoint inhibitors. Treatment-related adverse events (TRAEs) occurring in at least 10% of patients included pruritus (24%), fatigue (21%), diarrhea (16%), arthralgia (14%), and nausea (14%), hypothyroidism (13%), and rash (11%). Immune-related AEs (irAEs) at any grade occurred in 28% of patients, but 7% of patients experienced these as grade 3/4 events, including colitis (n = 1), severe skin reactions (n = 2), type 1 diabetes mellitus (n = 1), hepatitis (n = 1), and adrenal insuffi ciency (n = 1). 

Microsatellite Stable/pMMR: Pembrolizumab/Lenvatinib The combination of pembrolizumab and lenvatinib was tested in patients with advanced endometrial cancer who received prior platinum-based chemotherapy in the phase 3 Study-309/ KEYNOTE-775 trial (NCT03517449).

At a median follow-up of 11.4 months and in those with microsatellite stable (MSS)/pMMR disease, the median OS was 17.4 months (95% CI, 14.2-19.9) with pembrolizumab/lenvatinib vs 12.0 months (95% CI, 10.8-13.3) with physician’s choice of chemotherapy (HR, 0.68; 95% CI, 0.56-0.84; 

Results showed that the median PFS in patients with pMMR status was 6.6 months (95% CI, 5.6-7.4) and 3.8 months (95% CI, 3.6-5.0) with pembrolizumab/lenvatinib and chemotherapy, respectively (HR, 0.60; 95% CI, 0.50-0.72;

 < .0001). Here, the ORR was 30.3% (95% CI, 25.5%-35.5%) with pembrolizumab/ lenvatinib vs 15.1% (95% CI, 11.5%-19.3%) with physician’s choice; the median DOR was 9.2 months (range, 1.6-23.7) vs 5.7 months (range, 0.0-24.2), respectively (

In all-comers, the median OS was 18.3 months (95% CI, 15.2-20.5) and 11.4 months (95% CI, 10.5-12,9), respectively (HR, 0.62; 95% CI, 0.51-0.75; 

 < .0001). The median PFS was 7.2 months (95% CI, 5.7-7.6) with pembrolizumab/lenvatinib and 3.8 months (95% CI, 3.6-4.2) with chemotherapy (HR, 0.56; 95% CI, 0.47-0.66; 

 < .0001). The ORRs were 31.9% (95% CI, 27.4%-36.6%) and 14.7% (95% CI, 11.4%-18.4%) with pembrolizumab/lenvatinib and physician’s choice, respectively. Finally, the median DOR was 14.4 months (range, 1.6-24.2) and 5.7 months (range, 0.0-24.2).

Results of a subgroup analysis from KEYNOTE-775 demonstrated the improvement of pembrolizumab/lenvatinib over physician’s choice of therapy in patients with dMMR endometrial cancer. The median OS with pembrolizumab/lenvatinib-treated patients was NR (95% CI, NR-NR) compared with 8.6 months (95% CI, 5.5-12.9) for physician’s choice of therapy (HR, 0.37; 95% CI, 0.22-0.62; 

Here, the median PFS was 10.7 months (95% CI, 5.6-NR) and 3.7 months (95% CI, 3.1-4.4), respectively (HR, 0.36; 95% CI, 0.23- 0.57; 

 < .0001). The ORRs were 40.0% (95% CI, 28.0%-52.9%) and 12.3% (95% CI, 5.5%- 22.8%), respectively.

The combination was given accelerated approval in September 2019, followed by a regular approval in July 2021, for use in patients with advanced endometrial carcinoma that is not MSI-H/dMMR, who have disease progression following prior systemic therapy in any setting and are ineligible for curative surgery or radiation.

Regarding safety, toxicities associated with pembrolizumab/lenvatinib were consistent with those observed with each therapy given individually. The most frequent all-grade and grade 3 or higher TEAEs included hypertension (64% and 38%, respectively), hypothyroidism (all-grade, 57%), diarrhea (54% and 8%, respectively), nausea (all-grade, 50%), and decreased appetite (45% and 8%, respectively.

