Chris Ryan

In the phase 3 KEYNOTE-062 trial (NCT02494583), pembrolizumab (Keytruda) monotherapy showed noninferiority to chemotherapy for overall survival (OS) in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and a PD-L1 combined positive score (CPS) of 1 or higher, and a clinically meaningful benefit over chemotherapy in those with a CPS of 10 or higher, but when combined with chemotherapy, pembrolizumab was not superior to chemotherapy alone in either patient group.

The long-term findings from the trial, which were presented during the 2022 Gastrointestinal Cancers Symposium, showed that at a median follow-up of 54.3 months (range, 46.8-66.1), pembrolizumab monotherapy resulted in a median OS of 10.6 months (95% CI, 7.7-13.8) in those with a PD-L1 CPS of 1 or higher vs 11.1 months (95% CI, 9.2-12.8) with chemotherapy (HR, 0.90; 95% CI, 0.75-1.08). In those with a PD-L1 CPS of 10 or higher, single-agent pembrolizumab resulted in a median OS of 17.4 months (95% CI, 9.1-23.1) vs 10.8 months (95% CI, 8.5-13.8) with chemotherapy (HR, 0.62; 95% CI, 0.45-0.86).

In the subset of patients with a PD-L1 CPS of 1 or higher, the median OS with pembrolizumab plus chemotherapy was 12.5 months (95% CI, 10.8-13.9) vs 11.1 months (95% CI, 9.2-12.8) with chemotherapy alone (HR, 0.85; 95% CI, 0.71-1.02). In the subset of patients with a PD-L1 CPS of 10 or higher, the median OS with pembrolizumab/chemotherapy was 12.3 months (95% CI, 9.5-14.8) vs 10.8 months (95% CI, 8.5-13.8) with chemotherapy alone (HR, 0.76; 95% CI, 0.56-1.03). 

The addition of pembrolizumab to chemotherapy also failed to significantly improve progression-free survival (PFS) over chemotherapy alone in both subsets. The combination resulted in a median PFS of 6.9 months (95% CI, 5.8-7.8) vs 6.5 months (95% CI, 5.7-7.1) with chemotherapy alone in patients with a PD-L1 CPS of 1 or higher (HR, 0.84; 95% CI, 0.70-1.01). In the patient population with a CPS of 10 or higher, the median PFS with pembrolizumab plus chemotherapy was 5.8 months (95% CI, 5.6-8.2) vs 6.2 months (95% CI, 5.4-7.0) with chemotherapy alone (HR, 0.71; 95% CI, 0.52-0.96).

"With respect to the combination arms, not much has changed over the past 2 years," study author Zev A. Wainberg, MD, of UCLA Health, said in a presentation on the data. "We still see, unfortunately, and perplexingly to some extent, a negative impact of chemotherapy and pembrolizumab over chemotherapy alone. We see that in the patient population with a CPS of greater than 1. We see that as well in the patient population with a CPS greater than 10. Similarly, with respect to PFS, there was no advantage, even 2 years later, with pembrolizumab plus chemotherapy over chemotherapy alone in either [subset]."

Topline findings from KEYNOTE-062 trial showed that the study missed its primary OS end point.2 Subsequently, in July 2021, Merck announced plans to withdraw the accelerated approval indication for pembrolizumab in the third-line setting for select patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma with a CPS of 1 or higher, since the approval was contingent on positive findings from KEYNOTE-062 and the phase 3 KEYNOTE-061 trial (NCT02370498).3 The immunotherapy missed each trial’s primary end point of OS and PFS in those with a PD-L1 CPS of 1 or higher.

KEYNOTE-062 enrolled patients with locally advanced, unresectable, or metastatic gastric or GEJ adenocarcinoma. Patients needed to have a CPS of at least 1, HER2 neu negativity, and an ECOG performance status of 0 or 1. Patients were stratified by region, whether they had locally advanced or metastatic disease, and whether they received 5-fluorouracil (5-FU) or capecitabine.

A total of 763 patients were randomized 1:1:1 to receive pembrolizumab at 200 mg once every 3 weeks for up to 35 cycles (n = 256), pembrolizumab at the same schedule in combination with chemotherapy (n = 257), or chemotherapy alone (n = 250). Chemotherapy treatment included cisplatin at 80 mg/m2 every 3 weeks plus 5-FU at a daily dose of 800 mg/m2 for 5 days every 3 weeks or capecitabine twice daily for days 1 though 14 every 3 weeks. Treatment was continued until intolerable toxicity, disease progression, or patient or physician withdrawal.

The primary end points of the trial were OS and PFS, and the secondary end points included overall response rate and safety.

Additional data presented during the Symposium showed that in the subset of patients with a CPS of 1 or higher, the 24-month OS rate with pembrolizumab monotherapy was 26.6% vs 18.8% with chemotherapy. In the subset of patients with a CPS of 10 or higher, the 24-month OS rates with single-agent pembrolizumab and chemotherapy were 39.1% and 21.1%, respectively.

