ASH 2022: CAR T-Cell Therapy

How CAR T Therapies Stack Up Against Standard of Care for LBCL Across Lines of Treatment, Cost Perspectives

In abstracts featured at the 64th American Society of Hematology Annual Meeting (ASH) and Exposition, investigators detailed patient and financial outcomes associated with chimeric antigen receptor (CAR) T-cell therapies vs standard of care (SOC) for treatment of large B-cell lymphoma (LBCL). During 2022, the FDA approved 2 CAR T-cell therapies for use in second-line treatment,^1,2 offering new treatment choices but raising the question: What options remain once a patient relapses after CAR T?

Long-term liso-cel data. Jeremy Abramson, MD, director of the lymphoma program at Massachusetts General Hospital Cancer Center in Boston, presented updated outcomes from the TRANSFORM study (NCT03575351), which aimed to compare the efficacy and safety of the CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) vs SOC as second-line therapy in patients with relapsed or refractory LBCL.³ Both liso-cel and the SOC of salvage immunochemotherapy were followed by high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) in those responding to treatment. The multicenter phase 3 study included 184 patients, with 92 randomly assigned to each arm.

After a median follow-up of 17.5 months, the primary end point of event-free survival (EFS) was not reached (NR) for the liso-cel arm (95% CI, NR-9.5 months) vs a median (95% CI) of 2.4 (2.2-4.9) months for the SOC arm. Investigators also observed statistically significant results favoring liso-cel for the complete response (CR) rate (74% vs 43%, respectively; P < .0001) and progression-free survival (PFS) (median [95% CI], NR [12.6-NR] vs 6.2 [4.3-8.6] months; P < .0001). These updated findings confirmed results presented at the 2021 ASH Annual Meeting in Atlanta, Georgia, after a median follow-up of 6.2 months.³

• Median overall survival was also longer for those in the liso-cel arm, but the difference vs SOC was not statistically significant (NR vs 29.9 months; P = .0987).³
• These results showed deepened responses among some patients who had a partial response (PR) as of an interim analysis, as outcomes improved to a CR in 6 of 18 patients in the liso-cel arm and 3 of 8 in the SOC arm.³

“In TRANSFORM, liso-cel resulted in statistically significant and clinically meaningful improvements in EFS, CR rate, and PFS,” the abstract concluded. “These data reinforce liso-cel as a [second-line] treatment in [patients] with primary refractory or early relapsed LBCL.”

The FDA approved liso-cel for second-line treatment on June 24, 2022.²

After axi-cel, then what? Another abstract examined how well the CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) vs SOC set the stage for later antilymphoma therapies among patients with LBCL in the phase 3 ZUMA-7 trial (NCT03391466).⁴ As the authors explained, axi-cel is approved for treatment of relapsed/refractory LBCL after first-line therapy, but little is currently known about optimal management after a second line of therapy. (The FDA approved axi-cel for use in second-line treatment April 1, 2022.¹)

Of the 84 patients in the axi-cel arm of the ZUMA-7 trial who required subsequent third-line therapy, 60 received chemotherapy and 8 received cellular immunotherapy, which was axi-cel retreatment for those who initially responded to axi-cel. Those who received chemotherapy had a median (95% CI) PFS of 1.7 (1.4-2.0) months and an OS of 8.1 (5.8-11.5) months; the objective response rate (ORR) was 25%, and the CR rate was 13%. Specifically, among those who had shown an initial response to second-line axi-cel, the ORR was 32% and the CR rate was 18%.⁴

In the 8 patients who received cellular immunotherapy after axi-cel, the median (95% CI) PFS was 3.5 (1.1-not evaluable) months. Six of these patients then received SCT (1 auto-SCT, 5 allogeneic SCT [allo-SCT]), and all of them were alive as of the data cutoff date a median of 24.4 months after third-line therapy initiation.⁴

In the SOC arm, patients received 2 or 3 cycles of chemotherapy followed by high-dose therapy, with auto-SCT for those with PR or CR; 127 patients required third-line therapy, and 68 of these patients received third-line cellular immunotherapy. Their median (95% CI) PFS was 6.3 (3.4-16.3) months, and OS was 16.3 (8.7-not evaluable) months; ORR was 57%, and the CR rate was 34%.⁴

The authors of the abstract noted that retreatment with axi-cel as a third line of therapy appeared to be feasible and drive meaningful responses, but outcomes for patients who received subsequent third-line cellular therapy were numerically worse than those for patients who received cellular therapy in the second line. Although the findings must be confirmed by studies with larger sample sizes, these results may help inform treatment decisions after second-line therapy fails.

