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2022 ASH raises the possibility of cure, and vipotuzumab escorts the long-term survival of treatment-naïve DLBCL

 Last Update: 2022-12-30
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Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, with recurrence progressing
in 30% to 40% of patients with first-line standard therapy.
In recent years, the continuous progress of targeted drugs represented by antibody-drug conjugates (ADCs) has provided more treatment options
for DLBCL patients.
Polatuzumab Vedotin (Pola) is the world's first ADC drug targeting CD79b, and has attracted much attention
in the field of DLBCL because of its excellent efficacy.

Recently, the 64th American Society of Hematology (ASH) Annual Meeting in 2022 was grandly held, and at this highly anticipated international academic event, the relevant analysis results of the POLARIX study, a key study of vepotuzumab, were announced.

Highlights of this article:

Previous data from the POLARIX study showed that Pola-R-CHP broke through the efficacy of R-CHOP for the first time, significantly increasing the 2-year PFS rate and 2-year EFS rate, promoting patients to achieve more durable remission and less need for follow-up anti-lymphoma treatment
.

The latest analysis of 2022ASH shows that Pola-R-CHP is expected to reduce the risk of second-line treatment for DLBCL patients by 27% over 10 years, including those
with high-risk factors.

Patients with treatment-naïve DLBCL had better survival with lower ctDNA levels and the Pola-R-CHP regimen reduced ctDNA levels
.

Previous Review: POLARIX Study Confirms First Time Pola-R-CHP Solution Breaks R-CHOP "Ceiling"

Disease progression in up to 30 to 40 percent of DLBCL patients with first-line standard therapy, mostly within 24 months, seriously affects overall survival (OS) in these patients ^[1].
Compared with patients without disease progression (PFS24) at 24 months, patients who did not achieve PFS24 had a median OS of only 7.
2 months after disease progression and a five-year OS rate as low as 19 percent ^[2].
Therefore, it is a top priority to further improve the cure rate of DLBCL first-line treatment on the basis of R-CHOP and delay the progression of the disease
.

*R-CHOP, rituximab in combination with cyclophosphamide, vincristine, doxorubicin, prednisone

Fig.
1 Comparison of 5-year OS rates in patients who did not achieve PFS24 vs PFS24

In the past 20 years, whether it is increasing the intensity of chemotherapy or R-CHOP+ targeted drugs, many explorations and attempts made by many scholars have failed, and most studies have not shown efficacy benefits
.
Until 2017, the investigators conducted a randomized, double-blind, placebo-controlled international phase III study POLARIX study that explored the efficacy and safety
of vepotuzumab combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) regimens compared with R-CHOP.

The results of the first analysis showed that Pola-R-CHP significantly improved the 2-year progression-free survival (PFS) rate (76.
7 versus 70.
2%, P = 0.
02) and reduced the relative risk of disease progression, recurrence, or death by 27 percent compared with R-CHOP at a median follow-up of 28.
2 months ^[3].
Furthermore, patients in the Pola-R-CHP group had a higher 2-year event-free survival (EFS) rate (75.
6 versus 69.
4 percent), suggesting a more durable response and fewer patients requiring follow-up anti-lymphoma therapy (22.
5 versus 30.
3 percent).

FIGURE 2 COMPARISON OF 2-YEAR PFS RATES BETWEEN THE TWO GROUPS IN THE POLARIX STUDY

For people with high-risk factors, Pola-R-CHP increased the PFS24 rate by more than 6.
5% compared with R-CHOP, suggesting that Pola-R-CHP regimen as first-line therapy can promote the cure of more high-risk DLBCL patients.

Figure 3 The PFS24 rate of Pola-R-CHP compared to R-CHOP increased

In terms of safety, the overall safety profile of the two groups was comparable, and the proportion of patients in the Pola-R-CHP group receiving a full course of treatment was higher, and there were fewer adverse effects (AEs)
leading to dose reduction/treatment interruption.

Figure 4 AEs of the two groups

Based on the results of POLARIX research, Pola-R-CHP has become the first treatment regimen to surpass the classic R-CHOP in more than 20 years, and has been included in the first-line treatment recommendation of DLBCL in the Chinese Society of Clinical Oncology (CSCO) lymphoma guidelines in April 2022, and was approved for marketing in the EU in May 2022, bringing new first-line treatment options
to more Chinese and foreign DLBCL patients.

2022ASH Update: Pola-R-CHP reduces the risk of progression of DLBCL over the next 10 years, reducing the likelihood of late-line treatment

At this ASH meeting, investigators presented the results of an interim analysis of the POLARIX study ^[4], which evaluated the potential impact of Pola-R-CHP on second-line therapies and predicted real-world DLBCL populations
with its results.
The results showed that Pola-R-CHP was expected to reduce the risk of second-line therapy in patients over 10 years by 27% compared to R-CHOP, including those with high-risk factors, such as double-expressed lymphoma (DEL).

Consistent with previously reported PFS benefits, the Pola-R-CHP regimen also reduced the risk of late-line therapy by 34%.

Most patients in both groups of patients in the study required follow-up treatment, and risk factors included Ann-Arbor stage III–IV, bulky disease, and DEL
.
The investigators used the Fine-Grey method to estimate the cumulative incidence of second-line therapy over time, where death was a competitive risk
.
The results showed that the Pola-R-CHP group received significantly fewer patients receiving second-line therapy than patients in the R-CHOP group (cumulative incidence of second-line therapy at 24 months, 17.
1% versus 24.
4%), while reducing the risk
of late-line therapy by 34%.
Competitive risk mortality was similar
in both groups of second-line therapy.

