Professor Huang Huiqiang: Pola sends charcoal in the snow to help patients with non-transplantable R/R DLBCL to rekindle hope

The opening of every unknown world has been bravely foreseen by pioneers; Every journey of stealth in the dark of night, there are lighters fearlessly leading the way

Patients with relapsed or refractory (R/R) DLBCL are only about 10%

Patients with transplantation R/R DLBCL are not suitable and are in urgent need of effective second-line therapy

As a pioneer in the era of immunochemotherapy in the field of lymphoma, proto-rituximab (R) has revolutionized DLBCL treatment, and its combination of chemotherapy for first-line treatment can cure about 50-60% of patients with initial treatment of DLBCL, but still about 40%-50% of patients fail to achieve remission or relapse

Longstanding high-dose salvage chemotherapy sequential autologous hematopoietic stem cell transplantation (HDC-ASCT) has been the second-line standard of care for patients with first-time recurrence of DLBCL, significantly prolonging survival, whereas patients with R/R DLBCL are only about 10% likely to achieve a long-term cure from second-line standard ^therapy1,2

Figure 1 CR rates of commonly used salvage chemotherapy regimens

In the past, the vast majority of patients who were not candidates for transplantation were only treated with palliative care with chemotherapeutic immunotherapy regimens, such as rituximab plus gemcitabine and oxaliplatin (R-GemOx) or bendamustine plus rituximab (BR) regimens

In the era of new drugs, the treatment options available to patients with R/R DLBCL who are not suitable for transplantation are still very limited, there is no recognized standard second-line treatment, even if the "third degree" challenge to the second-line treatment of large B-cell lymphoma CAR-T cell therapy is also insufficient, nearly half (49%) of patients in the first month after infusion failed treatment, early progression, extranodal lesions ≥ 2, lactate dehydrogenase (LDH) increased, tumor load (TMTV) is the key factors for early ^{progression12}

Unlocking the mist, Pola escorts the unsuitable R/R DLBCL

In order to explore more effective treatments, the researchers compared the existing palliative care regimens, and a real-world data based on the SEEER medical database and including 439 patients proved that ^BR and R-GemOx had similar efficacy and controllable safety in the R/R DLBCL population, and the patient population had similar survival benefits
.

Figure 2 OS comparison between br group and R-GemOx group

In recent years, with the continuous emergence of new drugs, ADC drugs have attracted much attention
in the field of DLBCL.

The world's first ADC drug targeting CD79b, Pola-BR, demonstrated a gratifying outcome in the GO29365 ^study14,15
.

Compared with the BR group, the Pola-BR group significantly increased the CR rate of patients with R/R DLBCL who were not suitable for transplantation (40.
0% vs 17.
5%; P=0.
026) and optimal CR rate (57.
5% vs 20%)
.

After median follow-up of 22.
3 months, Pola-BR further extended progression-free survival (PFS, 9.
5 vs 3.
7 months; P<0.
001) and overall survival (OS, 12.
4 months vs 4.
7 months; P= 0.
002), and reduce the risk
of death by 58%.

Figure 3 CR rate versus optimal CR rate of Pola-BR and BR

Based on the results of the GO29365 study, Pola was awarded breakthrough therapy, priority drug and orphan drug certification by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), respectively, and was accelerated by the FDA in June 2019, and its joint program Pola-BR can be applied to adult patients with
R/R DLBCL.

The Pola-BR regimen has been included in the treatment recommendations
of the National Cancer Comprehensive Network (NCCN) guidelines and the Chinese Society of Clinical Oncology (CSCO) Lymphoma Diagnosis and Treatment Guidelines.

Figure 4 The development of Pola

To explore whether the Pola-R-GemOx regimen further improved survival outcomes in patients, a 2020 researcher STUDY of POLARGO showed a preliminary finding ^{of 16}, which was safe and tolerable in patients with R/R DLBCL and did not have a grade 5 adverse event (AE), AE leading to discontinuation, or grade ≥3 peripheral neuropathy
.

67% of patients achieved deep remission after Pola-R-GemOx treatment and successfully received CAR-T treatment or transplantation
.

It is believed that the publication of more research results in the future will provide more evidence
for more Pola joint programs to explore the field of R/R DLBCL.