Additional grade 3 or higher TEAEs with the combination included weight decrease (10%), anemia (6%), asthenia (6%), fatigue (5%), and proteinuria (5%). It should be noted that 5.7% of patients on pembrolizumab/ lenvatinib died due to grade 5 gastrointestinal disorders (1.2%), cardiac disorders (0.5%), general disorders (1.5%), infections (0.7%), decreased appetite (0.2%), and neoplasms, nervous system, psychiatric, renal, reproductive, or respiratory disorders (0.2% each). This was compared with 4.9% of patients on the physician’s choice arm.

“There are overlapping toxicities to also keep in mind, with the diarrhea and the hypothyroidism. It’s important to sort out: Are those related to the immunotherapy or to the lenvatinib?” Pothuri asked.

Ongoing phase 3 trials are tackling more checkpoint inhibitors alone or in combination in endometrial cancer, including RUBY (NCT03981796) with dostarlimab with carboplatin/paclitaxel, RUBY Part 2 with dostarlimab plus niraparib (Zejula; NCT03981796), AtTEnd (NCT03603184) with atezolizumab (Tecentriq), NRGY018 (NCT03914612) with pembrolizumab plus carboplatin/paclitaxel, KEYNOTE-B21 (NCT04634877) with pembrolizumab plus adjuvant chemotherapy with or without radiotherapy, and LEAP-001 (NCT03884101) with pembrolizumab plus lenvatinib.

Although CN-low endometrial cancer represents a subgroup of patients that has long been treated with chemotherapy, Pothuri admits that this likely not the optimal approach for this subset, which current research is attempting to confirm.

An additional trial of interest is the phase 2 ENGOT-EN3/NSGO-PALEO study (NCT02730429), which enrolled patients with primary stage IV or relapsed measurable/ evaluable endometrial cancer who have received at least 1 prior systemic therapy. Patients were randomized 1:1 to receive palbociclib (Ibrance) at 125 mg days 1 to 21 plus letrozole at 2.5 mg on days 1 to 28 vs placebo and letrozole at the same dosage schedule every 28 days until disease progression. The primary end point was investigator-assessed PFS. 

Data showed that the median PFS was 8.3 months and 3.0 months for the palbociclib/ letrozole and placebo/letrozole arms, respectively (HR, 0.56; 95% CI, 0.32-0.98; 

 = .0376).8 Additionally, the disease control rate was 63.6% and 37.8%, respectively.

“This was a phase 2 study and needs further study to determine if there is a role of CDK4/6 and hormonal therapy,” Pothuri added.

Patients with CN-high endometrial cancer form a group that is classically comprised of 

 positive-tumors, Pothuri explained, adding that homologous recombination deficiency is frequent in this subset and may be actionable.

For example, in a phase 2 trial (NCT01367002), patients with HER2-neu uterine serous carcinoma were randomized to receive carboplatin/paclitaxel for 6 cycles with or without IV trastuzumab (Herceptin) until progression or unacceptable toxicity. Data showed that in all patients the median PFS was 12.6 months with the addition of trastuzumab vs 8.0 months for carboplatin/ paclitaxel alone (HR, 0.44; 90% CI, 0.26-0.76; 

 In those with primary stage III to IV disease, the median PFS was 17.9 months and 9.3 months, respectively (HR, 0.40; 90% CI, 0.20-0.80; one-sided 

 = .013). In recurrent disease, the median PFS was 9.2 months and 6.0 months, respectively (HR, 0.14; 90% CI, 0.04-0.53; 

An updated analysis showed an OS benefit in the stage III to IV subgroup, in which the median OS was NR in the trastuzumab arm vs 25.4 months with chemotherapy alone (HR, 0.49; 90% CI, 0.25-0.97; 

“[There is] lots of great interest, and it is really an exciting time to be in the endometrial cancer space,” Pothuri said. “The role of trastuzumab and other HER2/neu-directed therapies for CN-high biomarker-positive tumors also needs further investigation in phase 3 trials.”

1. Pothuri B. Biomarker driven management of endometrial cancer. Presented at: 39th Annual CFS®: November 3-5, 2021; New York, NY. 