The combination of pembrolizumab and chemotherapy resulted in a 24-month OS rate of 24.5% in those with a CPS of 1 or higher, and 28.3% in those with a CPS of 10 or higher; these rates were 18.8% and 21.1% with chemotherapy alone, respectively.

Updated safety data showed that adverse effects (AEs) of any grade occurred in 95.3%, 97.6%, and 98.4% of patients in the pembrolizumab monotherapy, pembrolizumab/chemotherapy, and chemotherapy-alone arms, respectively; grade 3 or higher AEs were observed in 50.4%, 84.8%, and 82.4% of patients, respectively.

Within the pembrolizumab monotherapy arm, 11.4% of patients experienced AEs that led to treatment discontinuation and 9.8% had AEs that led to death; these rates were 34.0% and 6.8%, respectively, in the pembrolizumab/chemotherapy arm, and 23.8% and 5.3%, respectively in the chemotherapy-alone arm.

Wainberg noted that treatment with pembrolizumab alone resulted in fewer treatment-related AEs. Specifically, 54.7% of patients who received single-agent pembrolizumab experienced at least 1 treatment-related AE (TRAE) vs 94.0% and 91.8% of those in the combination and chemotherapy-alone arms, respectively. Furthermore, 17.3% of patients in the pembrolizumab group experienced grade 3 to 5 TRAEs, vs 73.2% and 69.3% of those in the combination and chemotherapy arms, respectively. Treatment-related AEs led to discontinuation in 4.3% of those on the pembrolizumab monotherapy arm and resulted in death in 1.2% of these patients; these rates were 27.6% and 2.0%, respectively, in the combination arm and 18.0% and 1.2%, respectively, in the chemotherapy arm.

The long-term follow-up safety and efficacy data from the KEYNOTE-062 trial were consistent with the final analysis, according to Wainberg.

Despite the fact that pembrolizumab plus chemotherapy did not prove to be superior to chemotherapy with regard to OS in either CPS subset, there are plans to further evaluate the combination in the first-line treatment of patients with gastric or GEJ adenocarcinoma, as part of the phase 3 KEYNOTE-859 trial (NCT03675737).

"The large, randomized, phase 3 trial has completed enrollment [and more information will] hopefully be available in the next year or so,” Wainberg concluded. “[That study] is looking at different cut offs of CPS and different end points."

1. Wainberg ZA, Shitara K, Van Cutsem E, et al. Pembrolizumab with or without chemotherapy versus chemotherapy alone for patients with PD-L1–positive advanced gastric or gastroesophageal junction adenocarcinoma: update from the phase 3 KEYNOTE-062 trial. 

. 2022;40(suppl 4):243. doi:10.1200/JCO.2022.40.4_suppl.243

2. Merck provides update on phase 3 KEYNOTE-062 trial evaluating KEYTRUDA (pembrolizumab) as monotherapy and in combination with chemotherapy for first-line treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma. News release. Merck; April 25, 2019. Accessed January 20, 2022. 

3. Merck provides update on KEYTRUDA (pembrolizumab) indication in third-line gastric cancer in the US. News release. Merck; July 1, 2021. Accessed January 20, 2022. 

Articles

Results from the phase 3 KEYNOTE-062 study appear mixed for both pembrolizumab monotherapy versus chemotherapy and pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced gastric or gastroesophageal junction adenocarcinoma.

Frontline Pembrolizumab Noninferior But Not Superior to Frontline Chemo in PD-L1+ Gastric/GEJ Adenocarcinoma

Second-line treatment with lisocabtagene maraleucel (liso-cel; Breyanzi) improved quality of life (QoL) in patients with relapsed or refractory large B-cell lymphoma (LBCL) compared with standard of care (SOC), according to data from a comparative analysis of the phase 3 TRANSFORM trial (NCT03575351) presented during the 2021 ASH Annual Meeting.

Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – 30 items (EORTC QLQ-C30), a linear mixed model for repeated measures (MMRM) group analysis found that those in the liso-cel arm had more favorable overall least square (LS) mean changes from baseline to day 126 vs the SOC arm in most of the domains analyzed.

Evaluable patients who received the CAR T-cell therapy (n = 47) experienced a mean change in cognitive functioning of 2.21 (range, -1.48 to 5.90) vs -2.09 (range, -6.00 to 1.83) in those who received SOC (n = 43); this translated to a difference of 4.30 (range, -0.76 to 9.36) on day 126 from baseline. Those in the liso-cel arm also experienced a mean change in fatigue of -1.95 (range, -7.40 to 3.51) compared with 3.75 (range, -2.17 to 9.68) in the SOC arm, equating to a difference of -5.70 (range, -13.24 to 1.84) on day 126 from baseline. In these domains, the liso-cel group improved, as the SOC group deteriorated.

