Scanning problems to assess the response to ICI drugs

[Olga]

Some valuable insights from a pretty fundamental pharmacokinetics review of the pembrolizumab (Keytruda) based on the results of the phase 1 in solid tumors (2195 patients) and in melanoma 1,2,3 phase clinical trials (thousands more):
Full text is avail. here:
Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613934/

- With repeat dosing every 3 weeks, steady-state concentrations are reached by 19 weeks;
- most responses occurring by 12 weeks but some responses noted as late as 36 weeks;
- Responses may be immediate or delayed;
- In total, 4 distinct patterns of response to immune checkpoint inhibitors have emerged: 1) timely regression of index lesions; 2) a slow but steady decline in tumor burden after stabilization of disease; 3) an initial increase in existing tumor burden followed by a delayed response; and 4) the appearance of new lesions followed by a delayed response. The latter 3 patterns of response are not seen with traditional cytotoxic therapies and may be associated with improved immunooncologic outcomes.

[D.ap]

Olga

Thank you for the article.

It’s truly exciting that we have come this far and are all a part of this new age immune therapy happening !

Since the fruisition of vaccines that you’ve been a part
of ,then targeted therapies being engineered, it’s wonderful that we’ve had the discovery of and benefits of checkpoint inhibitors in combating ASPS. Progressesive disease (PD),is being viewed as part of the process to the success of pd1 meds , when it’s shown as inflammation . Who’d thought that we’d be happy with that term?

With immunotherapeutic agents, which enhance antitumor immune responses (9), SD may also be viewed as an indicator of meaningful therapeutic effect. Beyond that, additional novel response patterns observed with these agents raise concerns about the interpretation and characterization of activity using WHO or RECIST criteria. In studies with cytokines, cancer vaccines, and monoclonal antibodies (e.g., ipilimumab), CR, PR, or SD has been shown to occur after an increase in tumor burden characterized as PD by WHO or RECIST criteria (10–13). For example, in patients with HIV-related Kaposi sarcoma on a stable antiviral regimen, anticancer responses to recombinant interleukin-12 varied from patient to patient across a broad time interval and included objective responses after apparent PD (10). Therefore, conventional response criteria may not adequately assess the activity of immunotherapeutic agents because PD (by initial radiographic evaluation) does not necessarily reflect therapeutic failure. Long-term effect on the target disease must also be captured.

Immune-Related Response Criteria(irRrc) has been established and is still being rewrote since it was first written.
The following was 2009 immune related response criteria (irRrc)
http://clincancerres.aacrjournals.org/c ... /7412.long

[Olga]

This is the newer artcile with the free full text:
Pitfalls in the radiological response assessment of immunotherapy.
https://www.ncbi.nlm.nih.gov/pubmed/29983829

[Olga]

There is a registered case of the proven pseudoprogression in ASPS patient during immune checkpoint inhibitor treatment (she was on a Atezolizumab - anti PDL-1 antibody):
Pseudoprogression of CNS metastatic disease of alveolar soft part sarcoma during anti-PDL1 treatment.
https://www.ncbi.nlm.nih.gov/pubmed/29991973
full free text avail.
Immune checkpoint inhibitors are increasingly used in treatment of metastatic renal cell carcinoma, melanoma, and nonsmall cell lung cancer, as well as in clinical trials for novel targets. We present a pediatric patient with metastatic alveolar soft part sarcoma who was treated with MPDL3280 (Atezolizumab), a monoclonal anti-programmed death ligand-1 antibody. Imaging results for the patient suggested disease progression of multiple brain metastases with stable systemic disease. The patient met response evaluation criteria in solid tumors (RECIST) criteria of progression of disease and was removed from treatment with MPDL3280. Subsequent surgical resection of the brain lesions revealed nonviable tumor with extensive lymphocytic infiltrates consistent with pseudoprogression. This case report adds to a growing number of reports that question reliance on RECIST criteria and suggest need for further refinement of RECIST or irRECIST during immune checkpoint inhibitor treatment