Identifying factors affecting immunotherapy, target therapy resistance essential for treatment efficiency
Identifying the primary mechanisms of resistance to immunotherapy from the beginning of treatment is important for efficient treatment, according to a presentation at ESMO Asia 2017.
“Mechanisms of primary resistance can be important for personalized strategies,” said Dr Marina Garassino from the National Cancer Institute of Milan, Italy, as these could be useful for clinicians in tailoring treatment plans for their patients.
Highlighting low mutational burden as one of the primary mechanisms of resistance to immunotherapy, Garassino presented the tumour mutational burden analysis of the CheckMate-026* study which underscored the benefit of high mutational burden in immunotherapy. In this study, there was better patient response to nivolumab among participants with high mutational burden vs those with low or medium mutational burden (hazard ratio [HR], 0.62 vs HR, 1.82). [N Eng J Med 2017;376:2415-2426]
Moreover, patients with the innate anti-PD-1 resistance signature related to EMT** also have a reduced likelihood of responding to immunotherapy, said Garassino. Alterations in the interferon gamma signalling pathway can also signify immunotherapy resistance, which can be a mutation of JAK***1/2. “[Additionally], PTEN# loss … can create some problems in the [regulatory T cells] and in the activated lymphocytes,” she added.
Identifying the immune phenotype also appears to play a significant role in determining immunotherapy response, said Garassino. Of the three main phenotypes (ie, inflamed, immune-excluded, and immune-desert), inflamed tumours are the most likely to respond to immunotherapy, while immune-desert or noninflamed tumours are the least likely to respond.
“The story of immunotherapy will be much more complex in the future than just dividing PD-L1 positive and PD-L1 negative,” said Garassino.
On the other hand, Garassino underscored the significance of losing the T790M mutation in target therapy resistance, citing the validation cohort from the AURA## trial demonstrating the association between loss of T790M and early resistance to osimertinib. Patients with T790M loss had a shorter time to treatment failure (TTF) compared with those who maintained T790M (5.7 vs 12.5 months), signifying early resistance to the study drug. [WCLC 2017, abstract 9000]
“If you lose T790M, you get a much worse prognosis than when you still have the T790M mutation,” said Garassino.
“[Loss of] T790M after the first- or second-generation [epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs)] and after osimertinib … can be an important negative prognostic factor. This is a very interesting field of research and we [hope to] see results in the future,” she added.
Garassino also discussed the potential of liquid biopsy as an adjunct to target therapy. “[With] liquid biopsy, you can monitor the presence or absence of T790M during osimertinib treatment to see if you have to add several other drugs if you lose the T790M.”
While its use in immunotherapy seems unclear, liquid biopsy could be “the future” of targeted therapy, concluded Garassino.