A list of oncogene-addicted tumours that can be treated with targeted therapies expands. The lessons learned from non-small cell lung cancer (NSCLC) regarding acquired resistance are likely to prove insightful, in terms of underlying mechanisms and novel approaches in clinical research. In a review article, published online 1 July 2014 in the Nature Reviews Clinical Oncology, a group of researchers explore breakthroughs in understanding and the treatment of acquired resistance, focusing on EGFR mutant and ALK rearrangement-positive NSCLC, which may be relevant across different oncogene-addicted solid malignancies.
A small proportion of patients with EGFR mutated and ALK rearranged NSCLC will not benefit from the initial therapy with tyrosine kinase inhibitors (TKI) therapy. In general, less is known about the basis for such de novoor intrinsic resistance than about acquired resistance. While in some cases of intrinsic resistance the basic principles may be broadly similar to acquired resistance (e.g., elevated baseline levels of known acquired resistance mechanisms), other novel intrinsic mechanisms, such as germline variation in tumour response pathways, can also exist.
Acquired resistance is defined as a progression after initial clinical benefit to targeted therapies. It usually occurs within 1–2 years of starting therapy. Mechanisms of acquired resistance may be pharmacological or biological.
Pharmacological acquired resistance occurs through failure of drug delivery to the target, e.g. as in isolated central nervous system (CNS) progression. Biological acquired resistance results from evolutionary selection on molecularly diverse tumours. Discussing about biological mechanisms of acquired resistance, the authors addressed alterations in the drug target, bypass track signalling pathways, phenotypic changes and downstream signalling.
Pharmacological resistance to targeted agents manifesting as a CNS progression, as a result of inadequate CNS drug exposures, is likely to be common. However, to accurately determine the “real world” CNS activity of the next generation of drugs, clinical studies will have to move beyond incidental case reports of CNS responses and more formally address how to capture CNS activity within clinical trial designs. The authors wrote that having dedicated cohorts of molecularly defined patients with untreated brain metastases, could identify CNS activity much earlier in drug development than current approaches, which often exclude patients with CNS disease from clinical trials.
Treatment approaches to acquired resistance include use of local ablative therapies to sites of progression and continuation of TKIs, cytotoxic chemotherapy or, if available, change in relevant targeted therapy.
With the recognition that acquired resistance within the CNS might reflect a failure of drug delivery, rather than a change in cancer biology, the use of local CNS therapy and continuation of the TKI is now being considered in many trials and in clinical practice. If the CNS becomes a relevant target for next-generation inhibitors associated with greater CNS penetration and/or greater potency, accurate prospective assessment of CNS response rates and time to progression and comparison to the equivalent data from the rest of the body, will be of great importance.
Clear guidance on the appropriate size of a CNS target lesion and whether a previously irradiated lesion that might enlarge due to radiation necrosis, or shrink or remain stable many months after the initial radiation treatment, can ever be reliably used to assess benefit from a targeted drug will be required.
When acquired resistance occurs outside of the CNS, as it reflects an evolutionary process, each event is presumed to arise initially from a single aberrant clone. Consequently, at the point of clinically detectable acquired resistance, much of the disease may still be under active suppression of the original TKI and may ‘flare up’ on discontinuation of the drug. This has two major consequences: first, either in the presence of relatively indolent progression, or after local therapy of sites of oligoprogressive disease, there is a strong theoretical benefit from continuing the original TKI unless a better systemic alternative is available.
If systemic alternative is cytotoxic chemotherapy, trials addressing the benefits of adding the chemotherapy into the existing TKI regimen, as opposed to stopping the TKI and switching to the chemotherapy are pertinent to conduct, and such studies are underway. Second, to avoid falsely attributing benefit from a new agent to activity against resistant disease, when it may only have activity against a re-emergence of the disease that was sensitive to the previous treatment with TKI, minimal washout time from the prior TKI is often recommended in the acquired resistance setting.
When combination targeted therapy is considered, it will be necessary to determine if it is preferable to use combination approaches upfront to suppress the emergence of resistance or to add additional targeted agents at the time of clinically apparent acquired resistance. Some maximally-suppressive combination targeted cancer regimens may be far more toxic than the original TKI.
While there are many challenges ahead, the progress made in the past few years in understanding of acquired resistance has been tremendous. The authors concluded that by continuing to study resistance mechanisms, the potential to truly transform some types of metastatic oncogene-addicted cancers into chronic diseases may now lie within the reach.