Breaking through the bottleneck, Pola torsion is not suitable for the treatment dilemma of transplantation R/R DLBCL

As an extension of clinical trials, real-world research (RWD) will face a more severe test
.

In RWD, Pola maintains a dominant position despite the fact that the patient's disease status is worse, such as the patient's previous treatment has more lines and is in worse physical condition
.

Figure 5 Pola's RWD data by country

A Greek RWD confirmed that patients with R/R DLBCL who are not suitable for transplantation are expected to receive transplantation after treatment with Pola-(B)^R17
.

The RWD retrospectively analyzed the efficacy
of 49 patients with R/R DLBCL after treatment with Pola-BR.

The results showed that the overall response rate (ORR) was 35% and the CR rate was 20% at the end of treatment, suggesting that patients with R/R DLBCL could achieve deep remission through the Pola-BR regimen
.

Nearly 40% of patients with R/R DLBCL who are unable to receive transplantation due to insensitivity to frontline treatment can be transformed into transplant-suitable after Pola-BR treatment, bringing the dawn
of cure to more patients.

Effectively bridged, Pola empowers CAR-T therapy

In the 2022 edition of the "GUIDELINES for the Management of Infections Related to CAR-T Cell Therapy for Malignant Hematological Tumors and Immune Targeted Therapy", targeted therapy was included in the bridging therapy of
CAR-T cell therapy.

Based on Pola's excellent performance in numerous clinical trials and real-world data, the Pola protocol is considered as a bridging protocol before CAR-T treatment to improve the success rate
of CAR-T treatment.

A German RWD study designed to evaluate the efficacy of Pola-BR in real-world settings showed ¹⁸ that the success rate of the Pola combination regimen as a CAR-T bridging treatment was 51.
2% in patients receiving CAR-T, and the OS rate in patients at 12 months was nearly 60%.

Figure 6 CAR-T bridging queue OS rate of German RWD

Another UK RWD also evaluated the efficacy of the Pola‐ BR regimen as a CAR-T bridging ^treatment19, with CR rates of nearly 20% in 40 patients with R/R DLBCL who received Pola-BR as bridging, and the success rate of CAR-T therapy in patients as high as 78%.

Figure 7 CAR-T bridging queue data for German and UK RWDs

As a rising star in the era of immune targeted therapy, Pola can not only improve the depth of remission and prolong the survival period of patients who are not suitable for transplantation R/R DLBCL, but also transform some patients who are not suitable for transplantation into patients who are suitable for transplantation, have more treatment options, and can also bridge CAR-T treatment and improve the success rate of treatment, reaching the effect of "1+1>2", and the future can be expected
.

Cancer Prevention and Treatment Center, Sun Yat-sen University

Professor Huang Huiqiang

Pola is the world's first approved ADC drug for DLBCL, based on its excellent performance in the GO29365 study, Pola was approved for marketing by the FDA and EMA, and has accumulated a large number of real-world application experience in various regions of the world, further verifying the efficacy and safety
of Pola in the treatment of R/R DLBCL.

For R/R DLBCL that is not suitable for transplantation, CAR-T therapy is a completely new treatment modality, but the risk of early progression is higher, especially in patients with large tumor burden, and the risk of early progression can be reduced by effective bridging therapy, and the ADC drug Pola, which targets CD79b, is a good bridging therapy option
.

It is expected that in the future, Pola will benefit more R/R DLBCL patients
after its listing in China.

Professor Huiqiang Huang

• Chief Physician Doctoral Supervisor

• Deputy Director of the Department of Internal Medicine, Cancer Prevention and Control Center of Sun Yat-sen University

• Chairman of the Lymphoma Professional Committee of the Chinese Geriatric Health Association

• Vice Chairman of CSCO China Anti-Lymphoma Alliance

• Chairman of the CSCO Thyroid Cancer Committee

• Vice Chairman of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association

• Chairman of the Youth Committee of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association

• Honorary Chairman of the Hematology and Tumor Professional Committee of Guangdong Anti-Cancer Association

• Vice Chairman of the Hematology Committee of Guangdong Association of Integrative Traditional and Western Medicine

• He is a standing member of the 2nd Blood Disease Translational Medicine Professional Committee of the Chinese Anti-Cancer Association

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