Abstract and Introduction
The combination of radiotherapy (RT) with targeted agents in non-small cell lung cancer (NSCLC) has been expected to improve the therapeutic ratio and tumor control. The EGFR blockade enhances the antitumor effect of RT. The ALK inhibition elicits anti-proliferative, pro-apoptotic and antiangiogenic effects in ALK-positive NSCLC cell lines, enhanced by the exposure to RT. The antiangiogenic agents normalize pathological tumor vessels, thus decrease tumor cell hypoxia and improve radiosensitivity. To date, however, none of the targeted agents combined with RT has shown proven clinical benefit over standard chemoradiation (CRT) in locally advanced NSCLC. The risk of potential excessive toxicity related to the therapeutic combination of RT and targeted agents cannot be ignored. Well-designed clinical trials may allow development of more effective combination strategies. Another potential application of combined RT and targeted therapies in oncogene-driven NSCLC is metastatic oligoprogressive or oligopersistent disease. The use of RT in oligoprogressive oncogene-driven NSCLC, while continuing first line targeted therapy, can potentially eradicate resistant cell clones and provide survival benefit. Likewise, the consolidation of oligopersistent foci (molecularly resistant to first line targeted therapy) may potentially interfere with the natural course of the disease by avoiding or delaying progression. We discuss here the molecular and radiobiological mechanisms of combining RT and targeted agents, and summarize current clinical experience.
Radiotherapy (RT) in non-small cell lung cancer (NSCLC) is an undeniable backbone of curative treatment for early and locally advanced disease, as well as palliation of symptoms in advanced disease.
Decoding of lung cancer genome and identification of driving molecular aberrations causing carcinogenesis stimulated the design of molecularly targeted therapies. These include monoclonal antibodies targeting specific antigens on the tumor cell surface, and small molecule tyrosine kinase inhibitors (TKI) acting intracellularly. Both groups of compounds interfere with crucial cellular signaling pathways involved in tumor cell growth and cancer progression. Activating epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements (occurring almost exclusively in lung adenocarcinomas) represent the most common druggable molecular events in NSCLC. Randomized clinical trials showed that in advanced NSCLC harboring specific molecular aberrations, EGFR and ALK TKIs provide superior response rate and progression-free survival (PFS), as well as lower toxicity compared to chemotherapy.[1,2]
Within the past few decades therapeutic progress in lung cancer has mainly been accomplished by the rational combination of various modalities. For example, sequential chemoradiotherapy (CRT) has been found to be more effective than RT alone and concurrent use of both modalities provides longer survival compared to their sequential administration. The pivotal RTOG 0617 trial showed that escalation of RT dose from 60 to 74 Gy did not translate into survival benefit.
Likewise, no benefit was demonstrated from maintenance or consolidation chemotherapy. In turn, the recent PACIFIC trial demonstrated survival benefit from 12-month consolidation immunotherapy with durvalumab, an anti-PD-L1 antibody, in locally advanced NSCLC patients who responded to concurrent CRT, making this approach the new therapeutic standard.[6,7]
The combination of molecularly targeted agents with RT has been expected to substantially improve the therapeutic ratio and tumor control. Indeed, preclinical models suggested that these agents may enhance tumor response to RT and elicit radioprotection of normal tissues. Whereas many of these models indicate synergistic interactions with exclusive RT, preclinical evidence on combination of targeted agents with CRT is relatively scarce.
Another promising strategy addressed in this review is adding consolidative RT to targeted systemic treatment in metastatic oligoprogressive or oligopersistent NSCLC harboring defined molecular aberration.
Transl Lung Cancer Res. 2021;10(4):2032-2047. © 2021 AME Publishing Company