Professor Cai Qingqing: New drugs continue to emerge, where is the treatment of relapsed and refractory diffuse large B-cell lymphoma? The 7th International Summit Forum on Anti-Leukemia and Lymphoma

Relapsed and refractory diffuse large B-cell lymphoma (R/R DLBCL) has always been a thorny clinical problem and is also a research hotspot
in the field of lymphoma.
On November 10-11, 2022, the "25th National Congress of Clinical Oncology 2022 CSCO Academic Annual Conference Harbin Branch, the 10th CSCO Leukemia and Lymphoma Expert Committee, and the 7th Anti-leukemia · On the occasion of the Lymphoma International Summit Forum and CSCO Leukemia & Lymphoma Expert Committee Tour - Harbin Station, on this occasion, Professor Cai Qingqing of the Affiliated Cancer Hospital of Sun Yat-sen University was invited to be interviewed to share the relevant progress
in the field of R/R DLLBL treatment.

Yimaitong: First of all, please talk about the current standardized treatment of R/R DLLCL and the progress of
new drugs.

At present, the standard treatment strategy for patients with R/R DLLBL after R-CHOP regimen is represented by platinum-based chemotherapy and HDC-ASCT
.
For example, after BEAC (carmustine, etoposide, cytarabine and cyclophosphamide) after RHAP (dexamethasone, high-dose cytarabine and cisplatin) combined with ASCT, R-ICE (RITUXIMAB, IFOSFAMIDE, ETOPOSIDE AND CARBOPLATIN) after BEAM (carmustine, etoposide, cytarabine and melphalan) ASCT
。 However, only 20%-35% of patients with R/R DLCCL are suitable for transplantation, 65%-80% of patients still have unmet treatment needs, the prognosis of patients with R/R DLCCL is poor, and the median OS of high-risk R/R DLBCL patients in China is only 7 months
.
There is an urgent need to find new treatments
.

• CAR-T

CAR-T is an effective option
for patients with R/R DLLBL who have failed R-CHOP, are not suitable for transplantation, or have failed HDC-ASCT 。 Current CD19-targeting CAR-T cell products for DLBCL include Axicabtagene ciloleucel (Axi-cel, ZUMA-1 study), Tisagenlecleucel (Tisa-cel, JULIET study), and Lisocabtagene maraleucel (Liso-cel, TRANSCEND study), at R/R Higher treatment was shown in all third-line and above treatments for DLBCL: ORR of 52-83% and CR rate of 40% to 58%.

But the special toxicities of CAR-T, such as CRS and neurotoxicity, are also of concern
.

In 2022, New England and The Lancet published three randomized phase III controlled studies of second-line CAR-T therapy versus platinum-based salvage chemotherapy + standard salvage therapy (SOC) for ASCT, in which the ZUMA-7 study and the TRANSFORM study compared the results of Axi-cel and Liso-cel versus standard second-line therapy, respectively, confirming the efficacy of the two CAR-T products compared with SOC: CR rate (65% vs 32% and 66% vs 39%) ) and median EFS (8.
2 months vs 2 months, 10.
2 months vs 3.
1 months) outperformed SOC
.
However, the BELINDA study did not observe a difference between
Tisa-cel and SOC.
ZUMA-7 does not allow bridging chemotherapy, excluding patients
requiring immediate treatment.
This exclusion may have introduced selection bias to include more patients with less
aggressiveness.
THE HIGH PROPORTION OF BRIDGING CHEMOTHERAPY IN THE BELINDA STUDY (83%) INDICATES THAT ENROLLED PATIENTS MAY HAVE HIGHER RATES OF DISEASE THAT IS AGGRESSIVE AND/OR CHEMOTHERAPY INSENSITIVE
.
Approximately 50% of patients in clinical practice receive bridging therapy
.
Follow-up in three studies remained short (notably the BELINDA and TRANSFORM studies), and long-term follow-up is needed to further clarify the effectiveness of
second-line CAR-T therapy.

• Novel drug treatments

1.
Monoclonal antibodies targeting CD19

(1) Tafasidamab is a novel humanized Fc domain-optimized immune-enhanced monoclonal antibody targeting CD19, which has a synergistic effect
with lenalidomide.
A phase II, multicenter, single-arm L-MIND study evaluated the efficacy and safety
of Tafasitamab + lenalidomide in patients with R/R DLLBCL who are not candidates for ASCT.
The ORR was 61%, the CR rate was 43%, the median OS was 33.
5 months, and the toxicity was controllable
.
In 2020, tafasitamab in combination with lenalidomide received FDA and EMA accelerated approval for the treatment of R/R DLBCL
that is not suitable for transplantation.

(2) Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) containing a humanized antibody targeting CD19, which is conjugated to
a pyrrobenzodiazepine dimer toxin.
The LOTIS-2 study evaluated the efficacy and safety of Lonca monotherapy for relapsed/refractory DLBCL with an acceptable safety
profile of 48.
3% ORR, 24.
8% CR, 23.
4% PR, median PFS of 4.
9 months, and median OS of 9.
5 months.
Studies have shown that Lonca has significant monotherapy antitumor activity and produces a durable response, providing a new treatment option
for patients with multi-line treatment of resistant R/R DLBCL.