Additionally, the liso-cel arm had a mean change in global health status/QoL (GH/QoL) of 3.08 (range, -1.83 to 7.99) from baseline to day 126; the SOC arm experienced a mean change of 0.04 (range, -5.24 to 5.31), resulting in a difference of 3.04 (range, -3.62 to 9.70) between the 2 arms. The liso-cel group also experienced mean changes in physical functioning and pain of -2.75 (range, -6.76 to 1.25) and -11.14 (range, -16.37 to -5.92), respectively, compared with -2.17 (range, -6.64 to 2.30) and -15.56 (range, -21.25 to -9.88), respectively, for the SOC group. The differences between the 2 arms in physical functioning and pain were -0.58 (range, -6.17 to 5.01) and 4.42 (range, -2.72 to 11.56), respectively.

Individual-level analyses demonstrated that the proportion of patients with meaningful improvement was higher for GH/QoL, and deterioration was lower with liso-cel vs SOC from day 126 to month 6.

At the 6-month mark, 53% of patients in the liso-cel arm reported improvement in GH/QoL, compared with 14% of those in the SOC arm. Eighteen of patients in the liso-cel arm reported deterioration of GH/QoL at this time point vs 57% of those on the SOC arm. Furthermore, 47% of patients in the liso-cel group experienced improvement in fatigue at 6 months vs 29% of those in the SOC group. Eighteen percent of patients in the liso-cel arm experienced deterioration with regard to fatigue at this time point vs 71% of those in the SOC arm.

“It is important to emphasize that higher scores on functionality domains and lower scores on symptom domains indicate a better QoL,” presenting study author Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center, said during the poster presentation on the data.

TRANSFORM enrolled patients between the ages of 18 and 75 years who had aggressive non-Hodgkin lymphoma and who were refractory or relapsed 12 months or less following first-line treatment containing an anthracycline and a CD20-targeted agent. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, be eligible for hematopoietic stem cell transplantation and have a left ventricular ejection fraction of over 40%. Patients with secondary central nervous system lymphoma were permitted. There was no minimum lymphocyte count.

Participants were randomized 1:1 to receive either SOC comprised of 3 cycles of salvage chemotherapy and BEAM (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem cell transplantation for responding patients, or liso-cel following lymphodepletion treatment. Crossover to the liso-cel arm was permitted for patients who failed SOC treatment. Patients received the CAR T-cell therapy at a dose of 100 x 106 CAR-positive T cells.

The primary end point of the trial was event-free survival (EFS), and key secondary end points comprised complete response (CR) rate, progression-free survival (PFS), and overall survival. Other end points of interest included duration of response, objective response rate, PFS on the next line of treatment, safery, and patient-reported outcomes (PROs).

In a prespecified interim analysis of data from TRANSFORM, liso-cel demonstrated highly statistically relevant and clinically meaningful improvement vs SOC regarding the primary end point of EFS, plus secondary end points of CR and PFS.2 In the analysis presented during the 2021 ASH Annual Meeting, Abramson reported findings pertaining to QoL.

Investigators evaluated QoL by leveraging the EORTC QLQ-C30 and FACT-LymS tools. The former evaluated cancer-associated symptoms and functioning and is comprised of 30 items that address 15 domains. Primary functional domains of interest that were evaluated in TRANSFORM were GH/QoL, physical functioning, and cognitive functioning. Primary symptom domains of interest were fatigue and pain. The FACT-LymS tool evaluated symptoms that were specific to lymphoma and was comprised of 15 items. With this assessment, higher scores are representative of better QoL.

To assess the between-treatment differences in overall LS mean change from baseline for each primary domain, a MMRM analysis was conducted, and this leveraged data collected up to day 126 for visits with a sample size per are of 10 or more. All analyses were prospectively defined, and the findings reported during the 2021 ASH Annual Meeting are descriptive.

To be eligible for PRO analyses, patients needed to complete a baseline assessment and at least 1 post-baseline assessment. Notably, a similar proportion of patients were included in the EORTC QLQ-C30 analyses sets for liso-cel (51%) and SOC (47%).

In the liso-cel group of 92 patients, 47 were evaluable for the EORTC QLQ-C30 analysis, and 45 were evaluable for the FACT LymS analysis. Notably, 45 patients were not included in the EORTC QLQ-C30 analysis because they did not complete a baseline assessment (n = 28), a post-baseline assessment (n = 1), or both (n = 16).

In the SOC group, 43 and 40 out of 92 patients were evaluable for the EORTC QLQ-C30 and FACT Lym-S analyses, respectively. Patients from this group were excluded from the EORTC QLQ-C30 analysis due to lack of baseline assessment (n = 20), lack of post-baseline assessment (n = 6), or lack of bothj (n = 23).

