Combining radiotherapy with targeted therapies in non-small cell lung cancer: focus on anti-EGFR, anti-ALK and anti-angiogenic agents
Review Article on Radiotherapy in Thoracic Malignancies

Combining radiotherapy with targeted therapies in non-small cell lung cancer: focus on anti-EGFR, anti-ALK and anti-angiogenic agents

Anna Wrona, Rafał Dziadziuszko, Jacek Jassem

Department of Oncology and Radiotherapy, Medical University of Gdańsk, 17 Smoluchowskiego St. 80-214 Gdańsk, Poland

Contributions: (I) Conception and design: A Wrona; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: A Wrona; (V) Data analysis and interpretation: A Wrona; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Anna Wrona. Department of Oncology and Radiotherapy, Medical University of Gdańsk, 17 Smoluchowskiego St. 80-214 Gdańsk, Poland. Email: annawrona@gumed.edu.pl.

Abstract: 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.

Keywords: Non-small cell lung cancer (NSCLC); radiotherapy; targeted therapy, tyrosine kinase inhibitors (TKI); monoclonal antibodies


Submitted Apr 11, 2020. Accepted for publication Dec 22, 2020.

doi: 10.21037/tlcr-20-552


Introduction

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 (3). The pivotal RTOG 0617 trial showed that escalation of RT dose from 60 to 74 Gy did not translate into survival benefit (4).

Likewise, no benefit was demonstrated from maintenance or consolidation chemotherapy (5). 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 (8). 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.


The scientific rationale for combining radiotherapy with targeted agents

Bentzen et al. (8) named five exploitable mechanisms describing the radiobiological basis by which a specific agent may interact with RT to improve the clinical outcome. The first mechanism, spatial cooperation, refers to the use of RT to target locoregional disease and systemic therapy for micrometastatic or occult systemic disease. The modalities are typically applied here sequentially to reduce toxicity, as spatial cooperation does not necessitate an interaction at the cellular level. Three other mechanisms require concomitant administration of drugs and RT. The strategy of cytotoxic enhancement is aimed at cell killing intensification by modulating the induction or repair of cellular DNA damage. Biological cooperation of drugs and RT exploits distinct sensitivity of particular cell populations within a heterogeneous tumor, or employs diverse mechanisms of cell killing. The rationale behind temporal modulation is to enhance the tumor response to fractionated RT, as the drug affects DNA damage repair, cellular repopulation, proliferation, reoxygenation and redistribution. The last mechanism, normal tissue protection, refers to substances which show cytoprotection of normal cells.

EGFR signaling pathway and radiation

The EGFR is frequently over-expressed or mutated in cancer cells, including NSCLC (9-12). NSCLC cell lines harboring somatic EGFR mutations on the intracellular domain exhibit increased radiosensitivity (13,14). Overexpression of EGFR protein promotes unregulated growth and likely contributes to RT resistance of NSCLC (12).

EGFR signaling pathway is involved in cell proliferation, apoptosis inhibition and accelerated DNA double-strand breaks (DSB) repair, and is related to downstream survival pathways upregulated by exposure to radiation (15-17). The two important signaling pathways, phosphoinositide 3-kinase/AKT (inhibiting apoptosis) and RAS/RAF/MEK/ERK (stimulating proliferation) induce radioresistance when activated, and their suppression is expected to radiosensitize tumor cells (18). The temporal modulation mechanism represents the scientific background of combining RT with EGFR inhibitors, and explains that expected benefit may not be restricted to EGFR-positive cancers. The EGFR blockade enhances the antitumor effect of RT (19,20). EGFR inhibition, by suppressing cellular DNA repair capacity and prolonging the presence of DSB, may render tumor cells more vulnerable to radiation-induced apoptosis. While reaching cell surface, radiation causes EGFR internalization. The receptor is captured by binding proteins Ku70/Ku80 and DNA-PKcs and translocated into the nucleus, activating there damage repair. If EGFR is blocked, the complex does not reach the nucleus, resulting in the inhibition of DNA repair. Additionally, both RT and EGFR inhibition increase apoptosis, as determined by caspase activity. When a TKI is combined with RT, poly(ADP-ribose) polymerase (PARP - an enzyme involved in DNA damage repair) cleavage increases, resulting in its reduced activity and suppressed DNA repair (17). Finally, EGFR inhibition by inducing G1- and G2-arrest reduces the rate of lung cancer cells in the radioresistant S-phase of cell cycle (21).

