Song Yongping and Zhang Wei: Climb the peak, innovate ADC drugs Pola-enabled transplantation and CAR-T therapy, and explore more therapeutic potential

Every unknown world is opened with pioneers who bravely foresee; Every journey of sneaking through the dark night is fearlessly led by the lighter
.
The series of reports "Solving the Problem - Unlocking the New Standard of DLBCL Cure" digs deep into the problems in the treatment of diffuse large B-cell lymphoma (DLBCL) and explores unmet clinical needs; Combined with clinical research and real-world treatment experience at home and abroad, we jointly explore the new standard
of precision diagnosis and treatment of DLBCL.
Polatuzumab Vedotin (Pola) is transformed into a North Star (Pole Star), which helps optimize diagnosis and treatment strategies under the guidance of leading experts in the field in order to improve the survival of
DLBCL patients in China.

Autologous hematopoietic stem cell transplantation (ASCT) is an important treatment for
relapsed and refractory (R/R) DLBCL.
However, the complete response (CR) rate of existing salvage therapies is low, which affects the development and efficacy
of subsequent transplantation.
How can I improve the efficacy of pre-transplant salvage therapy? After transplant failure, how to bridge CAR-T therapy? What should patients do after CAR-T treatment fails?

ASCT and CAR-T have unmet needs in R/R DLBCL

The advent of rituximab ushered in the era of immunochemotherapy in the field of lymphoma, and its classic R-CHOP regimen in combination with chemotherapy significantly improved response rates and survival in patients with DLBCL, but about 40% to 50% of patients still failed to achieve remission or relapse
after CR.
The prognosis of R/R DLBCL is poor, the challenges are severe, and existing treatments urgently need to be improved
.

* R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone

ASCT has long been an important means of
treatment of R/R DLBCL.
Patients with R/R DLBCL are first stratified according to whether they are eligible for transplantation, and for patients who are suitable for transplantation, major guidelines list ASCT as a standard option ^1-3
.

Pre-transplant salvage therapy up to CR is the key to transplant success, which has great significance for the prognosis of patients and can significantly improve the survival prognosis of
patients.
However, whether it is traditional chemotherapy or rituximab immunochemotherapy regimen, the CR rate as salvage therapy is less than 30%, and about half of patients who are suitable for transplantation do not respond to salvage therapy or do not respond well, which affects the development and efficacy of subsequent ^{transplantation4-7}
.

Fig.
1 CR rate of commonly used salvage chemotherapy regimens

In the real world, the CR rate of salvage therapy in patients with R/R DLBCL is lower, and a multicenter real-world study in China showed that the CR rate of patients with refractory DLBCL is only 9%, and the prognosis of these patients is ^poor7, so the efficacy of salvage therapy still needs to be improved
.

CAR-T cell therapy, as one of the treatment options for relapsing/progressing DLBCL after ASCT, also has certain shortcomings
.
Due to the rapid progression of some patients, in order to prevent the rapid deterioration of tumors and affect subsequent cell infusion, effective bridging therapy is required while waiting for CAR-T cell manufacturing and infusion, so as to control the disease and improve the success rate of
CAR-T treatment.
However, existing high-intensity chemotherapy regimens are highly toxic as bridging therapy and are associated with a higher incidence of treatment-related grade 3 to 4 infectious ^{complications8}, and safer bridging regimens
need to be explored.

In addition, the recurrence/progression rate at 2 years after CAR-T cell therapy was as high as 53%⁹, and the prognosis for patients with relapse was poor, with less than 25% responding to subsequent treatment and an average overall survival (OS) of only 3.
6 ^months10
.
For patients with R/R DLBC who have failed CAR-T cell therapy, there are few follow-up treatment options, and treatment is difficult
.

Climbing to the top, Pola offers new treatment options for patients with R/R DLBCL

In recent years, innovative drugs and new therapies have emerged one after another, and the survival prognosis of patients with R/R DLBCL is expected to further improve
.
Pola, the world's first approved CD79b ADC drug, has brought a new dawn to R/R DLBCL patients
.
In its pivotal study, GO29365, the Pola-BR regimen not only significantly improved optimal CR (57.
5 versus 20 percent) and BOR (70.
0 versus 32.
5 percent) in patients with R/R DLBCL, but also reduced the risk of death by 58 ^percent11
.
In the long-term follow-up of more than 4 years, no new safety signals were found in the Pola-BR group, and adverse reactions were controllable
.