2. Levine DA,The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. 

. 2013;497(7447):67-73. doi:10.1038/nature12113 

3. Oaknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the anti–programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair–defi cient endometrial cancer: a nonrandomized phase 1 clinical trial. 

. 2020;6(11):1766-1772. doi:10.1001/jamaoncol.2020.4515 

4. Oaknin A, Gilbert L, Tinker AV, et al. Interim analysis of the immune-related endpoints of the mismatch repair defi cient (dMMR) and profi cient (MMRp) endometrial cancer cohorts from the GARNET study. 

. 2021;162(suppl 1):S12-S13. doi:10.1016/S0090- 8258(21)00672-7 

5. FDA grants accelerated approval to pembrolizumab for fi rst tissue/ site agnostic indication. FDA. May 23, 2017. Accessed November 4, 2021. https://bit.ly/3k62CMS 

6. O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab (pembro) in patients (pts) with microsatellite instability-high (MSI-H) advanced endometrial cancer (EC): Updated results from KEYNOTE-158. 

. 2021;32(suppl_5):S725-S772. doi:10.1016/annonc/ annonc703 

7. Makker V, Colombo N, Herráez AC, et al. A multicenter, open-label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: Study 309/KEYNOTE-775. 

. 2021;162(suppl 1):S4. doi:10.1016/ S0090-8258(21)00657-0

8. Mirza MR, BjørgeL, Marmé F, et al. A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/ recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial. 

. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/ annonc325 

9. Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. 

l. 2018;36(20):2044-2051. doi:10.1200/JCO.2017.76.5966 

10. Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel compared with carboplatin-paclitaxel-trastuzumab in advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress her2/neu (NCT01367002): updated overall survival analysis. 

. 2020;26(15):3928-3935. doi:10.1158/1078-0432.CCR-20-0953

In a presentation during the 39th Annual Chemotherapy Foundation Symposium, Bhavana Pothuri, MD, MS, explained the recent advances in subtypes and treatment options for patients with endometrial cancer.

ICIs Provide New Treatment Options for Subtypes of Endometrial Cancer 

An analysis of the MEDALIST study (NCT02631070) showed more durable response with luspatercept-aamt (Reblozyl) treatment compared with placebo in patients with lower-risk myelodysplastic syndrome (LR-MDS) and anemia that is refractory to or ineligible for erythropoiesis-stimulating agent (ESA) therapy, findings presented during the ASH Annual Meeting 2021 demonstrate.

Data showed that luspatercept also had a more tolerable safety profile when adjusted for exposure. Prior to this, there was a higher proportion of patients on luspatercept vs placebo who experienced fatigue at 30.1% vs 14.5%, respectively. Following exposure adjustment, these rates were more balanced at 26.2 vs 27.1 events per 100 patient-years, respectively.

Additionally, a small number of patients progressed to higher-risk MDS or acute myeloid leukemia (AML), the incidence of which proved to be comparable between the arms. However, those on luspatercept had a longer median time of progression to AML vs those on the placebo arm.

“Up through week 48, patients randomized to luspatercept in the MEDALIST study remained on treatment longer and had more durable and repeated episodes of red blood cell–transfusion independence [RBC-TI] response events than patients on placebo,” Uwe Platzbecker, MD, director of the medical clinic, University Hospital Leipzig, said in a virtual poster presentation on the data.

Patients with LR-MDS who are refractory or ineligible for treatment with ESAs have limited therapeutic options for anemia, Platzbecker noted. Luspatercept, a first-in-class erythroid maturation agent that enhances late-stage erythropoiesis, has FDA and European Medicines Agency indications for the treatment of patients with LR-MDS.

Specifically, the FDA approved luspatercept in April 2020 for the treatment of anemia failing an ESA and requiring 2 or more red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

The regulatory decision is based on overall findings from the phase 3 MEDALIST trial, which showed that luspatercept significantly reduced transfusion burden compared with placebo in patients with LR-MDS.