Clinical data on anti-EGFR antibodies and radiotherapy combinations in locally advanced NSCLC

Cetuximab is a human-murine chimeric IgG1 monoclonal antibody that binds to the extracellular region of the EGFR, and acts as a competitive antagonist. It stimulates EGFR internalization and can promote antibody-dependent cellular cytotoxicity (ADCC). The idea of combining RT and cetuximab has been considered promising on the basis of proven radiosensitizing effect and frequent overexpression of EGFR in NSCLC. Indeed, compared to RT alone, concomitant administration of cetuximab and RT improves local control and survival in head and neck cancer (22,23). Preclinical models using NSCLC cell lines revealed similar efficacy of cetuximab and cisplatin in combination with RT (24). The pilot SCRATCH study proved that in stage III NSCLC cetuximab can be safely combined with RT following induction chemotherapy (25). In a phase II study including elderly and/or poor performance status (PS) stage III NSCLC patients not eligible to concomitant CRT, addition of cetuximab to definitive RT provided median overall survival (OS) of 15.1 months, without excessive toxicity (26). Similar results (median survival of 19.6 months) were obtained in the prospective phase II NEAR trial using intensity modulated RT (IMRT) and weekly cetuximab followed by a maintenance period (27). The toxicity was mild: 3.3% of patients experienced grade 3 pneumonitis and 37% any grade 3 toxicity. In the phase II Satellite SWOG study induction chemotherapy followed by concurrent cetuximab and definitive RT provided median OS of 17 months, with acceptable toxicity profile (28). Grade 3 diarrhea and skin toxicity occurred in 11.3% and 4.2% of patients, respectively, and grade ≥3 RT-induced esophagitis and pneumonitis in 1.4% and 5.6% patients, respectively (seemingly less compared to schedules using concurrent CRT). Similar results (median OS of 19.4 months) and acceptable toxicity (no grade 3-4 esophagitis) were seen in another phase II study of cetuximab combined with RT and continued with chemotherapy as consolidation (29). EGFR gene copy number assessed by fluorescence in situ hybridization (FISH) was not predictive of efficacy outcomes. In a phase II study, consolidation with docetaxel and cetuximab after concurrent RT with cetuximab was associated with unacceptable pulmonary toxicity: 19% of patients developed severe pneumonitis and there were eight treatment-related deaths among 27 evaluable patients (30). The phase II RTOG 0324 trial showed feasibility and median OS of 22.7 months with the combination of cetuximab with CRT, followed by consolidative chemotherapy in stage IIIA/B NSCLC (31). Adverse events included 20% grade 4 hematologic toxicities, 60% grade ≥3 non-hematologic toxicities (similar to historic CRT control seen in the LAMP/ACR427 trial), 8% grade 3 esophagitis (compared to 28% in the LAMP/ACR427 trial), 7% grade 3–4 pneumonitis, and 2% fatal pulmonary events. The Cancer and Leukemia Group B phase II trial 30407 confirmed feasibility of a therapeutic combination consisting of cetuximab, RT and pemetrexed/carboplatin chemotherapy in stage III NSCLC (32). The 18-month OS rate was 54% in the CRT/cetuximab arm, compared to 58% in the CRT arm, with no apparent differences in toxicity. No significant OS difference was noted between squamous and non-squamous NSCLC patients (median 22.2 vs. 22.4 months, respectively). Another phase I/II study demonstrated safety and efficacy (median OS of 26.7 months) of induction cetuximab combined with chemotherapy, followed by concurrent cetuximab and CRT in stage III NSCLC (33). Treatment efficacy was not correlated with the EGFR status, and the survival data numerically exceeded those reported in similarly designed trials without cetuximab (34). Grade 2 pneumonitis occurred in 21% of patients, and grade 3 esophagitis in 13%. In a randomized phase II study using daily cisplatin (6 mg/m2 iv) combined with concurrent hypofractionated RT (66 Gy/24 fx) in stage III NSCLC, the addition of weekly cetuximab to CRT did not improve disease control (35). More patients in the cetuximab arm experienced grade ≥3 toxicity (65% vs. 45%, P=0.03), which included: dysphagia (23%), pneumonia (6%), late esophageal toxicity (8%) and late pulmonary toxicity (4%). EGFR status showed neither prognostic nor predictive value. Median OS for the entire group was remarkably high—31.5 months, and was not significantly different between the study arms (36). The authors concluded that hypofractionation rather than addition of cetuximab, might have contributed to impressive OS in this trial. Finally, the pivotal randomized phase III RTOG 0617 study with factorial design evaluated standard (60 Gy/30 fx) vs. high dose (74 Gy/37 fx) RT with concurrent and consolidation carboplatin/paclitaxel regimen with or without cetuximab in stage III NSCLC (4). Median OS in the cetuximab and no-cetuximab arms was 25 months and 24 months, respectively (P=0.29). The addition of cetuximab was associated with a higher rate of grade ≥3 toxicity (86% vs. 70%, P=0.0001), with explicitily increased acute pulmonary toxicity. G3 pneumonitis occurred in 7% and 4% of patients receiving 60 Gy with and without cetuximab, respectively. G3 pneumonitis was experienced by 5% and 0% of patients receiving 74 Gy with and without cetuximab, respectively. The preplanned retrospective analysis showed no difference in outcomes between low (EGFR H score <200) and high (EGFR H score ≥200) EGFR expressing tumors. Cetuximab might have had a detrimental effect in the cohort with EGFR H score <200, and a benefit in those with a H score ≥200. In the former group median OS in patients who did and did not receive cetuximab was 19.5 and 29.6 months, respectively (P=0.056), whereas in the latter—42 months and 21.2 months, respectively (P=0.032). Intriguingly, RT dose of 74 Gy was associated with shorter OS compared to standard dose 60 Gy (median 20.3 vs. 28.7 months, P=0.004).