Hospital vs pharmacy costs. A third abstract leveraged a hospital database to assess health system costs and health care resource utilization associated with CAR T-cell therapy vs SCT for treatment of LBCL.⁵

In 37 hospital systems nationwide, a total of 852 patients with a mean age of 60 years received treatment with CAR T (n = 208), auto-SCT (n = 595), or allo-SCT (n = 49). Characteristics including age, sex, race, health coverage, and comorbidities were similar across the 3 procedure types. CAR T-cell therapy was less likely to be delivered as an inpatient procedure than auto-SCT (89.9% vs 94.8%; P = .01).

The cost data revealed that the mean cost of CAR T-cell therapy was higher than that of either of the SCT procedures (CAR T, $371,136; auto-SCT, $96,515; allo-SCT, $169,269; P < .001). However, CAR T did carry a lower mean nonpharmacy cost ($41,375 vs $51,778 and $111,594, respectively; P < .001). Mean intensive care unit cost was also lower for CAR T and auto-SCT than for allo-SCT ($86,755 and $86,497 vs $191,980; P < .001).⁵

Among those treated in the inpatient setting, mean length of stay was shorter for CAR T-cell therapy than for auto-SCT or allo-SCT, at 18 vs 21 and 28 days, respectively (P < .001).⁵

The authors concluded that although CAR T-cell therapy carried a higher overall price tag driven primarily by pharmacy costs, it imparted less of a burden in terms of hospital utilization. They cautioned that their findings apply only to the hospitals included in their data source. 

References
1. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. FDA. Updated April 1, 2022. Accessed December 17, 2022. https://bit.ly/3RqnXzB

2. U.S. FDA approves Bristol Myers Squibb’s CAR T cell therapy Breyanzi for relapsed or refractory large B-cell lymphoma after one prior therapy. News release. Bristol Myers Squibb. June 24, 2022. https://bit.ly/3W45UAY

3. Abramson JS, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel) versus standard of care (SOC) with salvage chemotherapy followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients with relapsed or refractory large B-cell lymphoma (LBCL): primary analysis of the randomized, phase 3 TRANSFORM study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. https://ash.confex.com/ash/2022/webprogram/Paper159702.html

4. Ghobadi A, Munoz J, Westin J, et al. Outcomes of subsequent anti-lymphoma therapies in patients (Pts) with large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) or standard of care (SOC) in the second-line (2L) ZUMA-7 study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. https://ash.confex.com/ash/2022/webprogram/Paper158303.html

5. Cui C, Feng C, Rosenthal N, et al. Hospital costs and healthcare resource utilization (HRU) for chimeric antigen (CAR) T-cell therapy and stem cell transplant (SCT) in patients with large B-cell lymphoma (LBCL) in the United States (US). Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Accessed December 19, 2022. https://ash.confex.com/ash/2022/webprogram/Paper157309.html

SPOTLIGHT: TRANSFORM Data Support Liso-cel as Second-line Treatment for LBCL, Says Jeremy Abramson, MD

The TRANSFORM (NCT03575351) data presented at the 64th American Society of Hematology Annual Meeting and Exposition confirm findings presented last year on lisocabtagene maraleucel (liso-cel, Breyanzi) in second-line treatment.^1,2 Jeremy Abramson, MD, director of the lymphoma program, Massachusetts General Hospital Cancer Center, told Evidence-Based Oncology™ (EBO) how these new insights for patients with high-risk relapsed/refractory large B-cell lymphoma, and the importance of the longer follow-up period.

EBO: How do the TRANSFORM data being presented this year confirm and build on last year’s findings?

