Abstract CN09-01: Lessons learnt in clinic from resistance to first generation molecular targeted therapies in solid cancers
Authors: Awada Ahmad 
Published: March 2020

Abstract
Molecular-targeted therapies (MTT) joined surgery, radiotherapy and chemotherapy in the therapeutic armamentarium of cancer in the last two decades. We learned at least eight lessons from the development of dozens of MTT in solid cancers as following:
1. Treatment of unselected populations should be discouraged
2. The identification of a driver genetic abnormality as well as the discovery of a selective agent are key
3. “Rare” tumors are good niches for MTT
4. Chemotherapy (also radiotherapy) remain important for the synergy with targeted agents in selective settings
5. Better outcome seen in the metastatic setting and rarely in the adjuvant one
6. Expected and unexpected side effects arose from MTT
7. Discovery of the resistance mechanisms is a high priority and that
8. One gene may predict resistance, but no single gene, protein, pathway can predict full efficacy.
Just like chemotherapy, resistance to therapy remains a major cause of failure to MTT. Understanding the mechanisms of resistance, and in particular to first generation MTT, was key in order to develop further generations of MTT overcoming this resistance and improving the outcome of patients. I propose to focus on three tumor types to illustrate how this resistance has been tackled: Genotype-driven NSCLC, HER-2 and hormone receptor positive breast cancer and finally gastrointestinal stromal tumors (GIST). EGFR-mutated NSCLC responded well to first generation inhibitors such as gefitinib and erlotinib. One of the mechanism of resistance was the discovery of T790M mutation. Osimertinib was effective on this resistant mutation and even move to the first-line setting by improving the progression-free survival of the patients. ALK translocation in NSCLC followed the same path with the development of alectinib which showed superior efficacy compared to crizotinib a first generation drug for ALK translocated NSCLC. In summary, the understanding of resistance mechanism from one side and the development of more potent drugs improved the outcome of our patients. Trastuzumab, a monoclonal antibody improved significantly the survival of HER-2 positive breast cancer (15% of the whole breast cancer population). Nevertheless, resistance occurs in a number of patients. The mechanisms behind this resistance are multiple and will not be summarized here. Different strategies were developed to tackle the resistance and to improve the outcome. The development of other monoclonal antibody, such as pertuzumab, targeting a different epitope of HER-2 than trastuzumab and in combination with trastuzumab, showed a therapeutic clinical value. Finally, the development of tyrosine kinase inhibitors beyond the first generation drug (lapatinib), such as neratinib and more recently tucatinib as well the development of antibody drugs conjugates such as T-DM1 all these therapeutic developments showed significant activity in case of resistance to trastuzumab and hopefully will help not only to control the disease but also to cure this group of breast cancer. Hormone receptor positive breast cancer develops resistance to aromatase inhibitors. One of the mechanism of resistance is the development in approximately 30% of patients of activated ESR1 mutations. Several selective estrogen receptors degraders are currently in development to overcome this problem with promising results. Finally, GIST tumors responded well and for years to imatinib a first generation drug targeting C-KIT. Several drugs were developed in case of resistance such as sunitinib, regorafenib but with limited results. More potent drugs are currently in development. One of the mechanism of resistance to imatinib was the development of secondary mutations which should be targeted with more selective agents. The development of new potent agents is one way to tackle the resistance. Other approaches included the development of combinations therapies with chemotherapy, other MTT and more recently immunotherapy. CAR-T approaches might be an interesting modality and studies in solid tumors are already ongoing. Finally, one of the potential way to overcome the resistance (which appears during the evolution of the disease and in particular under the pressure of therapies) is to block the disease as early as possible of course at the micrometastatic state but also at what is considered today as residual disease following neoadjuvant systemic therapy or the molecular recurrence by using liquid biopsies before positive radiological recurrence. Innovative therapeutic strategies and study designs are needed here not only to understand the mechanisms behind residual/molecular recurrence disease but also to study/treat these settings.
Citation Format: Ahmad Awada. Lessons learnt in clinic from resistance to first generation molecular targeted therapies in solid cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr CN09-01. doi:10.1158/1535-7163.TARG-19-CN09-01