Panitumumab, a fully human anti-EGFR IgG2 monoclonal antibody, can augment radiation response in NSCLC cell lines (37). A phase II RTOG 0839 randomized study evaluated preoperative CRT with or without panitumumab, followed by consolidation chemotherapy in potentially operable stage IIIA, N2 NSCLC patients (38). As expected, panitumumab exerted high incidence of rash (grade 2–3 in 29% vs. 0% in the CRT alone arm), but esophageal toxicity was similar in both arms. The addition of panitumumab did not improve PFS and OS. Mortality rate in the panitumumab arm was unexpectedly high (14%), although its relationship with this compound is not fully understood.

Nimotuzumab, a humanized anti-EGFR IgG1 monoclonal antibody, has a lower incidence of skin toxicity compared to other drugs in this class (39). Two phase I studies showed efficacy and acceptable toxicity of nimotuzumab combined with palliative RT in advanced NSCLC (40,41). Preliminary results of the phase II study in stage III NSCLC confirmed the efficacy and safety of RT in this combination (42).

The results of studies using definitive CRT combined with anti-EGFR antibodies are disappointing. Importantly, in contrast to combining anti-EGFR antibodies with RT, their combinations with CRT have not been subjected to thorough preclinical studies, and there is no strong evidence of synergistic effect from this approach.