Abramson: There are a number of insights that we now have with the primary analysis that we didn’t have yet at the time of the interim analysis with a median follow-up of 6 months. Now, with 17.5 months of median follow-up in the primary analysis of TRANSFORM, we can be confident in the durability of these responses. We see a plateau on our progression-free and event-free survival curves, providing comfort that these are deep and durable remissions, which is difficult to discern when you only have 6 months of median follow-up. We also have longer follow-up in the standard-of-care arm, and with longer follow-up in the standard-of-care arm, we’re seeing that the standard of care continues to underperform historically relative to this new, modern treatment. The fact that two-thirds of patients assigned to what has been our standard treatment have been failed by that treatment and approved for crossover to liso-cel tells us that the standard of care is failing the vast majority of patients. Thankfully, we have these new products that allow us to move on from there.

We also can glean some insights from these patients who crossed over to receive liso-cel as a third-line treatment on this trial. Among these two-thirds of patients assigned to standard of care who crossed over to receive liso-cel, the median time from approval to crossover to receipt of liso-cel was quick at 15 days. However, what we saw is that the complete response rate, progression-free, and overall survival for these patients was actually inferior to patients who receive liso-cel on the liso-cel arm as second-line treatment in this trial. What that suggests to me is that earlier treatment with liso-cel in the second line, rather than the third-line setting, is going to maximize the cure rate for our patients.

EBO: How were patients from the standard-of-care arm able to cross over to receive liso-cel?

Abramson: Patients on the standard-of-care arm all underwent leukapheresis prior to the randomization. So before we even knew whether patients would be in the liso-cel arm or the standard-of-care arm, all patients [underwent leukapheresis]. What that meant was we had all patients’ T cells and generated liso-cel product on all of them. That meant that if a patient who was assigned to the standard-of-care arm either did not respond, progressed, or relapsed on the standard-of-care arm, we already had liso-cel available for that patient and so the crossover was effectively immediate.

Now, I should note that that isn’t something that would happen in the real-world setting. In the real-world setting, if a patient received a second-line treatment, such as R-ICE [rituximab, ifosfamide, carboplatin, and etoposide phosphate] or R-DHAP [rituximab, dexamethasone, high-dose cytarabine, and cisplatin] or R-GDP [rituximab, gemcitabine, cisplatin, and dexamethasone], and they failed to respond to that treatment, they would then have to undergo leukapheresis, the manufacturing period, and ultimately receive their CAR T-cell product in a much more delayed fashion than we were allowed to do on this study, which I think really helped us optimize the treatment for the patients assigned to the standard-of-care arm. 

References
1. Abramson JS, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel) versus standard of care (SOC) with salvage chemotherapy followed by autologous stem cell transplantation (ASCT) As second-line (2L) treatment in patients with relapsed or refractory large B-cell lymphoma (LBCL): primary analysis of the randomized, phase 3 TRANSFORM study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition December 10-13, 2022; New Orleans, LA. Abstract 655. https://ash.confex.com/ash/2022/webprogram/Paper159702.html

2. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-2308. doi:10.1016/S0140-6736(22)00662-6

ASH Abstracts Reveal Disparate CAR T-Cell Therapy Access and Outcomes in MM, DLBCL

Access to and outcomes of chimeric antigen receptor (CAR) T-cell therapies may differ by characteristics such as race, ethnicity, gender, and geographic location among patients with cancer, according to data from abstracts presented at the 64th American Society of Hematology Annual Meeting and Exposition in December.^1,2

These individualized treatments represent an innovative form of immunotherapy that can induce durable disease response, but prior research has suggested that these breakthrough therapies may not be reaching all patients equally. One abstract presented at the meeting detailed a study examining predictors of CAR T-cell therapy receipt among Medicare patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who had at least 2 prior lines of therapy.¹

The investigators linked claims data to individual characteristics and county-level measures of socioeconomic disadvantage. Of 15,472 patients with DLBCL, they focused on the 266 patients who had received rituximab (Rituxan) plus chemotherapy as their first line of treatment and then received either CAR T-cell therapy (n = 104) or a comparator therapy (n = 162) as a third or later line of therapy. These comparator therapies included stem cell transplant, polatuzumab-based therapy, and salvage combinations of rituximab and chemotherapy.