In the MEDALIST analysis that was presented at the 2021 ASH Annual Meeting, investigators sought to further characterize the effects of luspatercept in this patient population, including duration of treatment and response, median number of study treatment doses received, duration of RBC-TI responses, number of responses per patient, exposure-adjusted rates of treatment-emergent adverse effects (TEAEs), and time to progression to AML.

In MEDALIST, patients had the following: MDS-RS, which comprised at least 15% ring sideroblasts or at least 5% with a 

 mutation, with less than 5% blasts in bone marrow and without del(5q); Revised International Prognostic Scoring System very low-, low-, or intermediate-risk MDS; RBC transfusion dependence (mean ≥2 units per 8 weeks). Moreover, patients must have been either refractory or intolerant to ESAs or be ESA naïve and unlikely to respond to these agents. Patients could not have received prior treatment with disease-modifying agents.

Participants were randomized 2:1 to receive luspatercept at 1.0 mg/kg subcutaneously every 21 days (n = 153) or placebo every 3 weeks (n = 76). On the luspatercept arm, doses were titrated up to a maximum of 1.75 mg/kg. Crossover between the 2 groups was not permitted.

Disease and response assessments were done at week 25 and again every 6 months. Patients were followed for at least 3 years after the final dose for AML progression, subsequent MDS treatment, and overall survival.

As of November 26, 2020, the median duration of treatment was 50.9 weeks (range, 6-207) in the luspatercept arm vs 24.0 weeks (range, 7-103) in the placebo arm; the median doses of study treatment were 17 (range, 2-66) and 8 (range, 3-34), respectively. Moreover, the highest dose level received was 1.75 mg/kg in 68.6% of luspatercept-treated patients and 84.2% in placebo-treated patients.

Duration of response (DOR) was longer with luspatercept than placebo. In patients who achieved RBC-TI for 8 weeks or longer in weeks 1 to 24, the median DOR was 30.2 weeks (range, 8.1-201.1) and 13.6 weeks (range, 9.1-66.4) in patients on luspatercept vs placebo, respectively. In those who achieved RBC-TI for 8 weeks or more in weeks 1 to 48, the median DOR was 29.9 weeks (range, 8.1-201.1) and 17.4 weeks (range, 9.1-66.4), respectively.

Investigators also evaluated the number of responses occurring in responders during the entire treatment period. In the luspatercept responders (n = 58), patients either had 1 (20.7%), 2 (29.3%), 3 (22.4%), or 4 or more responses (27.6%). In the placebo responders (n = 10), 6 patients had 1 response (60.0%), 3 had 2 responses (30.0%), and 1 had 3 responses (10.0%).

“Most responding patients in the luspatercept group had multiple, separate responses,” Platzbecker said.

Regarding safety, luspatercept was still found to have a tolerable safety profile after adjusting for exposure. Exposure-adjusted TEAE incidence rates per 100 person-years included: dizziness (19.2% with luspatercept vs 8.9% with placebo), bronchitis (10.7% vs 2.2%, respectively), diarrhea (25.8% vs 18.4%), nausea (20.1% vs 13.7%), fatigue (26.2% vs 27.1%), asthenia (22.3% vs 21.5%), nasopharyngitis (8.8% vs 9.0%), cough (19.8% vs 25.0%), anemia (8.2% vs 13.6%), and arthralgia (6.3% vs 21.1%).

When investigating the median time from initial MDS diagnosis to AML progression, which occurred in 2.6% of luspatercept-treated patients and 3.9% of those on placebo, Platzbecker noted that this was 61.7 months (range, 56.7-223.6) with luspatercept and 32.7 months (range, 30.1-60.4) with placebo.

In December 2021, the FDA granted priority review to a supplemental biologics license application for luspatercept for the treatment of anemia in adults with non–transfusion dependent β-thalassemia. The European Medicines Agency has also validated the Type II variation for the agent’s use in the same indication.

1. Platzbecker U, Santini V, Komrokji RS, et al. Analysis of duration of response, exposure-adjusted safety, and progression to acute myeloid leukemia for patients with lower-risk myelodysplastic syndromes receiving luspatercept in the MEDALIST study. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 1524.

