PD-L1 Inhibitors and Urothelial Carcinoma-Love is easy and difficult to defend

Article source: Med

Author: Ala Lei

Too long to watch the version

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On August 27th, we wrote a tweet-PD-1 indication "first show": Even if there are thousands of new lovers, why is it always the first love? In fact, when searching for information, I found an interesting point

Urothelial cancer, why do you like it?

Don’t choose Zhanhong Aya, don’t choose gold inlaid jade

Urothelial carcinoma (UC), a common tumor of the genitourinary system, is divided into bladder cancer (about 90%-95%) and upper urothelial carcinoma (about 5%-10%)

Data source: https://gco.

Bladder cancer is mainly divided into non-muscular invasive bladder cancer and muscular invasive bladder cancer

Immunotherapy and UC's "childhood childhood"

Actually, fate has already begun

Compared with other tumors, immunotherapy and UC have known each other very early

Figure: Research paper by Morales et al.

Morales and his team conducted trials in 9 patients with bladder cancer

In 1990, the US FDA approved BCG intravesical perfusion for the treatment of non-muscular invasive bladder cancer

Tumor antigens are divided into tumor-specific antigens and tumor-related antigens, which can induce the body to produce an anti-tumor immune response

The data describes the number of mutations in each type of tumor cell, and the right side represents an estimate of the number of neoantigens in different tumor types

From this picture, we can also find that melanoma has the highest average number of neoantigens, which is one of the important reasons why it has become a "hot" in immunotherapy research

Overall, due to earlier and more understanding of the immunopathology of UC, coupled with the success of BCG, UC has been brought to the forefront of immunotherapy research

PD-L1 and UC: The beauty of the first encounter

The mechanism of PD-1/PD-L1 will not be described in detail here
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To put it simply, PD-1 is expressed on the surface of T cells.
When it binds to PD-L1 on the surface of tumor cells, it will cause the disability or apoptosis of T cells
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Using PD-1/PD-L1 inhibitors to block the combination of PD-1 and PD-L1 can restore the vitality of T cells to eliminate tumor cells
.

PD-L1 inhibitors first made progress in the second-line treatment of UC
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Take PD-L1 atelizumab, which was first approved for UC, as an example
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The IMvigor 210 study is a single-arm, multi-center, phase II clinical study, including 2 cohorts
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A total of 310 patients were enrolled in cohort 2 to evaluate the effect of atilizumab in advanced UC that has progressed after platinum-based chemotherapy
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The results showed that the patient’s objective response rate (ORR) was 15%, the complete response rate (CRR) was 5%, and the median overall survival (OS) was 7.
9 months
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Based on this result, on May 18, 2016, atelizumab was approved by the FDA for accelerated second-line treatment of advanced UC [3]
.

In less than a year, based on the results of IMvigor 210 study cohort 1, the FDA accelerated the approval of atelizumab for the first-line treatment of advanced UC on April 18, 2017
.
Cohort 1 included a total of 119 patients with newly-treated advanced UC who could not tolerate platinum, with an ORR of 23% and a median OS of 15.
9 months [4]
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So far, the story seems to be smooth sailing

Here is a brief explanation of the FDA's "accelerated approval" process
.
The FDA's accelerated approval process allows a new drug to be "conditionally" approved for marketing based on alternative endpoints (such as ORR) to meet the unmet clinical treatment needs of some important diseases
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The conditions attached to the accelerated approval require that a new drug be converted to full approval after it has been listed in a confirmatory clinical trial that has the benefit of improving the survival of the patient, otherwise it will be withdrawn from the market qualification.

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The IMvigor 211 study and the IMvigor 130 study are the key to determining whether atelizumab can be "fully approved"
.

PD-L1 and UC: the ups and downs experienced

Let’s first look at the IMvigor 211 study, which is a multi-center, open-label, phase III randomized controlled study, enrolling 931 patients with advanced UC who have progressed after platinum-based chemotherapy
.
Among them, there are 234 patients with PD-L1≥5%, and the effectiveness of these patients is analyzed
.
The results showed that the median OS of the atilizumab group and the chemotherapy group were 11.
1 months and 10.
6 months, respectively (P=0.
41), the difference was not statistically significant; the ORRs of the two groups were similar, 23% and 22, respectively.
%
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Based on this result, on March 8, 2021, Roche announced that it would voluntarily withdraw the second-line UC indication of atilizumab in the United States [5]
.