Additional data presented during the 2021 ASH Annual Meeting showed that with regard to the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS), the difference in mean change between the 2 arms was -0.16 (range, -2.71 to 2.40). On the 126-day mark, the liso-cel group had a FACT-LymS mean change of 1.48 (range, -0.30 to 3.26), compared with 1.63 (range, -0.41 to 3.68) in the SOC group. Notably, for FACT-LymS, similar proportions of patients between the investigative and control arms experienced deterioration (24% and 29%, respectively) and improvement (47% and 43%) at month 6.

“Overall QoL was either improved or maintained from baseline in patients with relapsed/refractory LBCL who received liso-cel as second-line treatment,” Abramson concluded. “These results were achieved despite only responders to salvage chemotherapy remaining in the SOC arm past day 64. These findings corroborated with previously reported HRQoL associated with liso-cel treatment.”

1.Abramson J, Solomon S, Arnason J, et al. Improved quality of life (QOL) with lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, compared with standard of care (SOC) as second-line (2L) treatment in patients (Pts) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL): results from the phase 3 transform study. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 3845.

2.Bristol Myers Squibb announces positive topline results from phase 3 TRANSFORM trial evaluating Breyanzi (lisocabtagene maraleucel) versus chemotherapy followed by stem cell transplant in second-line relapsed or refractory large B-cell lymphoma. News release. Bristol Myers Squibb; June 10, 2021. Accessed December 14, 2021. 

Liso-cel was found to improve quality of life in patients with large B-cell lymphoma compared with standard of care. 


Compared with SOC, Liso-Cel Improved QoL in Second-Line Treatment of Relapsed or Refractory LBCL

In patients with multiple myeloma who experienced early clinical relapse following initial therapy, a single infusion of ciltacabtagene autoleucel (cilta-cel) produced early and deep responses and encouraging minimal residue disease (MRD) negativity, according to data from cohort B of the phase 2 CARTITUDE-2 trial (NCT04133636).

The findings, which were presented during the 2021 ASH Annual Meeting, showed that of the 13 patients who had MRD-evaluable samples at the 10-5 threshold, 92.3% (95% CI, 64.0%-99.8%) achieved negative status at the time of data cutoff.

At a median follow-up of 10.6 months, the CAR T-cell therapy elicited an objective response rate (ORR) of 95% (95% CI, 74.0%-99.9%). A complete response (CR) or better was achieved in 79% (95% CI, 54.4%-93.9%) of patients, and 90% (95% CI, 66.9%-98.7%) experienced a very good partial response (VGPR) or better.

The median time to first response to cilta-cel was 1.0 month (range, 0.9-2.6), and the median time to best response was 2.5 months (range, 0.9-11.8). Notably, the median duration of response (DOR) was not yet reached. Moreover, the 6-month progression-free survival (PFS) rate was 90% (95% CI, 64.1%-97.3%); at 12 months, this rate was 84% (95% CI, 57.9%-94.5%).

“The efficacy and safety profile of cilta-cel in these high-risk patients with myeloma who experienced early clinical relapse following initial therapy support the continued exploration of cilta-cel in earlier lines of treatment,” lead study author Niels Van de Donk, MD, PhD, of Amsterdam UMC, Vrije Universiteit Amsterdam, said in a poster presentation on the data.

Patients with multiple myeloma who experience early clinical relapse, despite treatment with proteasome inhibitors (PI), immunomodulatory drugs (IMiD), and monoclonal antibodies, have a median survival of less than 2 years.2 Van de Donk explained that this underscores an unmet need for novel and durable treatment strategies for this population.

The multicohort CARTITUDE-2 trial was launched to evaluate cilta-cel in earlier-line settings for patients with multiple myeloma. Data from the initial analysis of cohort B showed that at a median follow-up of 4.7 months, cilta-cel induced an ORR of 89%, with 28% of patients achieving a CR or better and 67% experiencing a VGPR or better. At the 2021 ASH Annual Meeting, investigators shared updated findings from cohort B.

Cohort B of the trial was comprised of patients with early relapse following initial therapy with a PI or an IMiD. Early relapse was defined as disease progression in 12 months or less following autologous stem cell transplant (ASCT), or the initiation of an anti-myeloma therapy for those who have not undergone transplant. Patients needed to be treatment-naïve to CAR T-cell and anti-BCMA therapies.

Study participants underwent a screening period that ranged from 1 to 28 days, followed by apheresis, and then bridging therapy, as needed. Patients then received lymphodepletion comprised of cytarabine at a daily dose of 300 mg/m2 in combination with fludarabine at 30 mg/m2 from days -5 to -3. On day 1, patients then received a single infusion of cilta-cel at a target dose 0.75 × 106 (0.5-1.0 × 106) CAR-positive viable T cells/kg.

Post-infusion assessments were conducted from day 1 to 100, and these looked at safety, efficacy, pharmacokinetic, pharmacodynamic, and biomarker data. From day 101 up to the end of the cohort, post-treatment assessments will be conducted.