Table 1 summarizes the key studies of anti-EGFR antibodies in combination with radiotherapy.

Table 1
Table 1 Selected trials of radio(chemo)therapy combined with anti-EGFR antibodies in NSCLC
Full table

Clinical data on EGFR tyrosine kinase inhibitors and radiotherapy combinations in locally advanced NSCLC

A phase I study showed safety of oral gefitinib 250 mg (with no dose limiting toxicity) administered concurrently with full dose CRT in stage III NSCLC (43). Another phase I study revealed moderate esophageal and pulmonary toxicity (grade 3–4 in 27% and 20% of patients, respectively) of weekly docetaxel and daily gefitinib concurrently with RT in stage III NSCLC (44). Dose-limiting esophagitis and pulmonary toxicity occurred at a weekly docetaxel dose of 25 mg/m2, setting down the maximum tolerated dose at the level of 20 mg/m2/week. Induction chemotherapy followed by concurrent CRT with gefitinib demonstrated acceptable toxicity profile, however OS was disappointing (median 16 months) (45). The phase III SWOG S0023 study using gefitinib maintenance therapy vs. placebo after CRT and consolidative docetaxel in molecularly unselected stage III NSCLC showed favorable safety profile, but potential detrimental effect of gefitinib (median OS of 23 vs. 35 months in the placebo arm) (46). The Cancer and Leukemia Group B (CALGB) 30106 phase II trial showed promising OS (median 19 months) in poor risk patients (PS 2 and/or weight loss ≥5%) with wild type or EGFR mutated stage III NSCLC receiving induction chemotherapy, definitive RT with concurrent gefitinib, followed by gefitinib in consolidation (47). The median OS of good risk patients receiving concurrent CRT with gefitinib was dismal (median 13 months). OS was not related to EGFR status, but the trial was underpowered to draw any firm conclusions. Acute in-field toxicities (dermatitis, esophagitis, pneumonitis) were not increased with gefitinib, and there was no case of interstitial lung disease. Another Asian feasibility study demonstrated efficacy (median OS of 28.5 months) and acceptable toxicity (grade 1–2 rash in 71% of patients, grade 2–3 pneumonitis in 5.8%) of induction chemotherapy followed by RT plus gefitinib in stage III molecularly unselected NSCLC patients (48). Currently, ongoing trials (LOGIK0902/OLCSG0905 and WJOG6911L) assess the therapeutic ratio of RT combined with EGFR TKIs in EGFR-mutated NSCLC (49,50).

Erlotinib, another EGFR TKI, showed acceptable tolerance at a dose of 150 mg daily given concurrently with CRT in a phase I study in stage III NSCLC (51). The rate of in-field dermatitis or radiation pneumonitis was not increased. Another prospective study demonstrated acceptable toxicity (4% grade 3 pneumonitis, 4% grade 3–4 esophagitis, no fatal events) and promising outcomes of concurrent EGFR TKIs (gefitinib or erlotinib) and RT in stage III-IV NSCLC (52). The safety and relative efficacy (median OS of 17 months) of induction chemotherapy followed by RT combined with erlotinib in poor risk stage III NSCLC patients was also demonstrated in the CALGB 30605/RTOG 0972 phase II study (53). A randomized phase II study demonstrated that combining erlotinib with RT in molecularly unselected poor risk stage III NSCLC patients increases complete response rates compared to RT alone, however without OS benefit (54). Adverse events, with the dominant skin toxicity, were significantly more common in the erlotinib arm, but there was no increase of esophageal and pulmonary toxicity. A single-arm prospective phase II trial using erlotinib in combination with CRT in stage III NSCLC showed impressive OS (median 36.5 months) with low toxicity (55). This trial represents the first study to analyze the data considering EGFR status. The activating EGFR mutation was detected in 10% of tumors and did not impact OS and toxicity. This study suggests that erlotinib can be safely combined with CRT, with the caveat that it was not administered on the same days as chemotherapy because of overlapping toxicity concerns.