Let’s look at the IMvigor 130 study again.
It is a multi-center, randomized, phase III study that included 1231 patients with advanced-stage newly-treated UC, divided into three groups: atilizumab + chemotherapy (group A), atiride Razumab monotherapy (group B), placebo + chemotherapy (group C)
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The results showed that the median PFS of group A and group C were 8.
2 months and 6.
3 months, respectively (one-side P=0.
007); the median OS were: 16.
0 months and 13.
4 months, respectively (one-side P=0.
027) )
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The FDA continues to retain atelizumab as the first-line indication for advanced UC [6]
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However, during the IMvigor 130 study, the Data Monitoring Committee (DMC) found that compared with patients receiving cisplatin, the survival rate of patients with low PD-L1 expression in the atelizumab monotherapy group was reduced
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Therefore, in August 2018, the FDA updated the specific requirements for the indications of atelizumab: "If you cannot tolerate cisplatin chemotherapy, the FDA-approved test results show PD-L1≥5%" or "if you cannot tolerate cisplatin chemotherapy.
" Subject to any platinum-containing chemotherapy, regardless of the expression level of PD-L1"
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It is also regrettable to get along in the adjuvant treatment after UC
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The IMvigor 010 study is a multi-center, open-label, randomized phase III clinical trial to evaluate the efficacy and safety of ateliizumab adjuvant therapy after radical resection in high-risk patients with myometrial infiltrating UC.
The results are Published in Lancet Oncology in March 2021
.
The data showed that the median disease-free survival (DFS) of the atilizumab group and the observation group were 19.
4 months and 16.
6 months, respectively, showing no statistical difference (P=0.
24); the median of the two groups OS was not reached, the 12-month OS rates were 88% and 81%, and the 18-month OS rates were 79% and 73% [7]
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In fact, in addition to atelizumab, other PD-1/PD-L1 clinical studies have also encountered a lot of setbacks
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Duvalvumab actively withdrew from the FDA on February 22, 2021, as an indication for the second-line treatment of advanced UC
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The Keynote-361 study of pembrolizumab (first-line treatment of advanced UC) did not meet the primary endpoint
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Avirumumab’s JAVELIN Bladder 100 study reached the primary endpoint.
In June 2020, it was approved by the FDA for the maintenance treatment of locally advanced or metastatic urothelial cancer patients who have not progressed after first-line platinum-containing chemotherapy
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The relationship between PD-L1 level and efficacy does not seem to be so easy to use in UC!

At present, it is generally believed that patients with high PD-L1 expression who use PD-1/PD-L1 inhibitors with lower efficacy are more ideal
.
In UC's data, this correlation is not uniform
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In the IMvigor 210 study cohort 2, Checkmate 275 (nivolumab) showed a correlation between PD-L1 and efficacy; however, in the IMvigor 210 study cohort 1, Checkmate 032 (nivolumab), IMvigor 010 study No such correlation was observed in both
.

On the one hand, different companies' PD-L1 detection platforms and antibodies used are different, which will affect the definition of positive values ​​and the judgment of results
.
For example, in the IMvigor 010 study, it was found that the expression level of PD-L1 did not show a correlation with treatment benefits, but it was a predictor of DFS.
This is consistent with the results of related studies using the VENTANA SP142 or VENTANA SP263 test, but it is consistent with the 22C3 test There are differences in related research results
.

On the other hand, the expression of PD-L1 in tumor tissues is heterogeneous, dynamic, and may be regulated by various factors in the tumor microenvironment.
Tumor biopsy at a single time point cannot capture this dynamic change
.
Therefore, searching for more effective and sensitive biomarkers is the focus of common attention of experts and scholars in the field
.

At present, in addition to PD-L1, tumor mutation burden (TMB), circulating tumor DNA (ctDNA), RNA-Seq-based immune-related scores (for example: CXCL9, CXCL10 expression of effector T cells, IFNα, IFNγ), etc.
, a number of studies It is ongoing, and it is hoped that these studies can bring more precise conclusions
.

There is a saying that goes like this, see people's hearts over time, and see the true feelings in adversity
.
The ups and downs between PD-L1 inhibitors and UC can prompt us to explore tumor immunity and immunotherapy more deeply
.
In addition to immune monotherapy and immune combined chemotherapy, research on immune combined radiotherapy, combined immune targeted therapy, and ADC drugs is also underway.
The story of UC immunotherapy is far from over.
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