The primary objective for cohort B of the CARTITUDE-2 trial was MRD 10-5 negativity, as assessed by next-generation sequencing. Secondary objectives included ORR, DOR, time and duration of MRD negativity, and incidence and severity of adverse effects.

At baseline, patients had a median age of 58 years (range, 44-67), and 73.7% were male. Additionally, 10.5% of patients had extramedullary plasmacytomas, 21.1% had bone marrow plasma cells greater than 60%, and 15.8% had a high-risk cytogenetic profile with tumors harboring del17p. All 19 patients received 1 prior line of therapy. Just under 80% (78.9%) of patients previously underwent ASCT.

Moreover, 21.1% of patients were triple-class exposed, and 15.8% were triple-class refractory. No patients were penta-drug exposed or refractory. Additionally, 78.9%, 31.6%, 15.8%, and 10.5% were refractory to lenalidomide (Revlimid), bortezomib (Velcade), daratumumab (Darzalex), and thalidomide (Thalomid), respectively. Overall, 78.9% of patients were refractory to their last line of therapy. The median time from initial diagnosis to trial enrollment was 1.15 years (range, 0.5-1.9).

The safety profile for cilta-cel was manageable, according to Van de Donk. The incidence of initial grade 3 or 4 cytopenias that did not recover to grade 2 or less by day 60 was 16% for thrombocytopenia and 11% for lymphopenia and neutropenia.

Additionally, cytokine release syndrome (CRS) was reported by 84% of patients, with 1 patient (5%) experiencing a grade 4 event. The median time to CRS was 8 days (range, 5-11), with a median duration of 3.5 days (range, 1-7). Notably, 63% of patients received tocilizumab (Actemra) to manage this effect, and CRS resolved in all patients.

Moreover, 1 patient experienced grade 1 immune effector cell–associated neurotoxicity syndrome; the time to onset of this effect was 11 days and the duration was 4 days. One patient experienced grade 3 movement and neurocognitive treatment-emergent toxicities; the patient presented with bradykinesia, bradypsychia, cognitive impairment, encephalopathy, gait disturbance, and motor dysfunction on day 38 following cilta-cel infusion.

Van de Donk noted this patient had multiple risk factors associated with the development of these toxicities.

“He was treated with high-dose methylprednisolone, plasmapheresis, and intravenous immunoglobulin. This patient is neurologically stable, with some improvement, and has since achieved CR to cilta-cel,” Van de Donk said. “Overall, implementation of patient management strategies across the CARTITUDE program has reduced the incidence and severity of movement and neurocognitive TEAEs.”

One patient died following infusion of the CAR T-cell therapy; the death occurred on day 158 and it was because of disease progression.

Van de Donk N, Delforge M, Agha M, et al. Efficacy and safety of ciltacabtagene autoleucel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy, in patients with multiple myeloma and early relapse after initial therapy. Presented at: 2021 ASH Annual Meeting; December 11-14, 2021; Atlanta, GA. Abstract 2910.

Majithia N, Rajkumar SV, Lacy MQ, et al. Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents. 

. 2016;30(11):2208-2213. doi:10.1038/leu.2016.147

An early and deep response was seen with a single infusion of cilta-cel in patients with multiple myeloma who experienced early clinical relapse. 

As Second-Line Treatment in Early Relapse Myeloma, Cilta-Cel Produces Deep Responses

The use of ciltacabtagene autoleucel (cilta-cel) in patients with triple-class relapsed/refractory multiple myeloma demonstrated a significant efficacy advantage over physician’s choice of treatment (PCT), according to data from a meta-analysis of the phase 1/2 CARTITUDE-1 trial (NCT03548207).

Results from the main analysis, which leveraged indirect treatment comparisons (ITCs), were presented during the ASH Annual Meeting 2021. The overall effect estimate was found to be strongly in favor of cilta-cel, with a 76% reduction in the risk of death compared with PCT in both the modified intent-to-treat (mITT; HR, 0.24; 95% CI, 0.22-0.27) and ITT (HR, 0.24; 95% CI, 0.10-0.60) populations. The CAR T-cell therapy was also found to reduce the risk of a next line of treatment by 83% vs PCT.

Consistent results were reported across the additional analyses on the first index dates for OS. The CAR T-cell therapy reduced the risk of death by 78% vs PCT (HR, 0.22; 95% CI, 0.14-0.35) in the mITT population. In the ITT population, the CAR T-cell therapy reduced the risk of death by 72% vs standard of care (HR, 0.28; 95% CI, 0.17-0.47). An analysis using first index dates was also conducted for PFS, and the effect estimate indicated that cilta-cel reduced the risk of disease progression and death by 78% (HR, 0.22; 95% CI, 0.08-0.43) in the mITT population and 82% (HR, 0.28; 95% CI, 0.10-0.45) in the ITT population.

