PD-(L)1 Clinical Development Challenges and Opportunities: Over 80% of Combination Therapy in Nearly 5,000 Clinical Trials

TextBai Lu

Last year marked the tenth anniversary of the FDA approval of the first checkpoint inhibitor, ipilimumab, a monoclonal antibody against CTLA4, for the treatment of melanoma
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This approval has arguably revolutionized cancer treatment and paves the way for the clinical advancement of immune checkpoint inhibitors and other immuno-oncology (IO) therapies

On February 10, a report published in Nature Reviews Drug Discovery analyzed the latest developments in clinical trials of PD1/PDL1 antibodies and summarized emerging treatment modalities
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Clinical trials continue to grow

Clinical trials continue to grow

There are currently 5683 clinical trials evaluating PD1/PDL1 mAbs as monotherapy or in combination with other therapies, of which 4897 are active (Figure 1)
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This represents a 278% increase in the total number of clinical trials over the past 5 years, compared to the authors' analysis in 2017

Figure 1 | Overview of clinical trials of PD1/PDL1 mAbs in 2017 and 2021
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As of December 2021, there are 5,683 clinical trials evaluating anti-PD1/PDL1 mAbs

While the total number of clinical trials has been increasing every year, year-over-year growth has been slowly declining
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The total number of clinical trials evaluating PD1/PDL1 mAbs has increased by 29% in the past year, compared with a 50% increase from 2017 to 2018 (Figure 2)

Figure 2 | Overview of PD1/PDL1 mAb Clinical Trials Growth from 2017 to 2021
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(Source: Nature Reviews Drug Discovery)

Combination therapy leads the way

Combination therapy leads the way

Data analysis showed that of the 4897 active trials, 4062 (83%) were testing PD1/PDL1 in combination with other IO therapies, targeted therapy, chemotherapy and radiation therapy
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Among these combination models, IO therapy led the way with 1,058 active trials, followed by targeted therapy with 1,008

Comparing the average planned patient recruitment for monotherapy trials and combination therapy trials, the data show that the average planned patient recruitment per monotherapy trial has fallen sharply over the years, compared with 2014 (the highest number of patients recruited for monotherapy trials).
1 year) decreased by a factor of nearly 7 (Figure 3)
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Conversely, the average planned patient recruitment per combination therapy trial declined by a smaller amount, falling nearly 2-fold from its 2015 peak

Figure 3 | Comparison of monotherapy and combination therapy trials
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Since 2014, most new trials have been combination therapy trials (bar graph)

As anti-PD1/PDL1 clinical trials continue to move toward a combined strategy, the authors update their analysis of the targets pursued by such models
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In addition to PD1/PDL1, nearly 300 targets and pathways are being tested, an increase of 18% since the last update (Figure 4)
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Figure 4 | Target overview of combination therapy trials in 2017, 2020, 2021
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(Source: Nature Reviews Drug Discovery)

Although VEGF/VEGFR-targeted combination therapy trials do not appear to have seen much growth since 2020, VEGF/VEGFR-targeted therapy, chemotherapy, and CTLA4 inhibitors remain the preferred combination therapy strategies (Figure 5)
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In contrast, chemotherapy and CTLA4 combination trials showed a downward trend
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Figure 5 | Primary targets assessed in combination with PD1/PDL1 mAbs
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The graph shows the number of combination therapy trials initiated each year since 2011
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The TOP 20 targets assessed by combination therapies are listed in descending order based on the number of trials starting in 2021
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(Source: Nature Reviews Drug Discovery)

Global Patient Recruitment and PD1/PDL1 Inhibitor Use Overview

Global Patient Recruitment and PD1/PDL1 Inhibitor Use Overview

According to the authors' previous analysis, China leads the way in patient recruitment rates in both monotherapy and combination therapy anti-PD1/PDL1 clinical trials
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To truly understand the status of global patient recruitment rates, information from 147 IQVIA-administered anti-PD1/PDL1 clinical trials spanning 960 independent sites was collected for analysis
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Consistent with previous findings, patient recruitment rates in monotherapy trials continued to decline in the United States and China, although the rate of decline was much lower in China (Figure 6)
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Interestingly, some Asia-Pacific countries (Australia, New Zealand, South Korea, Thailand) have seen increased patient recruitment rates for both monotherapy and combination trials
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This spike may be the result of increased activity in clinical trials of novel anti-PD1/PDL1 drugs ('Other PDx')
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Monitoring of these regions will provide insight into global trends in patient recruitment rates
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Figure 6 | Median patient recruitment rates by country and percent change between consecutive years, 2019 to 2021
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(Source: Nature Reviews Drug Discovery)

The authors further explored real-world data on anti-PD1/PDL1 drug use
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Analysis of the use of three-generation anti-PD1/PDL1 drugs shows that the market size of anti-PD1/PDL1 drugs is growing intensively in terms of use and dissemination at the country level
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This trend was observed across all generations of anti-PD1/PDL1 drugs
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Typically sales of anti-PD1/PDL1 drugs (such as pembrolizumab, atezolizumab, or nivolumab) start in the United States and several large market countries (such as France and Germany), and then rapidly spread globally
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Taking into account the high prices of drugs, high-income countries have the highest per capita use
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Novel anti-PD1/PDL1 treatment modality

Novel anti-PD1/PDL1 treatment modality

There are currently 93 bispecific antibodies against PD1/PDL1 in development, 4 of which are directed against both PD1 and PDL1
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Regarding the development stage, 62% of them are in preclinical phase, 23% are in clinical phase I, 11% are in clinical phase II, and 4% are in clinical phase III
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Cumulatively, these bispecific antibodies are being developed utilizing 28 different targets/mechanisms, including other immune checkpoint pathways, such as CTLA4 and LAG3, which are already in clinical phase III development (Figure 7)
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Figure 7 | Overview of PD1/PDL1 bispecific antibody targets
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(Source: Nature Reviews Drug Discovery)

In addition, data analysis revealed about 15 small-molecule PD1/PDL1 inhibitors, most of which are in early stage (preclinical and phase I) and are being developed for oral administration
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Both bispecific antibodies and small-molecule oral PD1/PDL1 inhibitors represent recent advances in the field, which may continue to promote the combination of these drugs
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in conclusion

in conclusion

With the development of bispecific antibodies and novel delivery platforms for PD1/PDL1 therapeutic modalities, emerging combination therapy strategies are promising
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Global patient competition for anti-PD1/PDL1 studies continues
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In light of this, the FDA says it needs to optimize drug development in this area, including sponsoring collaboration on PD1/PDL1 combination therapy strategies and encouraging head-to-head randomized studies of PD1/PDL1 inhibitors to demonstrate differentiation
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These challenges are expected to continue in the near future
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As the field of PD1/PDL1 drugs and clinical trials continues to evolve, it will be important to monitor the challenges and opportunities in this field
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References:

1# Julia A.
Beaver et al.
The Wild West of Checkpoint Inhibitor Development.
N.
Engl.
J.
Med.
2021.

2# Samik Upadhaya et al.
Challenges and opportunities in the PD1/PDL1 inhibitor clinical trial landscape.
Nature Reviews Drug Discovery.
2022

3# Samik Upadhaya et al.
Combinations take centre stage in PD1/PDL1 inhibitor clinical trials.
Nature Reviews Drug Discovery.
2020