Table 2 summarizes the key studies of anti-EGFR TKIs in combination with radiotherapy in NSCLC.

Table 2
Table 2 Selected trials of radio(chemo)therapy combined with EGFR tyrosine kinase inhibitors in NSCLC
Full table

ALK signaling pathway and radiation

c-MET represents an upstream activator of AKT and its activity is associated with radioresistance (56,57). Recent studies revealed that EML4-ALK fusion protein may network with similar signaling pathways, such as c-MET (58,59). Crizotinib was designed as the first generation ALK, ROS1 and MET inhibitor. The preclinical model using a panel of NSCLC cell lines with varying expression levels of c-MET and EML4-ALK showed that crizotinib did not affect cellular radiosensitivity (60). It was hypothesized that crizotinib may by-pass the radiosensitizing effect of c-MET inhibition by activating the AKT pathway. Subsequent preclinical studies demonstrated a radiosensitizing potential of crizotinib in ALK-positive NSCLC cell lines (61,62). Crizotinib in combination with RT was also shown to inhibit ALK autophosphorylation and phosphorylation of its downstream effectors: AKT, STAT3 and ERK1/2, leading to radiosensitization of cells harboring the EML4-ALK rearrangement (61). In another preclinical model crizotinib exerted potent and selective anti-proliferative, pro-apoptotic and antiangiogenic radiation-enhancing effects in ALK-positive NSCLC cell lines (62). In the ALK-positive xenografts the combination of crizotinib and RT was most effective in reducing tumor proliferation and perfusion. In contrast, in tumors that lack ALK rearrangement dual combination was inferior compared to RT alone.

Clinical data on ALK inhibitors and radiotherapy combinations in locally advanced NSCLC

The NRG/RTOG1306 trial evaluated erlotinib and crizotinib as a 3-month induction preceding standard CRT in stage III EGFR-positive or ALK-positive NSCLC (63). The study stopped early with only 59 patients enrolled out of 234 planned and the results were disappointing. The median loco-regional PFS was 25.7 months in EGFR-positive NSCLC patients treated with induction erlotinib, and 14.7 months in ALK-positive NSCLC patients treated with induction crizotinib. The median OS (39.5 months) was reached only for the EGFR-positive NSCLC patients who did not receive erlotinib. Serious adverse events occurred in 7% of EGFR-positive patients receiving induction erlotinib (one patient developed esophageal fistula), 35% of EGFR-positive patients receiving CRT alone (vomiting and pneumonia being the most common), in 44% of ALK-positive patients receiving induction crizotinib (pneumonitis, thromboembolic event and esophagitis was experienced by one patient each) and in 29% of ALK-positive patients receiving CRT alone (one patient experienced pneumonia and another atrial fibrillation).

With the absence of firm data for concurrent ALK TKIs and RT, there is a concern that this strategy may increase radiotoxicity due to radiosensitizing effect in normal tissues. Indeed, the clinical case reports using RT combined with next-generation ALK TKIs (alectinib, lorlatinib) showed radiation-induced central nervous system (CNS) necrosis (64,65). One crizotinib-refractory ALK-positive NSCLC patient developed radiation necrosis in a CNS metastatic site after 12 months of alectinib treatment and over 7 years from the completion of RT (whole brain radiotherapy, followed by radiosurgery) (64). As pointed out by the authors, the risk of this sequelae remains long after RT.

Angiogenesis inhibition and radiation

The antiangiogenic agents, through neutralization of vascular endothelial growth factor A (VEGF-A), lead to the normalization of pathological tumor vessels, decrease hypoxia of cancer cells and increase their radiosensitivity through the mechanism of biological cooperation (66). Bevacizumab, an anti-VEGF antibody, was also shown to enhance radiosensitivity by inhibiting DSB repair in endothelial cells via direct suppression of the PIK3/AKT/DNA-PKcs signaling pathway (67). Preclinical models demonstrated that the combination of bevacizumab with RT markedly inhibits tumor growth and promotes radiation-induced ceramide-dependent apoptosis of endothelial cells (68).