"These results are consistent across both populations and all available index dates," presenting study author Parameswaran Hari, MD, MRCP, MS, of the Medical College of Wisconsin, said in a poster presentation on the data. "In the absence of head-to-head randomized comparisons between cilta-cel and treatments used in real-world clinical practice, our meta-analysis of ITCs suggests that cilta-cel offers substantially more clinical benefit than PCT [in this population]."

The CAR T-cell therapy is currently under investigation in patients with triple-class exposed relapsed or refractory multiple myeloma as part of the CARTITUDE-1 trial. No clear standard of care currently exists for this population; as such, no randomized clinical trials could be designed to directly compare the efficacy of cilta-cel with other relevant options. To gain some insight, ITCs between cilta-cel and PCT have previously been conducted.

For the analysis presented at the 2021 ASH Annual Meeting, investigators pooled ITCs examining cilta-cel vs PCT in this patient population to derive single-summary effect estimates of comparative effectiveness. A total of 5 ITCs were included in the analysis.

Outcomes of interest included overall survival, progression-free survival, time to next treatment, and objective response rate (ORR), and if data from at least ITCs were available for one of these outcomes, then a meta-analysis was conducted. These analyses utilized robust variance estimation to account for the use of CARTITUDE-1 in each pairwise ITC. Investigators calculated pooled summary effect estimates with the use of a random effects model; these were presented as hazard ratios with corresponding 95% confidence intervals.

Moreover, analyses comprised ITCs that used all index dates for both populations, and additional analyses were performed with ITCs using the first index date for these populations.

Data on PCT were extracted from the long-term follow-up results of 3 global randomized clinical trials with daratumumab (Darzalex): the phase 3 POLLUX trial (NCT02076009), the phase 3 CASTOR trial (NCT02136134), and the phase 1 EQUULEUS trial (NCT01998971). PTC data were also leveraged from the Flatiron database, the US-based retrospective MAMMOTH study, a representative German patient registry maintained by Oncology Information Service (OIS), and the prospective LocoMMotion study.

Notably, each of the ITCs utilized a data cutoff of February 2021 for CARTITUDE-1 except for the MAMMOTH ITC, which used a data cutoff of September 2020. Patients in the PCT group of each ITC had to satisfy the key eligibility criteria for CARTITUDE-1 and who received at least 1 subsequent therapy after meeting these criteria; by using inverse probability of treatment weighing, investigators made this comparable to CARTITUDE-1.

The mITT population was comprised of those who had been infused with cilta-cel in CARTITUDE-1, and all eligible patients in the PCT arms who had not progressed or died within 47 days (52 days for OIs and LocoMMotion) after treatment initiation. The ITT population was comprised of all enrolled patients in CARTITUDE-1 and all eligible patients in the PCT arms.

The ITT population included 229 patients from the Flatiron Health Multiple Myeloma Registry, 329 patients from the post-daratumumab clinical trials cohort, 190 patients from the MAMMOTH trial, 222 from the OIS Registry, and 246 from the LocoMMotion study. The mITT population was comprised of 196 patients from the Flatiron registry, 267 patients from the post-daratumumab cohort, 122 patients from MAMMOTH, 174 patients from the OIS Registry, and 163 patients from LocoMMotion.

Data from the first index date analysis for ORR showed that the CAR T-cell therapy significantly increased the odds of achieving response by 86 and 14 times compared with PCT in the mITT and ITT populations, respectively.

“In the absence of head-to-head randomized comparisons between cilta-cel and treatments used in real-world clinical practice, this meta-analysis of indirect treatment comparisons suggests that cilta-cel offers substantially more clinical benefit than physician’s choice of treatment for patients with triple-class exposed relapsed or refractory multiple myeloma,” the study authors concluded.

Hari P, Berdeja J, De Stefano V, et al. Meta-analysis of ciltacabtagene autoleucel versus physician’s choice in the treatment of patients with relapsed or refractory multiple myeloma. Presented at: 2021 ASH Annual Meeting; December 11-14, 2021; Atlanta, GA. Abstract 1676.

A CARTITUDE-1 meta-analysis data shows that ciltacabtagene autoleucel  performs better than standard-of-care therapy in terms of survival and response rates in patients with triple-class relapsed/refractory multiple myeloma.

Cilta-cel Demonstrates Significant Advantage Over SOC in Triple-Class R/R Myeloma

Results from the phase 3 GMMG-HD7 trial, show that minimal residual disease (MRD) rates were superior when isatuximab (Sarclisa) was added to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Isa-RVd) as indication therapy compared with RVd alone in patients with transplant-eligible newly diagnosed multiple myeloma.

The results of the study, which were presented during the 2021 ASH Annual Meeting, showed that patients who received Isa-RVd (n = 331) achieved a MRD negativity rate of 50.1% at the end of induction therapy vs 35.6% in those who were given RVd alone (n = 329; odds ratio, 1.83; 95% CI, 1.34-2.51; 

 < .001). Consistent benefit favoring the isatuximab regimen was observed across all clinically relevant subsets.

