ES21.04 Optimal Systemic Treatment of OMD

Abstract

A series of randomized trials (1-3), 2 of them specifically conducted for non-small cell lung cancer (NSCLC) patients (2,3), have shown that those with OMD could get clinical benefit from the addition of local ablative therapy to the standard systemic treatment. All 3 trials demonstrated improvement of progression-free survival (PFS), and 2 of them suggested overall survival (OS) benefit (1,2). OS was the primary endpoint of the 2 studies. In each of the trials, however, the “standard systemic treatment” was not specified; in fact, it was merely described that the systemic therapy was determined by the treating oncologists from a set of “standard-of-care options” (3). It would be easy to imagine that the “standard-of-care options” for OMD in these trials would be no different from those for other stage IV diseases. For NSCLC, they are cytotoxic chemotherapies according to histologic subtypes, appropriate target-based therapies when the tumors have druggable targets, and, more recently, immune-oncology (IO) drugs when the tumors have potentially predictive markers, such as PD-L1 (4) or tumor mutation burdens (5). The question is, is the optimal systemic therapy of OMD really exactly same with the “standards” of other, more advanced, poly-metastatic stage IV NSCLC? First of all, let me suppose that the disease is truly oligo-metastatic, meaning there are no other metastatic foci than those which are detected by the image scans. In this scenario, you do not require systemic therapy at all; the disease is “cured” by a series of local ablative therapies, since no other diseases exist. However, in the vast majority of the patients, this would not be the case. Instead, there should be some other “microscopic” metastases which are undetected by the scans, evade the local therapies, and get relapsed without systemic treatment. By focusing on the “microscopic metastases” status, you could make analogy to post-operative adjuvant therapy. After the apparently curative surgery, without no “macroscopic” metastases in sight, we usually use conventional chemotherapies for prevention of recurrence. It is hoped that these “cytotoxic” drugs would eradicate the residual cancer cells, leading to true “cures”. The long-tails of the survival curves, with increased number of long-term survivors with the adjuvant chemotherapy (6), show that this theory actually works. On the other hand, use of target-based drugs as post-operative adjuvant therapy has so far had only limited success (7,8). The PFS is elongated, without OS benefit (7). It appears that the patients do as good with the use of “targeted” drugs after relapse, and those drugs suppress tumors only as long as they are taken (9). In other words, they appear “cytostatic” and unable to “cure” the disease. Results of IO adjuvant trials are not yet available, but the “long-tails” of the survival curves of IO treatment make us hope for strong cytotoxic, “cure-oriented” effect. Therefore, when you aim at “cure” of the OMD, you should choose cytotoxic chemotherapies and/or IO drugs. However, if you are to “control” the disease and get some OS improvement, target-drugs are strong candidates. Let me see the topic from another viewpoint. The “local ablative” therapies employed in OMD are surgery and (stereotactic) radiotherapy. Which systemic therapy would make a better partner to which local therapy? Almost all target drugs are eventually turned ineffective, due to acquired resistance. However, in some cases, you could elucidate the resistance mechanism and conquer it (10), with modification of the target-based “precision” medicine. At present, investigation of the tumor itself is the most certain method, as expressed in the “tissue is the issue” slogan. Very often, however, tiny pathological specimens obtained from transbronchial or CT-guided biopsies are insufficient for the full molecular analysis. Surgical resection of the tumor has advantages both in terms of curative therapy and supply of ample specimens. It also minimizes the late effect on pneumonitis, which is a rare but dreadful toxicity of target-based tyrosine kinase inhibitors. Taken together, use of surgery would be (more) appropriate when you use target-based drugs in OMD. On the other hand, there are some clinical data that prior use of radiotherapy is associated with better outcome of IO therapy, implying the so-called “abscopal” effect (11). Investigations are on-going, which are aimed at showing synergistic effect of stereotactic radiotherapy and IO treatment (12,13). This could be applied in the management of OMD. So, in conclusion, what is the optimal systemic treatment of OMD? It depends on the aim of the therapy, cure vs elongation of PFS/OS, as well as on the choice of main local therapy, surgery vs radiotherapy. Future studies should specify the aim of the clinical investigation, not only to maximize the efficacy of local therapies and benefit to the patients, but to increase the statistical power of the clinical trials.