O+Y approved indications and core clinical trials are sorted out

WenSixi

One month ago, nivolumumab combined with ipilimumab (O+Y) dual immunotherapy was officially approved in China for unresectable, newly-treated adult patients with non-epithelial malignant pleural mesothelioma
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A week ago, the Lung-MAP S1400I study of O+Y for the second-line treatment of advanced NSCLC was officially published in JAMA oncol.
Only one day later, O+Y was the first-line treatment of CheckMate for recurrent or metastatic head and neck squamous cell carcinoma.
The 651 study also announced that it failed
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However, this twists and turns may be nothing to O+Y, who is accustomed to the storm
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Since 2015, O+Y has been approved by the FDA for multiple indications including melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, and pleural mesothelioma
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Behind the fruitful results is a huge investment in a number of clinical studies for different indications
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According to the NextClinTrial database of Medicine Rubik's Cube, excluding exploratory early clinical trials, O+Y has carried out a total of 30 key clinical trials for the purpose of drug registration or change guidelines

In the past, NSCLC "chemo-free" immunotherapy regimens were limited by the expression level of PD-L1.
The success of CheckMate-227/9LA marked the release of the first "chemo-free" first-line regimen that would benefit a broad patient population
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The Lancet's CheckMate-743 broke the deadlock and became the first and only phase III clinical trial to prove that first-line immunotherapy prolongs the survival of malignant pleural mesothelioma
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In addition, O+Y is also the first combination therapy that is more effective than sunitinib for medium/high-risk renal cell carcinoma, and the survival benefit has nothing to do with PD-L1 expression; the first to be approved for MSI- Tumor immune combination therapy for the second-line treatment of H/dMMR colorectal cancer.
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Holding the hand or the seven-year itch?

Since the FDA first approved in September 2015 and was approved in China in June 2021, ipilimumab and nivolumab are about to enter their seventh year of marriage
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Legend: The synergistic mechanism of PD-1 and CTLA-4 (T cell activation is mediated by the interaction of TCR and CD28 receptors with MHC-II and B7 costimulatory molecules located on APC
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On the one hand, anti- CTLA-4 antibody can effectively inhibit the inhibitory signal transmitted by B7 binding; on the other hand, anti-PD-1/PD-L1 antibody can inhibit the PD-L1 binding between T cells and tumor cells) Source: Reference [2]

Although the combination of nivolumab and ipilimumab, by targeting two different checkpoints (PD-1 and CTLA-4), the potential synergistic mechanism is demonstrated in a complementary manner, which has achieved a lot of hope Clinical results
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However, security issues have slowed the development of such strategies

Source: Reference [2]

Data show that compared with PD-1/CTLA-4 monotherapy, the higher benefit of combination therapy comes at the cost of higher immunotherapy-related adverse reactions (irAE), including rash, pruritus, diarrhea, hepatitis, pneumonia, hypothyroidism psychosis
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If it is not detected and controlled in time, it may be life-threatening

In other words, because the management of irAE and the application of immunosuppressive treatment programs require close communication, patients who have difficulty communicating with medical staff, have low compliance, and seek medical treatment in other places may not be suitable candidates for combined immunotherapy
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The joys and sorrows of CTLA-4 are not connected?

Although stumbling, ipilimumab and nivolumab were involved in the evidence, and they lived tepidly
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In contrast, the KEYNOTE-598 study of the first-line failure of the combination of ipilimumab and pembrolizumab in advanced NSCLC is somewhat confusing

KEYNOTE-598 Research Key Data (Source: WCLC 2020)

The same is CTLA-4 combined with PD-1, why is O drug OK but K drug not? The discussion part of the original JCO journal published simultaneously: "In the KEYNOTE-598 study, the OS of the control group (K drug + placebo) is consistent with the historical data of the PD-L1 TPS ≥50% of the population in the previous KEYNOTE-024/042 study.
; The OS benefit of the experimental group (K+Y) is also similar to the PD-L1≥50% subgroup data of the CheckMate-027 study
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Although horizontal comparisons between different trials need to be cautious, the above findings suggest that K+Y negative results cannot Interpreted as differences in population baselines

Next, the author analyzed that for people with PD-L1TPS≥50% of advanced NSCLC who can benefit from immunotherapy, CTLA-4/PD-1 combination therapy may not provide additional benefits on the basis of PD-1 inhibitors.
Benefit
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"It is plausible that despite having different targets and mechanisms of action, combined CTLA-4 and PD-1 inhibition may not provide benefit beyond PD-1 inhibition alone in this NSCLC population most likely to benefit from immunotherapy.

There is no worst, only worse
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Another CTLA4 monoclonal antibody, tisilimumab, combined with PD-L1 monoclonal antibody duvaliuzumab, has carried out 10 key clinical trials for drug registration purposes.

Tisilimumab combined with duvalizumab core clinical layout (source: NextClinTrial database)

Although the prospects are not very clear, there are not a few companies betting on CTLA-4 combination therapy and even CTLA4/PD-(L)1 antibodies
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For example, Merck introduced the Q+K combination of anti-CTLA-4 monoclonal antibody quavonlimab combined with pembrolizumab from Kangfang Bio, and announced positive phase I/II research data in December 2020; Corning Jerry PD-L1/CTLA4 double antibody KN046, Kang Fang Bio-PD-1/CTLA4 dual anti-AK104 has also successively disclosed encouraging early data in a variety of solid tumors
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A week ago, on July 15, Betta Pharmaceuticals announced that the clinical trial of the combination of bartilimumab (PD-1) and zefliximab (CTLA-4) for the treatment of advanced solid tumors jointly declared with Agenus had been obtained.
NMPA approved the development
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Immediately afterwards, Tianyan Pharmaceuticals announced yesterday that anti-CTLA-4 monoclonal antibody candidate products ADG116 and ADG126 and Merck’s pembrolizumab will initiate two open-label, dose escalation and expansion studies clinical trials to evaluate this The clinical efficacy of combination therapy in patients with advanced/metastatic solid tumors
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Perhaps the combination therapy is also a besieged city.
People outside the city want to come in and people inside the city want to go out
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Love is an ancient puzzle, and the joys and sorrows between different CTLA-4s are not connected
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In the future, the highly anticipated CTLA4/PD-(L)1 combination therapy still has a long way to go: whether the risk/benefit ratio and clinical activity of CTLA-4 inhibitors can be changed by changing the dose, dosing regimen, and biological activity.
The activity and the site of action have been substantially improved? Is it possible to carry out a large-scale randomized controlled trial between different CTLA-4 monoclonal antibodies (such as quavonlimab and ipilimumab), and even between PD-(L)1/CTLA-4 combination therapy and double antibodies (the probability cannot be relied on enterprise-sponsored) ? How does the "optimal" dosage and schedule vary from disease to disease? In addition, how to identify biomarkers to predict the best response population and treatment-mediated toxicity is also an important unsolved problem
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