Clinical data on antiangiogenic agents and radiotherapy combinations in locally advanced NSCLC

The randomized phase III ECOG 3598 study demonstrated increased toxicity and no survival benefit (median OS 16 vs. 15.3 months) from the addition of thalidomide (an antiangiogenic agent, originally introduced as a sedative and antiemetic compound) to CRT in stage III NSCLC (69). Grade 3 adverse events were more common in the thalidomide arm (53% vs. 44%, P=0.004). Importantly, 11% of patients in the thalidomide group developed grade ≥3 thromboembolic events, compared to 3% in the CRT alone group (P<0.001).

A phase I study of bevacizumab in escalating dose combined with RT preceded by chemotherapy in stage III NSCLC was terminated early due to high rates of radiation pneumonitis (70). Bevacizumab was also evaluated in two phase II trials including, respectively, stage III non-squamous NSCLC (71) and limited stage small cell lung cancer (72). In both studies, bevacizumab was administered concurrently with CRT and alone as maintenance therapy. These studies were closed prematurely due to high incidence of tracheoesophageal fistulae (TEF) (5 of 34 patients) (71). This serious toxicity was the result of post-radiation esophageal injury followed by impaired neovascularization and wound healing caused by bevacizumab. The phase I/II trial evaluated bevacizumab administered concurrently with CRT and erlotinib, following induction chemotherapy in stage III NSCLC (72). The main non-hematological grade ≥3 toxicity was prolonged esophagitis (39%, one case of tracheoesophageal fistula). The median OS of 18.4 months was disappointing, and the authors did not recommend the use of this combination. The SWOG S0533 pilot trial investigated the addition of bevacizumab to CRT followed by consolidation docetaxel in stage III NSCLC, in two risk strata: high risk—squamous histology, hemoptysis, tumor cavitation and/or proximity to major vessels; low risk—none of these features) (73). Median OS was 46 months and 17 months for the low-risk and high-risk strata, respectively, with two cases of fatal pulmonary hemorrhage. The authors stated that it is not possible to successfully integrate bevacizumab to CRT in stage III NSCLC, particularly in patients with high risk of pulmonary hemorrhage.

The clinical data on multi-targeted antiangiogenic TKIs (sunitinib, vandetanib) or recombinant human endostatin in combination with RT in NSCLC are also disappointing (74,75).

Table 3 highlights the key studies of antiangiogenic agents in combination with radiotherapy in NSCLC.

Table 3
Table 3 Selected trials of radio(chemo)therapy combined with antiangiogenic agents in NSCLC
Full table

The concept of combining targeted therapies with radiotherapy in oligoprogressive and oligopersistent NSCLC

Molecularly targeted therapies represent the standard of care in oncogene-addicted advanced NSCLC. Despite initial response, virtually all patients will develop drug resistance and disease progression (on average after 10–14 months). Around a half of relapses present as oligoprogression, i.e., progression in just a few metastases with otherwise optimal control in the other sites (76). This phenomenon is explained by primary intratumor heterogeneity, where targeted therapies selectively favor intrinsically resistant tumor cell clones. Prolonged administration of a targeted agent may induce acquired resistance development through emergence of secondary mutations, activation of by-pass signaling pathways or phenotypic transformation (77). Oligoprogressive oncogene-addicted advanced NSCLC may be managed by changing systemic therapy, continuation of the same systemic therapy beyond progression, but also by incorporating local therapy, preferentially stereotactic body RT (SBRT), into primary systemic therapy. The idea behind using SBRT, novel RT technique delivering focused high ablative dose of radiation to the target, is to eradicate resistant clones while continuing first line systemic therapy.