“This is the highest MRD negativity [rate] described to date in a randomized phase 3 trial setting [for newly diagnosed, transplant-eligible multiple myeloma]," lead study author Hartmut Goldschmidt, MD, of University Hospital Heidelberg and National Center of Tumor Diseases, said during a presentation on the data. “The addition of isatuximab had no significant impact on the safety profile or dose intensity of RVd.”

RVd has long been considered the standard preferred first-line regimen for patients with transplant-eligible, newly diagnosed multiple myeloma. It is important that efforts are made to maximize treatment response before transplant to improve outcomes in these patients.

Isatuximab was designed to target a specific epitope on CD38, which is highly and uniformly expressed in myeloma cells. In March 2020, the FDA approved isatuximab for use in combination with pomalidomide (Pomalyst) and dexamethasone for use in adult patients with multiple myeloma who had received 2 or more prior therapies, including lenalidomide (Revlimid) and a proteasome inhibitor.

The following year, in March 2021, the regulatory agency approved isatuximab plus carfilzomib (Kyprolis) and dexamethasone for use in adult patients with relapsed or refractory multiple myeloma who have previously received 1 to 3 lines of therapy.

GMMG-HD7 is the first phase 3 trial to examine the addition of isatuximab to RVd in the induction and maintenance treatment of patients with newly diagnosed multiple myeloma who were eligible to receive high-dose therapy (HDT) and autologous stem cell transplant (ASCT). To be eligible for enrollment, patients needed to be between the ages of 18 and 70 years.

A total of 662 patients were enrolled to the trial and were randomized 1:1 to receive isatuximab plus RVd (n = 331) or RVd (n = 329). In the induction phase of treatment, patients received treatment in three 6-week cycles. Following HDT and ASCT, patients will enter the maintenance phase of the trial, where they will be randomized again to receive either isatuximab plus lenalidomide or lenalidomide alone for 4-week cycles. The study will come to completion after 3 years of treatment or when patients experienced progressive disease.

The primary end point of the trial is MRD negativity at the end of induction treatment. Secondary end points include complete response (CR) after induction and safety.

The data cutoff at the time of the presentation was April 2021. The study is still evaluating patients following the second randomization in the maintenance phase of the trial, according to Goldschmidt.

Baseline characteristics were found to be generally balanced between the 2 treatment arms. Across the arms, the median age was 59.5 years (range, 26-70), and the majority were male. Regarding World Health Organization performance status in the investigative arm, 47.7% had a status of 0, 41.4% had a status of 1, and 10.6% had a status of greater than 1; in the control arm, these rates were 51.1%, 39.5%, and 9.1%, respectively. Most patients across the arms did not have renal impairment at baseline, nor did they have high-risk cytogenetics.

Regarding, Revised International Staging System disease stage in the investigative arm, 23.3% had stage I disease, 65.9% had stage II disease, 8.5% had stage III disease, and 2.4% had disease that was not classified. In the control arm, 30.1% had stage I disease, 56.2% had stage II disease, 7.9% had stage III disease, and 5.8% had disease that was not classified.

The addition of isatuximab to RVd did not significantly impact the safety profile or dose intensity of RVd. Results showed that 63.6% of patients who received the isatuximab regimen (n = 330) experienced an any-grade adverse effect (AE) vs 61.3% of those who received RVd (n = 328). Additionally, in the investigative and control arms, 34.8% and 36.3% of patients, respectively, reported a serious toxicity with treatment. Four deaths (1.2%) were reported on the Isa-RVd arm, vs 8 (2.4%) on the RVd arm.

Furthermore, 26.4% of patients on the investigative arm experienced leukocytopenia or neutropenia vs 9.1% of those on the control arm. Four patients on the Isa-RVd arm reported infusion-related reactions; these data were not available for the RVd arm.

"Isa-RVd showed a manageable and consistent safety profile in patients with transplant-eligible, newly diagnosed multiple myeloma with no new safety signals observed,” Goldschmidt noted.

Other phase 3 trials are investigating the efficacy of isatuximab in the treatment of patients with transplant-eligible and -ineligible, newly diagnosed multiple myeloma. The drug is being explored in combination with RVd and carfilzomib, lenalidomide, and dexamethasone.

1. Goldschmidt H, Mai EK, Nievergall E, et al. Addition of isatuximab to lenalidomide, bortezomib and dexamethasone as induction therapy for newly-diagnosed, transplant-eligible multiple myeloma: the phase III GMMG-HD7 trial. Presented at: 2021 ASH Annual Meeting; December 11-14, 2021; Atlanta, GA. Abstract 463.

2. FDA approves new therapy for patients with previously treated multiple myeloma. News release. FDA; March 2, 2020. Accessed December 11, 2021. https://bit.ly/2TAebOh

3. FDA approves Sarclisa (isatuximab) in combination with carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma. News release. Sanofi; March 31, 2021. Accessed December 11, 2021. 

