PD-1/PD-L1 combination therapy is fully combed: 119 studies and 65 programs 8% are approved for marketing

Article source: Med

Over the past ten years, targeting PD-1 and PD-L1 has opened up a new era for cancer clinical treatment

The data shows that there are 253 PD-1/PD-L1 antibody and drug target combinations being tested

What is the actual situation of a large number of immunization combined program trials? Is it "blindly" optimistic or "cautious" pessimistic, on which side is the balance of time?

Recently, in a review article in "Cancer Treatment Reviews" (IF=12.

The researchers systematically searched the Phase II trials of PD-1/PD-L1 inhibitors combined with other anticancer therapies published between January 1, 2018 and December 31, 2020, and 119 articles were included in the final analysis

Most of the literature focuses on gastrointestinal tumors (n=25), followed by breast tumors (n=22) and genitourinary system tumors (n=15)

Distribution of tumor types according to the number of articles published in the Phase II trial articles evaluating PD-1/PD-L1 combination therapy published in 2018-2020 (Source: Cancer Treat Rev)

Overall, 65 different combination therapies were explored in various situations

PD-1/PD-L1 monoclonal antibody + other immunotherapy drugs

46 articles reported the phase II results of PD-1/PD-L1 inhibitors combined with other immunotherapy drugs

Later, the researchers further explored these two combined treatment options in phase III trials with 10 different settings

List of O+Y approved indications (source: NextPharma database)

PD-1/PD-L1 monoclonal antibody + targeted drugs

Forty articles reported the results of the combination with targeted drugs

In the follow-up, five combination programs continued to advance to phase III clinical trials, including atelizumab combined with bevacizumab for the treatment of RCC, atilizumab combined with T-DM1 for the treatment of HER2-amplified breast cancer, and pembrolizumab Monoclonal antibody combined with enzalutamide in the treatment of prostate cancer, pembrolizumab combined with lenvatinib in the treatment of endometrial cancer, and pembrolizumab combined with trastuzumab + chemotherapy in the treatment of HER2-amplified gastroesophageal cancer

At present, the FDA has approved pembrolizumab+lenvatinib for endometrial cancer and renal cell carcinoma based on phase II data

PD-1/PD-L1 monoclonal antibody + chemotherapy

22 articles reported the results of anti-PD-1/PD-L1 antibody combined with chemotherapy

Subsequently, six combination schemes entered the phase III trial: Atelizumab + carboplatin and albumin paclitaxel neoadjuvant therapy in NSCLC patients; Nivolumab + cis in patients with advanced gastroesophageal tumors Neoadjuvant therapy with platinum and fluorouracil; neoadjuvant therapy with nivolumab + carboplatin and paclitaxel in patients with NSCLC; after neoadjuvant therapy with pembrolizumab + carboplatin and paclitaxel in patients with triple-negative breast cancer Sequential doxorubicin or epirubicin and cyclophosphamide treatment; pembrolizumab + carboplatin and pemetrexed neoadjuvant treatment in patients with advanced non-squamous NSCLC; in patients with advanced gastroesophageal tumors Pembrolizumab + cisplatin and fluoropyrimidine neoadjuvant therapy

(Editor’s note: At present, the combination of PD-1/PD-L1 and chemotherapy is widely used in clinical applications, and has become the mainstream of the approved indications in China

PD-1/PD-L1 monoclonal antibody + radiotherapy ± chemotherapy

Eleven articles evaluated the relationship between PD-1/PD-L1 inhibitors and radiotherapy, including 4 studies of immunotherapy combined with radiotherapy and chemotherapy

According to the author, this is the first systematic review of Phase II trials of PD-1/PD-L1 inhibitors in combination with other anti-cancer therapies

Most literature reported the outcome of a single-arm trial (n = 87, 73%), and the objective response rate was the most common primary endpoint (n = 69, 58%)
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The objective response rate reported in 109 articles (92%) ranged from 0% to 91%
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Ninety-seven articles (82%) clearly reported treatment-related adverse events of grade 3 or above, ranging from 0% to 100%
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Of the 65 different combinations included in this analysis, 5 have been approved by the FDA for 9 different indications (3 are based on phase II trial results, and 6 are based on subsequent phase III trials)
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Since the analysis is only for phase II trials published between 2018 and 2020, and domestic PD-1/PD-L1 related studies (except carrelizumab) are not included, the study inevitably has certain limitations, but it is sufficient Thought-provoking
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The authors stated that it is important to determine the efficacy index (primary endpoint) to determine whether the combination therapy needs to be further evaluated
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In addition, it is also necessary to identify predictive markers of efficacy and establish selection criteria for the best combination therapy in order to further improve trial results and ultimately change clinical practice
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Perhaps this is the huge unmet need currently facing clinical trials
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references:

A systematic review of phase II trials exploring anti-PD-1/PD-L1 combinations in patients with solid tumors.
Cancer Treat Rev.
2021 Oct 17;101:102300.
doi: 10.
1016/j.
ctrv.
2021.
102300.