2. US Food and Drug Administration (FDA) approves Reblozyl (luspatercept-aamt), the first and only erythroid maturation agent, to treat anemia in adults with lower-risk myelodysplastic syndromes (MDS). New release. Bristol Myers Squibb; April 3, 2020. Accessed December 12, 2021. 

3. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. 

 2020;382(2):140–151). doi:10.1056/NEJMoa1908892

4. US Food and Drug Administration accepts for priority review supplemental biologics license application for Reblozyl (luspatercept-aamt) in adults with non-transfusion dependent (NTD) beta thalassemia. News release. Bristol Myers Squibb; December 3, 2021. Accessed December 12, 2021. 

In the MEDALIST analysis that was presented at the 2021 ASH Annual Meeting, investigators sought to further characterize the effects of luspatercept in patients with low-risk myelodysplastic syndrome.

Luspatercept Induces High Response With Tolerable Safety in Low-Risk MDS

Ciltacabtagene autoleucel (cilta-cel) induced objective response in 97.9% of patients with relapsed/refractory multiple myeloma and led to a stringent complete response (sCR) rate of 82.5%, according to updated findings from the phase 1b/2 CARTITUDE-1 trial (NCT03548207) that were presented during the 2021 ASH Annual Meeting.

Additionally, the 2-year progression-free and overall survival (OS) rates were 60.5% and 74.0% in all patients, respectively, and minimal residual disease (MRD) negativity (10-5) was achieved in 92% of evaluable patients for MRD (n = 61). The 2-year progression-free survival (PFS) rates were improved in those who had MRD negativity sustained for at least 6 and 12 months, at 91% and 100%, respectively, as well as the 2-year OS rates at 100% and 100%, respectively.

“These data are encouraging, and they suggest that cilta-cel will be an important treatment option for patients with multiple myeloma,” lead study author Thomas Martin, MD, clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplantation Program, and associate director of the Myeloma Program, of theUniversity of California, San Francisco, said in a presentation on the data.

Cilta-cel is a BCMA-directed CAR T-cell therapy with 2 BCMA-targeting single-domain antibodies that are designed to confer avidity. A biologics license application seeking the approval of the agent is currently under priority review status with the FDA for use in adult patients with relapsed and/or refractory multiple myeloma.

In November 2021, the FDA extended the Prescription Drug User Fee Act target date for the application to review recently submitted data linked with an updated analytical method following an information request that was issued by the agency.

 The new action date is February 28, 2022.

At the prior readout of CARTITUDE-1 data, which had a median follow-up of 12.4 months, the objective response rate with the CAR T-cell therapy was also 98% and the sCR rate was 67%.3 The 1-year PFS and OS rates were 77% and 89%, respectively. Additionally, neither the median PFS (95% CI, 16.8–not estimable [NE]) nor the duration of response (95% CI, 15.9–NE) had been reached.

In the open-label, multicenter, phase 1b/2 CARTITUDE-1 trial, investigators enrolled patients with progressive multiple myeloma as per International Myeloma Working Group criteria, an ECOG performance status of less than 1, who had measurable disease, had received at least 3 prior therapies or were double refractory, and prior exposure to a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.

Following screening and apheresis, patients underwent bridging therapy, if needed, before they received lymphodepletion with cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m

, both administered daily for 3 days. Five to 7 days following lymphodepletion, patients were administered a single infusion of the CAR T-cell therapy at a targeted dose of 0.75 x 10

 CAR-positive viable T cells/kg (range, 0.5 x 10

Following the infusion, patients were evaluated for efficacy and safety.

The primary end point in the phase 1b portion of the trial was to characterize the safety of cilta-cel and confirm the recommended phase 2 dose; in the phase 2 portion, the primary end point was to evaluate the efficacy of cilta-cel.

Regarding baseline characteristics for the 97 patients, the median age was 61.0 years (range, 43-78), 58.8% of patients were male, and 17.5% of patients were Black/African American. Moreover, 19.6% of patients had plasmacytomas that were either extramedullary (13.4%) or bone based (6.2%). High-risk cytogenetic profiles were reported in 23.7% of patients, which included del(17p) in 19.6%, t(14;16) in 2.1%, and t(4;14) in 3.1% of patients. Most patients (91.9%) had tumor BCMA expression on at least 50% of cells.