FIGURE 5 CUMULATIVE INCIDENCE OF THE TWO GROUPS OF SECOND-LINE THERAPY IN THE POLARIX STUDY

Whether treated with Pola-R-CHP or R-CHOP, patients with DLBCL received similar second-line therapies, suggesting that first-line use of Pola-R-CHP did not change the choice of
subsequent therapy.
The types of second-line therapies used in both groups and the rate of application are shown
in Figure 6.

Fig.
6 Types and proportions of second-line therapy in the two groups

Pola-R-CHP is estimated to reduce the risk of second-line therapy by 27% within 10 years and reduce the burden of treatment for patients

To estimate the effect of Pola-R-CHP as first-line DLBCL on the incidence of second-line therapy over the next 10 years, the investigators constructed a dynamic multi-cohort partitioned survival model that included DLBCL patients with an international prognostic index (IPI) score of 2-5 to analyze the effects of
Pola-R-CHP and R-CHOP regimens in depth.
The results show that Pola-R-CHP is expected to reduce the risk of patients receiving second-line therapy by 27% within 10 years, prompting up to 27,741 patients in six countries to avoid the burden
of later treatment.
Further exploration of longer follow-up is needed to determine the number of treatments these patients should have avoided during third- and
later-line therapy.

Fig.
7 Estimated incidence of second-line therapy in first-line patients receiving Pola-R-CHP or R-CHOP regimen (2023-2033)

Note: The orange + blue area represents the estimated total incidence of patients returning to second-line therapy after first-line treatment with R-CHOP (Pola-R-CHP was not introduced); The number of patients requiring second-line therapy in patients treated with Pola-R-CHP decreased cumulatively by 27,741 over 10 years (six countries), with 14,585 cases in each country (US); 3,869 (Germany); 2,999 (UK); 2,200 (France); 1,986 (Italy); 2,102 (Canada).

ctDNA has prognostic value in patients with treatment-naïve DLBCL or may guide treatment

In order to explore the significance of circulating tumor DNA (ctDNA) analysis in the treatment of DLBCL, the researchers conducted an exploratory analysis based on the POLARIX study data and found that ctDNA analysis has prognostic value for patients with treatment-naïve DLBCL ^[5], and different treatment options can be selected according to the early changes in the patient's ctDNA level
。

There was no statistically significant difference in baseline ctDNA levels between groups, with patients with baseline ctDNA levels above the median mean number of mutant molecules per milliliter (MMPM) of 135, patients with baseline ctDNA levels below 135 having longer PFS and OS, and patients with more ctDNA levels decreasing after one treatment cycle having longer PFS and OS
。 In addition, in the exploration of the optimal risk cut-off value, the researchers found that setting the logarithmic multiple change (LFC) threshold of 2.
5 better identified patients with a lower risk of outcome (LFC< 2.
5 vs LFC≥2.
5, PFS HR 2.
89, 24-month estimate 65.
7% vs 87.
0%; OS HR 1.
87, 24-month estimate 86.
2% vs 91.
8%)
.

Fig.
8 PFS in patients in the Pola-R-CHP group

In the Pola-R-CHP group, patients with ctDNA clearance had better clinical outcomes
than those who did not clear their ctDNA on day 1 of cycle 2 (C2D1).
Multivariate analysis found that both LFC2.
5 and ctDNA clearance predicted PFS and OS in patients treated with Pola-R-CHP (Figure 9), and also had prognostic significance
in patients treated with R-CHOP.

Figure 9 Baseline risk factors for patients

Viptozumab enhances the possibility of first-line cure of DLBCL and helps achieve long-term survival
In the history of more than 20 years, the combination program Pola-R-CHP of vepotuzumab shook the "ceiling" status
of R-CHOP for the first time.
According to the data of the POLARIX study released earlier, the application of Pola-R-CHP to the first-line treatment of DLBCL can bring more cure possibilities, and there are still quite excellent performance
in high-risk patients such as high IPI score, ABC subtype, and double expression that are more difficult to treat.

The estimated analysis results presented at this ASH meeting further demonstrate the therapeutic potential
of Pola-R-CHP in the first-line treatment of DLBCL.
Vipotuzumab is expected to reduce the risk of disease progression in the next 10 years by prolonging the PFS of patients, thereby reducing the possibility of late-line therapy, helping to reduce the treatment burden of DLBCL patients and achieve long-term survival
.
In addition, early use of ctDNA analysis may guide the treatment of treatment-naïve DLBCL patients, and choose a vepotuzumab regimen with better efficacy, reduced ctDNA levels, and significantly prolonging survival
.
It is believed that in the future, vepotuzumab will become a star in the field of DLBCL and lead the direction
of treatment.

References:

1.
Coiffier B, et al.
Blood.
2010; 116(12):2040-2045.

2.
Maurer MJ, et al.
Ann Oncol.
2018 Aug 1; 29(8):1822-1827.

3.
Tilly H, et al.
Lymphoma.
N Engl J Med.
2022; 386(4):351-363.

4.
Frédéric Boissard, et al.
Poster on ASH 2022 (2958).

5.
Alex F.
Herrera, et al.
Oral on ASH 2022 (542).

Editor: Chole Reviewed: Evelyn Typesetting: Moly Execution: Moly

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