*Pola-BR: Pola plus bendamustine and rituximab; BOR, the best overall response rate

Fig.
2 BOR and CR rate results of Poola-BR and BR

In the real world of worse patients, the Pola regimen still showed high response rates
.
A real-world study in Taiwan, China, showed that although 50% of the patient population was primary refractory DLBCL patients and difficult to treat, the overall response rate (ORR) of the Pola regimen could reach 45.
2%, of which the CR rate was 29.
1%, which facilitated subsequent ^{transplantation12}
.

Bridging transplantation, empowering CAR-T, Pola explores more therapeutic potential of R/R DLBCL

Based on the high response rate and controllable safety shown by the Pola combination regimen in studies, Pola can enable transplantation and CAR-T therapy
.
As a salvage treatment for R/R DLBCL patients before transplantation, Pola can improve the success rate of transplantation; The Pola protocol bridges CAR-T, which helps to improve the survival prognosis of patients; After CAR-T treatment failure, the Pola regimen can also turn the tide, providing a new treatment option
for patients with DLBCL who have progressed/relapsed.

A real-world study in Greece confirmed that approximately 40% of patients with R/R DLBCL WHO COULD NOT RECEIVE ASCT DUE TO A POOR RESPONSE TO FRONTLINE THERAPY WERE CONVERTED TO ASCT AFTER TREATMENT WITH POLA-BR REGIMENS, WHICH COULD ALTER POOR PROGNOSTIC OUTCOMES AND FURTHER PROLONG ^SURVIVAL13
.

Figure 3 Real-world research results in Greece

Allogeneic hematopoietic stem cell transplantation (allo-HSCT)
is also an option for patients with DLBCL who relapse/progress after ASCT.
Real-world studies in Germany and China have shown that the Pola combination regimen can be used as a bridging therapy before allo-HSCT, promising additional survival benefits
.
Thirty- to 50% of patients successfully underwent allo-HSCT after Pola bridging, with a more significant survival benefit, particularly those with CR or partial response (PR) after Pola bridging (^14,15
).

Fig.
4 Results of real-world research allo-HSCT bridging scheme in Germany and China

Fig.
5 Achieving CR/PR after bridging therapy with Pola regimen in a real-world study in China compared with OS in patients who did not achieve it

In addition to hematopoietic stem cell transplantation, the Pola combination regimen can also enable CAR-T therapy and bring better clinical benefits
.
Compared with the more toxic high-intensity chemotherapy regimen, the Pola combination regimen creates an opportunity
for bridging CAR-T therapy due to its good efficacy and controllable safety.
Real-world studies in Germany and the UK have confirmed that the Pola combination regimen can be used as an effective bridging therapy before CAR-T therapy, with a success rate of more than 50% for CAR-T therapy and a 12-month OS rate of nearly 60% ^{for patients16,17}
.

A real-world UK study confirmed that more than 40% of patients with R/R DLBCL who have failed CAR-T therapy can still achieve relief from the salvage therapy of the Pola-BR ^regimen18, and nearly 20% of these patients can achieve CR.

Multicenter large-scale studies in the United States have also confirmed that Pola-BR can bring clinical benefits
as a salvage therapy for patients with CAR-T failure.
In a range of salvage regimens of single- or multi-agent regimens, patients with CAR-T failure treated with Pola-BR regimens had better response rates than other salvage regimens (ORR, 73%; CR rate, 40%), median progression-free survival (PFS) of 136 ^days19
.

Fig.
6 Results of different salvage treatments after CAR-T treatment failure in real-world studies in the United States

Both clinical studies and the real world have shown that Pola can confer more potential on transplantation and CAR-T therapy, and is a promising treatment option
.
We look forward to the publication of more comprehensive evidence-based medical evidence demonstrating the clinical benefits
of the Pola combination regimen for R/R DLBCL.