The use of isatuximab with the RVd regimen in the induction phase may improve minimal residual disease negativity rates in patients with multiple myeloma, phase 3 results show. 

High MRD Negativity Rates Shown With Isatuximab/RVd in Transplant-Eligible, Newly Diagnosed Myeloma

Phase 1b/2 exploratory anlaysis data show that non-chemotherapy–based targeted regimen comprised of tucatinib (Tukysa), palbociclib (Ibrance), and letrozole resulted in improved central nervous system (CNS) progression-free survival (PFS) in patients with hormone receptor–positive, HER2-positive breast cancer.

Results from the study (NCT03054363), which were presented during the 

, showed that in 15 patients with CNS metastases, the median CNS-PFS was 8 months with the triplet regimen. Additionally, the 1-year CNS-PFS rate in these patients was 20% (n = 3), and the 2-year CNS-PFS rate was 13% (n = 2).

“The majority of patients had treated (non-measurable) CNS lesions, limiting the evaluation of CNS response and biasing outcome towards stable disease [SD],” lead study author Elena Shagisultanova, MD, PhD, of the University of Colorado Cancer Center, and colleagues, wrote in a poster on the data. “Moreover, we demonstrate the ability to get prolonged clinical benefit with this regimen post first CNS progression in carefully adjudicated cases.”

For the trial, investigators examined the combination of a HER2-targeted TKI, a CDK4/6 inhibitor, and an anti-hormonal agent in patients with hormone receptor–positive, HER2-negative metastatic breast cancer who had untreated asymptomatic or treated stable CNS metastases.

To be eligible for enrollment, patients needed to be post-menopausal or premenopausal on ovarian suppression. Moreover, they must have received 2 or more HER2 inhibitors at any time of their disease, 1 or more HER2-targeted agents in the metastatic setting, and up to 2 endocrine agents for metastatic disease. Patients were allowed to have received prior treatment with letrozole. However, if patients received prior treatment with HER2 TKIs or CDK4/6 inhibitors, they were excluded.

Study participants received tucatinib at a twice-daily dose of 300 mg, palbociclib at a daily dose of 125 mg for 21 days on and 7 days off, and letrozole at a daily dose of 2.5 mg. Efficacy was evaluated using RANO-BM and RECIST v1.1 criteria and based on investigator assessment. Moreover, investigators examined CNS-PFS, which was defined as intracranial progression or death, and bi-compartmental PFS.

Previous results from the trial showed that the combination had an acceptable safety profile and encouraging antitumor activity in this population.2 In the poster shared during the 2021 SABC, investigators reported data from an exploratory analysis of intracranial efficacy in patients who had CNS metastases.

Within the 15 patients with CNS MTS, the mean age was 47 years (range, 22-70), and the mean number of prior lines of therapy received for metastatic disease was 2 (range, 1-5). Additionally, 9 patients (60%) received prior CNS radiation, 1 patient (7%) underwent neurosurgery alone, 3 patients (20%) underwent neurosurgery and radiation, and 2 patients (13%) did not receive any prior treatment for CNS disease. All patients had previously received HER2-targeted therapy with trastuzumab (Herceptin) and pertuzumab (Perjeta), and 5 patients received ado-trastuzumab emtansine (T-DM1; Kadcyla).

Of the 15 patients enrolled to the trial, 14 were evaluable for disease; 1 patient was determined to have non-evaluable disease because they had no evidence of disease in the CNS for 24 months. At a data cutoff date of November 1, 2021, 12 patients had received treatment; 5 of these patients had SD for 6 months or longer with the combination, 6 had SD for less than 6 months, and 1 experienced a complete response.

Two patients were not treated; 1 patient who had a non-measurable dural lesion had SD for 5 months, and the other patient had a measurable lesion and had SD for 8 months.

Regarding safety, prior data showed that the most common grade 3 or higher adverse effects (AEs) reported with the triplet regimen included neutropenia (58%), leukopenia (24%), diarrhea (17%), and fatigue (14%). Notably, these AEs were determined to be manageable. Moreover, no cases of cerebral edema were reported in patients with CNS metastases, including those who received radiation for isolated CNS progression during the study.

1. Shagisultanova E, Gradishar W, Brown-Glaberman U, et al. Intracranial efficacy of tucatinib, palbociclib and letrozole combination in patients with HR+/HER2+ breast cancer and brain metastases. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract P1-18-26.

2. Shagisultanova E, Chalasani P, Brown-Glaberman UA, et al. Tucatinib, palbociclib, and letrozole in HR+/HER2+ metastatic breast cancer: report of phase IB safety cohort

. 2019;37(15):1029. doi:10.1200/JCO.2019.37.15_suppl.1029

The ability to prolong central nervous system progression-free survival in patients with hormone receptor–positive, HER2-positive breast cancer has been demonstrated in an early clinical trial.