The median number of prior lines of therapy was 6.0 (range, 3-18) and most patients received at least 5 prior therapies (66.0%). Additionally,87.6% of patients were triple-class refractory and 42.3% were penta-drug refractory. Patients were refractory to carfilzomib (Kyprolis; 64.9%), pomalidomide (Pomalyst; 83.5%), and/or an anti-CD38 antibody (99.0%). Nearly all patients (99.0%) were refractory to their last line of therapy, and the median years since diagnosis was 5.9 years (range, 1.6-18.2).

The median administered dose of cilta-cel was 0.71 x 10

CAR + viable T cells/kg (range, 0.51-0.95 x 10

In the longer follow-up that included the 97.9% ORR (n = 95/97), the very good partial response rate or better was 94.9% and the partial response rate was 12.4%. Of the 2 nonresponders, 1 did not have measurable disease at baseline and consequently could not be evaluated for response but is currently in remission; the second patient had evidence of increased lytic disease and did not experience an objective response before that time.

The median time to first response was 1.0 month (range, 0.9-10.7), the median time to best response was 2.6 months (range, 0.9-17.8), and the median time to complete response or better was 2.9 months (range, 0.9-17.8). The median duration of response was still not estimable (21.8 months–NE).

The median PFS was not reached in both all patients (95% CI, 64.3-79.4%) and in those who achieved a sCR (95% CI, 25.2-NE). In patients who achieved a sCR, the 2-year PFS rate was 71.0%. The median OS has also not been reached.

Cilta-cel was also found to have a manageable safety profile, with no new safety signals, including new events of neurotoxicity and neurocognitive treatment-emergent adverse effects, observed with the longer follow-up.

“After implementation of mitigation strategies throughout the CARTITUDE program with more than 200 patients treated, the incidence of movement in neurocognitive AEs has decreased to 0.5%,” Martin, who is also co-leader of the Cancer Immunology & Immunotherapy Program at the UCSF Helen Diller Family Comprehensive Cancer Center, said. “There were no additional treatment-related deaths at 2 years of follow-up.”

Fifteen secondary primary malignancies were previously reported in 11 patients overall, all of which were found to be unrelated to cilta-cel via investigator assessment; 6 of these new secondary primary malignancies (acute myeloid leukemia, myelodysplastic syndrome, and 4 cutaneous) were reported since the median estimated 1 year of follow-up.

“I’ll remind everyone that this was a heavily pretreated population, with all patients having previously being exposed to IMiDs and alkylators, and the majority of patients receiving stem cell transplantation,” Martin added. “These patients are also experiencing unprecedented survival, and thus, I think these rates of secondary malignancy appear consistent with the population that was involved in this study.

Cilta-cel is currently being tested in earlier-line settings for patients with multiple myeloma, as seen in the CARTITUDE-2 (NCT04133636), CARTITUDE-4 (NCT04181827), and CARTITUDE-5 (NCT04923893) studies.

“Outpatient administration of cilta-cel is also being explored in these studies,” Martin concluded.

1. Martin T, Usmani SZ, Berdeja JG, et al. Updated results from CARTITUDE-1: phase 1b/2Study of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor T cell therapy, in patients with relapsed/refractory multiple myeloma. Presented at: 2021 ASH Annual Meeting; December 11-14, 2021; Atlanta, GA. Abstract 549.

2. US Food and Drug Administration grants BCMA CAR-T cilta-cel priority review for the treatment for relapsed/refractory multiple myeloma. News release. Legend Biotech Corporation; May 26, 2021. Accessed December 13, 2021. 

3. Legend Biotech announces extension of PDUFA date for cilta-cel. News release. Legend Biotech Corporation; November 1, 2021. Accessed December 13, 2021. 

4. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. 

. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8

Updated results from CARTITUDE-1 reveal deep and durable response to ciltacabtagene autoleucel treatment in patients with multiple myeloma. 