Unadjusted analysis showed that patients 76 years and older were less likely to receive CAR T-cell therapy than those aged 66 to 75 years, but the difference was not statistically significant (odds ratio [OR], 0.501; P = .06).
After excluding patients who were evaluated for clinical trial participation, leaving 65 patients who received CAR T-cell therapy and 144 who received a comparator, multivariate adjusted analysis showed that CAR T-cell therapy recipients were less likely to be women (OR, 0.463; P = .04), have a Charlson Comorbidity Index score of at least 3 (OR, 0.451; P = .04), or be residents of the American South (OR, 0.284; P = .02). However, no association was observed between CAR T receipt and Area Deprivation Index.

“Despite the small sample size of this study, the findings suggest that access to CAR T-cell therapy should be particularly improved in female patients and patients living in the South, possibly due to geographical limitations of CAR T centers and a high population of socioeconomically disadvantaged racial minorities,” the authors wrote.

Even when patients do receive CAR T-cell therapy, however, disparities can persist. A second abstract detailed how investigators harnessed data from the US MM Cellular Therapy Consortium of 215 patients with relapsed/refractory multiple myeloma (MM) who received idecabtagene vicleucel (ide-cel), a CAR T-cell therapy approved by the FDA in March 2021.2 The investigators noted that, although the KarMMa clinical trial (NCT03361748) showed impressive efficacy data for ide-cel, racial and ethnic minority groups were underrepresented in its participants. As such, they aimed to shed light on the safety and efficacy of ide-cel in diverse, real-world patient populations.

The 215 patients in this analysis were treated at 11 institutions and had a median age at ide-cel infusion of 64 years (range, 36-83 years). They had received a median of 6 prior lines of therapy before receiving ide-cel (range, 3-19). More than 3 in 4 (76%) would have been excluded from the KarMMa trial.

According to self-reported identification, 70% (n = 150) of patients were non-Hispanic White, 17% (n = 36) were non-Hispanic Black, 10% (n = 21) were Hispanic, and 3% (n = 8) were Asian, Pacific Islander, American Indian, or Alaskan Native. The latter group was omitted from the analysis due to the small sample size.

Among the 215 participants, the best overall response rate was 84%, and 34% of patients achieved at least a complete response (CR). Of these 83 patients who achieved a CR or better, 66% were minimal residual disease negative.

Analysis by race and ethnicity showed that Black patients were more likely to experience several negative outcomes compared with White and Hispanic patients. They were more likely to:

• develop any grade cytokine release syndrome: 97% vs 84% and 76%; P = .05
• have a longer hospital stay: median, 12.5 days vs 9 days and 8 days; P = .01
• experience severe prolonged cytopenia: 87% vs 72% and 56%; P = .07

Although overall survival was similar across the racial and ethnic groups, Hispanic and Black patients combined had shorter progression-free survival compared with White patients (median, 5.9 vs 9.0 months; P = .08), which appeared to be driven by a worse overall response rate among Hispanic patients.

The authors of the abstract concluded that their data showed racial and ethnic differences in safety and progression-free survival among patients receiving ide-cel for relapsed/refractory MM.

“As a greater volume of patients are treated with CAR T therapy and follow-up time matures, we will have increased power to further investigate racial and ethnic differences in patient and clinical characteristics and clinical outcomes,” they wrote. 

References
1. Saunders A, Inguva S, Keating SJ, Chirikov V. Examination of disparities in access to chimeric antigen receptor (CAR) T cell therapies in Medicare patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who had failed at least 2 prior lines of therapy (LOT). Presented at: 64th American Society of Hematology Annual Meeting and Exposition December 10-13, 2022; New Orleans, LA. Abstract 4906. https://ash.confex.com/ash/2022/webprogram/Paper160313.html
2. Peres LC, Oswald LB, Dillard C, et al. Racial and ethnic differences in clinical outcomes among multiple myeloma patients treated with CAR T therapy. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 252. https://ash.confex.com/ash/2022/webprogram/Paper158478.html