2.
Bispecific antibodies targeting CD20xCD3

(1) Glofitamab is composed of
two fragments targeting CD20 antigen and a single CD3-binding fragment.
Quite good efficacy
was observed in R/R B-NHL.
Glofitamab monotherapy also induces durable remission in patients with multi-line treatment-resistant DLBCL (including those who have received CAR-T): ORR of 51.
6%, CR rate of 39.
4%, and a favorable safety profile
.

(2) Epcoritamab (GEN3013) is a subcutaneously administered CD3xCD20 bispecific antibody with significant activity
against R/R B-NHL.
The latest results from EPCORE NHL-1's Phase II DLBCL Expansion Cohort confirm Epcoritamab's activity in R/R DLCL: AN ORR of 63% (39% CR), a median DOR of 12 months, and 89% of patients still in CR at 9 months
.
Compared with patients treated with previous CAR-T, patients who were not treated with CAR-T had a higher response rate to single-agent Epcoritamab and Epcoritamab safety control, and most CRS events were low-level
。 Cohort 5 of the EPCORE NHL-2 study evaluated the safety and initial efficacy of Epcoritamab+GemOx in patients with R/R DLCL who were not eligible for ASCT, and efficacy was evaluated in 25 patients: ORR was 92% (CMR: 60%, PMR: 32%), and the median duration of CMR was 7.
5 months
.
No new safety events associated with Epco+GemOx treatment were identified, and CRS grades occurred at a lower
level.

3.
ADC targeting CD79b

Polatuzumab vedotin is an ADC formed by coupling a humanized anti-CD79b antibody to the anti-mitotic agent MMAE (monomethylastatin E) to treat CD79b-expressed follicular lymphoma (FL) and DLBCL
。 polatuzumab vedotin in combination with rituximab and bendamustine (pola-BR) was more effective than standard BR: CR rates (40% vs 17.
5%) and long-term survival (median PFS 9.
5 versus 3.
7 months; Median OS 12.
4 vs 4.
7 months) are good
.
These results led to FDA and EMA approval of the pola-BR regimen for the treatment of R/R DLLBL
that is not suitable for transplantation.

4.
Nuclear output protein 1 (XPO1) inhibitors

Celinisol is an orally selective XPO1 inhibitor with an ORR of 28% (GCB: 34%, FL conversion: 39%, previous ASCT: 42
%) in monotherapy with previous R/R DLLBCL.
The median follow-up was 11.
1 months, the median DOR was 9.
3 months, the median DOR of CR patients was 23 months, the median OS was 9.
1 months, and the adverse events were mostly grade 1/2, which could be effectively managed by supportive care or dose adjustment.
No specific organ toxicity and cumulative toxicity were reported
.

5.
ADC targeting CD30

The phase I/dose amplification test of the CD30-targeting antibody drug conjugate vebutuximab combined with lenalidomide in the treatment of R/R DLLBCL showed good antitumor activity, with an ORR of 57% and a CR rate of 35%; The median PFS and median OS were 10.
2 months and 14.
3 months, respectively, providing more treatment options
for patients with refractory DLBCL with poor prognosis.

6.
Summary

The emergence of CAR-T has provided a new era of options for patients with R/R DLBL, which is now its standard third-line therapy, and may gradually become the second-line treatment
for patients with R/R DLCCL in the future.
For R/R patients who are not candidates for transplantation, combined pola-BR is a new option
.
New drugs have also shown satisfactory results in R/R DLLBCL, among which the more outstanding is Tafasitamab + lenalidomide combination program and CD3xCD20 bispecific antibody, Lonca, celiniso and other combination therapies are also worth exploring, looking forward to the latest research data
.

Yimaitong: In the field of R/R DLCL, CAR-T combined with ASCT is still under further exploration
.
What are your thoughts and expectations on this?

At present, individual studies at home and abroad have confirmed that ASCT combined with CAR-T treatment for R/R DLBCL has a higher sustained response rate than CAR-T alone, and more patients have achieved long-term disease-free survival through combination therapy, which has brought the dawn
of cure to patients with R/R DLBCL 。 The original study from the hematology team of Wuhan Tongji Hospital confirmed that HDT-ASCT combined with CAR-T therapy had a high and durable response rate in patients with R/R-aggressive B-NHL with low sensitivity or no response to salvage chemotherapy: ORR of 90.
5% (38/40) and CR rate of 81% (34/40)
at 3 months 。 A retrospective study published by the lymphoma team of Beijing Boren Hospital analyzed 17 patients with R/R DLLBL involved in central nervous system invasion, 8 patients completed ASCT combined with CAR-T cell therapy, ORR was 12/17 (71%) CRR of 11/17 (65%) at 3 months in the overall population, and CRR in the combined ASCT group and without ASCT group was 100% and 44.
4% (P<0.
01), respectively.
Patients treated with ASCT combined with CAR-T had significantly longer
PFS (P=0.
0015) and OS (P=0.
0052).
It is expected that future longer follow-up data and prospective clinical trials will provide stronger evidence of the efficacy
of this combination therapy.

Overall, the "strong combination" therapy of CAR-T combined with ASCT has shown satisfactory efficacy and controllable safety, and may become the most powerful means
of treating R/R DLBCL in the future.

What research have you and your team conducted or planned to conduct in the field of DLBCL? What are the expectations for the future?