The availability of effective TKIs for patients with metastatic NSCLC with targetable oncogenes such as EGFR, ALK, ROS1, and BRAF has transformed the treatment landscape, extending median expected OS from approximately 1 year to 3 years or more in recent studies.1,2 Initial treatment with TKIs is accompanied by rapid tumor shrinkage in the vast majority of cases, with prolonged benefit that often lasts years. Unfortunately, TKI resistance almost always emerges. In some cases, this initial resistance is due to secondary alterations in the oncogene itself, such as EGFR T790M mutations, which can often be targeted with other TKIs. Alternatively, the tumor becomes “oncogene independent,” driven either by different oncogenes (for example, MET amplification in the case of EGFR-mutant tumors) or by changes that lead to a shift in the tumor phenotype, such as small cell transformation3 or epithelial to mesenchymal transition.4,5 Recent studies with the third-generation EGFR inhibitor osimertinib suggest that oncogene-independent mechanisms are diverse and more frequent than secondary alterations in EGFR itself.6-8
How can we prevent, or at least delay, the emergence of TKI resistance? One approach may be to focus on targeting the residual cells, termed “drug-tolerant persister cells,” remaining after the initial tumor response to TKIs.9 Given that oncogene-driven cancers usually have marked tumor shrinkage and are essentially debulked after initial therapy, the residual disease may then be amenable to local consolidative therapy (LCT) with radiation or surgery to eliminate as much of the residual disease as possible. This approach builds on recent studies demonstrating potential benefit for patients with oligometastatic disease who are treated with LCT. In the case of oncogene-driven metastatic NSCLC, even polymetastatic cases may be transformed into an oligometastatic, or near-oligometastatic, state.
The term “oligometastases” was used initially by Hellman and Weichselbaum10 to describe a restricted locoregional tumor load. Several retrospective and small prospective trials in the setting of oligometastic disease11-14 demonstrated a potential clinical benefit for patients receiving aggressive therapy.15,16 Subsequently, a multi-institutional, randomized, phase II study examining the efficacy of LCT on PFS in oligometastatic NSCLC showed a superiority of the LCT arm during the preplanned interim analysis of 49 patients, and the study was terminated early due to efficacy with LCT, per the Data and Safety Monitoring Board. In this study, improved PFS was observed in the LCT arm with an mPFS of 14.2 months (95% CI [7.4 months, 23.1 months]) in the LCT arm vs 4.4 months (95% CI [2.2 months, 8.3 months]) in the maintenance therapy or observation (MT/O) arm (p = 0.022), as well as improved OS (37.6 months in the LCT arm vs. 9.4 months in the MT/O arm). In addition, the median time to appearance of new lesions was 14.2 months in the LCT arm (95% CI [5.7 months, 24.3 months]) versus 6.0 months in the MT/O arm (95% CI [4.4 months, 8.3 months]; p = 0.11) and time to new site failure was 11.9 months compared to 5.7 months in the no-LCT arm (p = 0.0497).17,18 It is important to point out that the early closure of this trial resulted in the random assignment of only 49 patients, which substantially limited subgroup analysis in this study. Furthermore, because this trial preceeded the integration of immunotherapy in NSCLC, it has not assessed the effects of LCT in this context.
Local consolidative therapies may work with multiple mechanisms. It is possible that initial systemic therapy that leads to stable or responsive disease leaves behind treatment-resistant malignant cells that are less likely to be eliminated by subsequent maintenance therapy and could serve as a source for subsequent metastatic spread, even in the absence of radiographic progression. In that case, LCT would reduce the burden of treatment-resistant cells.17 Aside from local effects of tumor cell killing, ablative therapies such as radiation therapy afford the benefits of tumor antigen release, T-lymphocyte expansion, and T-lymphocyte receptor diversification, which may manifest as enhanced immunosurveillance and antitumor immunity.19-21
The optimal timing of LCT remains an open question. One approach, which we refer to as “early LCT,” is to consolidate residual tumors around the time of expected maximal response (typically approximately 8 to 12 weeks for a TKI), with the goal of eliminating any potential reservoir of disease. An alternative approach is “late LCT,” or local therapy to one or a few sites of disease progression (“oligoprogression”). A potential advantage of early LCT is that it may eliminate residual disease before it has a chance to further disseminate systemically. A potential advantage of late LCT is that it may spare treatment to sites not ultimately destined to progress, thereby avoiding potential toxicities.
In our group, there are currently three studies testing LCT, either with TKIs or immunotherapy. For patients with EGFR¬-mutant NSCLC, the NORTHSTAR study (NCT03410043) is a randomized phase II study of osimertinib with or without LCT. For ALK fusion–positive NSCLC, the BRIGHTSTAR study (NCT03707938) tests brigatinib with LCT. Finally, for patients with wild-type EGFR and ALK, the LONESTAR study is a randomized phase III study (NCT03391869) assessing ipilumumab and nivolumab with or without LCT in immunotherapy-naive NSCLC cases. All three trials accept patients with both oligo- and polymetastatic NSCLC at diagnosis. In addition, the randomized phase III NRG study (NRG LU002; NCT03137771) tests LCT in patients with oligometastatic NSCLC after first-line systemic therapy. Together, these studies should provide important insights into the value of consolidative therapy in patients with metastatic NSCLC with or without an oncogene driver and could determine whether this approach becomes an important weapon in our armamentarium for treating these patients.
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