At the 64th American Society of Hematology (ASH) Annual Meeting and Exposition on 10–13 December, a lot of the focus of the meeting was on new data for established and experimental chimeric antigen receptor T-cells (CAR-T), as well as data from novel bispecific antibodies. Specifically, Bristol Myers Squibb’s CD19 CAR-T Breyanzi (lisocabtagene maraleucel) had updated results in the second-line (2L) treatment of large B-cell lymphoma (LBCL) and Novartis’ CD19 CAR-T rapcabtagene autoleucel had early-phase data in diffuse LBCL (DLBCL). In the bispecific space, Regeneron’s anti-CD20/CD3 antibody odronextamab impressed with pivotal data in relapsed/refractory (R/R) follicular lymphoma (FL) and Johnson & Johnson’s (J&J) novel GPRC5D/CD3 bispecific talquetamab with data in R/R multiple myeloma (MM).
Breyanzi demonstrates sustained benefit in 2L LBCL
In June, Breyanzi received a label expansion from the FDA for the 2L treatment of LBCL based on the Phase III TRANSFORM trial. An updated analysis was presented at ASH, and the trial compared Breyanzi to standard-of-care (SOC) chemotherapy followed by autologous stem cell transplant (ASCT). The primary endpoint was event-free survival (EFS).
At a median follow-up of 17.5 months, median EFS was not reached in the Breyanzi arm, versus 2.4 months for the SOC arm (hazard ratio [HR]:0.35). An overall survival difference (mOS) favoured Breyanzi but was not statistically significant. However, crossover was allowed in the study, and 67% of patients in the SOC arm crossed over to receive Breyanzi. Thus, a crossover-adjusted mOS analysis should be performed before concluding whether Breyanzi actually helped patients live longer.
The importance of an OS benefit for Breyanzi is paramount—if patients do just as well long term when using SOC chemotherapy in the 2L and then Breyanzi in the third line (3L), then the financial burden of using it in the 2L will be unjustified. Currently, Breyanzi in the EU and Japan is only approved for 3L+, but at a list price of $410,000 in the US, the use of Breyanzi in the much larger 2L population will have profound financial implications for health systems worldwide.
Currently, only Gilead’s Yescarta (axicabtagene ciloleucel) competes for a share of the 2L LBCL population with Breyanzi, but in the absence of a head-to-head comparison, other attributes such as side-effect profile and manufacturing success will affect physicians’ choice.
Rapidly manufactured autologous CAR-T cells could be a strong competitor to allogeneic CAR-Ts
Novartis’ CD19 CAR-T product Kymriah (tisagenlecleucel) has captured a significant share of the B-cell non-Hodgkin’s lymphoma (B-NHL) market and achieved $587m last year in global sales amidst intense competition by Yescarta and Breyanzi. Now, Novartis is seeking to gain a competitive advantage by cutting the time to manufacturing a CAR-T product down to two days, from the usual two–three weeks for the currently marketed products, using its proprietary T-Charge™ platform for its novel CD19 CAR-T agent rapcabtagene autoleucel (rapca-cel).
Preliminary data from a Phase I dose escalation study (NCT03960840) of rapca-cel was presented at ASH, from patients with R/R DLBCL in the 3L. Out of 28 evaluable patients, 65% achieved a complete response (CR) and the median duration of response was not reached at a follow-up of 10 months. Some of the data presented also suggested a T-cell expansion comparable to Kymriah at a much lower dose (25-fold). The side-effect profile seems consistent with other CAR-T products—7% of patients experienced Grade III neurotoxicity, deemed manageable by the investigators.
While this data is too preliminary to draw conclusions from, rapca-cel is certainly a product worth studying in a large-scale clinical trial, which however will have to be versus SOC CAR-T. Even if it demonstrates non-inferiority to other CAR-Ts, rapca-cel would still have the logistical upper hand. GlobalData’s Drug Sales Database projects an entry into the market for rapca-cel as early as 2026.
A new target emerges in multiple myeloma
The bispecific antibody space in MM is growing, with the recent FDA approval of J&J’s BCMA/CD3 antibody Tecvayli (teclistamab) and the movement of competing drugs in late-stage clinical trials. J&J has also gone after a novel target in MM, GPRC5D, a receptor highly expressed in transformed plasma cells, with talquetamab.
New results from the Phase I/II MonumenTAL-1 study presented at ASH make talquetamab a formidable new addition to the physicians’ armamentarium for R/R patients. Out of 143 patients treated with 0.4mg/kg talquetamab, and having received a median of five previous lines of therapy, the overall response rate (ORR) was 73%. The incidence of cytokine release syndrome (CRS), a known concern for bispecifics, was 79%, only 2% of which were higher than Grade III.
Tecvayli received marketing authorisation with very similar data, and the advantage of talquetamab is its novel mechanism of action, which will allow patients refractory to anti-BCMA therapeutics to be treated. Therefore, an accelerated approval is not out of the question, especially since the drug has already received breakthrough therapy and orphan drug designations by the FDA.
Odronextamab could be the next big player in follicular lymphoma
FL is an indolent type of B-NHL, for which anti-CD20 bispecifics already exist in the market, such as Roche’s Lunsumio (mosunetuzumab), approved by the EMA. Regeneron’s bispecific odronextamab reported new data from its pivotal Phase II study ELM-2 in R/R patients with Grade I–IIIa FL: 85 patients who received a median of three previous lines of therapy demonstrated an 81% ORR to odronextamab, and a median progression-free survival (mPFS) of 20.2 months. A dosing step-up infusion protocol largely prevented CRS of Grade III or higher.
This data is deemed great for this patient population, and given that Regeneron has already marked the trial as pivotal, it is likely that a regulatory submission will follow soon. GlobalData’s Drugs Database forecasts odronextamab to reach $515m in peak sales by 2028, versus $900m by 2028 for its competitor Lunsumio.