Cancer cell review: Clinical challenges of immuno-checkpoint inhibitors.

In a recent review published in the journal Cancer Cell, Dr. Emiliano Calvo of HM Sanchinarro University Hospital in Madrid, Spain, discussed the clinical challenges of immunotherapy in detail from three different perspectives and how to optimize it.
DOI: Less than 10 years after IO development became saturated, IO obtained FDA approval for 57 adaptations in 17 solid tumors, 82% of which were PD-1/PD-L1 antibodies.
clinical studies, the number of IO-active drugs being developed has increased from 2,030 to 3,876, an increase of 91% over the past two years, while the introduction of unique IO targets has increased by 77% over the same period.
, the number of approved drugs has declined in the last two years, mainly in the field of solid tumors.
PD-1/PD-L1 appears to be stable, but the number of active clinical trials has increased 20-fold in the past four years, but this does not match patient recruitment rates, with data showing a 70 percent decrease in the number of patients included in the PD-1/PD-L1 joint trial over the same period.
Overall, it can be argued that there are some saturation signals in IO drug development: relatively few innovative mechanisms of action, including clinical testing, approval stagnation, and saturation of studies targeting only certain tumor adaptations and targets.
IO Clinical Challenge Anti-Tumor Activity Although immuno-checkpoint inhibitors are unique in their ability to achieve long-term or even complete response, the fact is that most patients still do not benefit from treatment.
, it is imperative to identify reliable markers other than routine radiology assessments to identify tumor biology behavior in patients under IO.
false progressor (PP) is a patient who can benefit from ICI, while hyper-progressor (HP) needs to be detected early in order to be immediately transferred to other treatments.
IO endpoints in clinical trials have shown that the survival curve obtained with ICI drugs is different from conventional treatments.
can be observed in comparative studies with chemotherapy or targeted drugs, IO can show maximum drug benefits at the end of the curve.
, incorrect endpoint selection can cause the experiment to fail.
end point of efficacy in clinical trials requires capturing the longer active timing of these IO drugs, otherwise the benefits of the drug may be underestimated.
total lifetime (OS) is the gold standard in oncology trials, it does not correctly capture the long-term benefits of IO drugs.
new concept recently introduced , the untreated lifetime is the ideal end point for cancer treatment because it takes into account long-term survival patients who are progressive and do not require further treatment.
other indicators worth considering include the quality of life test or the time to start the next treatment.
, patient benefits should be considered in a more meaningful and comprehensive way, not just progress-free or total lifetimes.
immune-related adverse events IO treatment usually has different side effects than conventional tumor therapists, including different seizures, duration and severity, and immunotoxicity often requires permanent termination of treatment.
ICI-related adverse events are particularly challenging in complementary treatments, where late, sometimes severe toxicity can lead to permanent damage, and these patients could have been cured by surgery.
effective management of IO-related side effects depends on the early identification of symptoms and the rapid initiation of neutralized mechanism antidotes, such as steroids or other immunosuppressants, not just palliative drugs.
, it is questionable whether clinical trials can capture these special IO features through the standard Common Terminology Standard for Adverse Events (CTCAE) classification.
addition, there is a need to establish standardized definitions of objective immune-related adverse events in order to obtain a uniform classification in order to avoid misunderstandings of drug toxicity.
progress caused by life-threatening ICI may also need to be included in the CTCAE standard, as it can have serious consequences for patients.
dosage and schedule Strong end-of-drug outcomes, combined with clinical responses and major toxicity assessments, ultimately determine the recommended dose (RD) for Phase I trials, but most ICI dose-finding studies are unable to identify the maximum to-dosage (MTD) or RD.
further research needs to address whether dose adjustments for individual patients exposed to targeted drugs may result in better outcomes than regular doses.
this will mean cost savings, facilitation for patients, and potentially improved drug activity and toxicity through strict treatment indices.
, the optimal length of time patients will need to continue ICI treatment remains unclear.
further randomized trials are needed to explore early ICI discontinuation, and then challenge or biomarker and radiologically driven ICI switching doses to answer this important practical question.
, the authors' findings on immuno-checkpoint inhibitors may help researchers find new breakthroughs that could allow more patients to benefit from cancer immunotherapy.
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