The term oligopersistance refers to an oncogene-addicted NSCLC diagnosed at onset as oligometastatic. In this setting, local therapy is used as consolidation to combat oligometastatic lesions. At the development of acquired drug resistance 50–60% of the patients will recur in the original tumor sites (78). The repopulation of TKI-resistant clones present in the residual disease foci explains the biological phenomenon of oligopersistance. In most cases new distant metastases arise from these resistant clones of cancer cells. RT targeting oligopersistent tumor sites may potentially depopulate these clones and defer progression.

Clinical data on targeted agents and radiotherapy combinations in oligoprogressive oncogene-addicted NSCLC

Clinical experience with the use of SBRT in addition to EGFR and ALK TKIs in oligoprogressive NSCLC is mainly based on small retrospective series. The combination of SBRT and EGFR TKIs was initially evaluated in the context of advanced molecularly unselected oligoprogressive NSCLC. SBRT to the sites of disease progression in NSCLC patients treated with gefitinib, after first line chemotherapy failure, offered median PFS and OS of 7 and 19 months, respectively (79). In another retrospective series of unselected NSCLC patients experiencing oligoprogression while on erlotinib, and salvaged with SBRT to the sites of extracranial progression, median PFS and OS were 14.7 and 20.4 months, respectively (80). The survival parameters were substantially improved compared to historical outcomes of patients who only received systemic therapy. With SBRT, most new distant progressions occurred in new sites (only 6% of recurrences in the irradiation field). The treatment was well tolerated.

In the first small study evaluating oligoprogression in oncogene-addicted NSCLC adding local therapy (RT, surgery or radiofrequency ablation) to EGFR TKIs in patients experiencing oligoprogression provided median time to progression after local therapy, median time to switch to subsequent systemic therapy and median OS from local therapy of 10, 22 and 41 months, respectively (81). In other series using local therapy in addition to EGFR and ALK TKIs, median time to next progression from local therapy ranged between 6 and 11 months (76,82). Administering SBRT during crizotinib treatment in ALK-positive oligoprogressive NSCLC resulted in 86% of one-year local control in the irradiated foci, allowing longer crizotinib exposure and providing OS benefit (83). Patients who underwent SBRT continued crizotinib for 28 vs. 10 months in patients not offered local therapy. One-year local control rate with single-fraction equivalent dose of >25 Gy and ≤25 Gy was 100% and 60%, respectively (P=0.01). No acute or late >G2 radiation-related toxicity was reported. In a retrospective match cohort of EGFR-positive NSCLC patients with oligoprogression during TKIs therapy, the median OS in those who did and did not receive additional SBRT was 28.2 and 14.7 months, respectively (P=0.026) (84). Undergoing SBRT was an independent predictor of OS and PFS in the multivariate analysis. In the largest retrospective series of EGFR-positive NSCLC patients experiencing oligoprogression during first line EGFR TKI therapy, median PFS1 (calculated from time of initiation of TKI to first progression), PFS2 (calculated from time of initiation of TKI therapy to off-TKI disease progression) and OS were 10.7, 18.3 and 37.4 months, respectively (85). No unexpected toxicities were observed. A large retrospective series using TKIs with RT in oligoprogressive ALK-positive and EGFR-positive NSCLC showed impressive two-year OS of 62% (86).

In the clinic, targeted agents are usually withheld 1–3 days before SBRT, reasoning on the half-life time of 36 hours for erlotinib and 40–42 hours for gefitinib and crizotinib, or up to five treatment half-lives (allowing theoretical elimination of 95% of the drug). The drug is usually re-started when the acute radiation-induced toxicity grade ≥2 has disappeared (often the following day after RT if no toxicity is observed).

Table 4 summarizes key clinical trials addressing the role of radiotherapy in advanced oligoprogressive oncogene-addicted NSCLC.

Table 4
Table 4 Selected trials of radiotherapy combined with tyrosine kinase inhibitors in oligoprogressive oncogene-driven NSCLC
Full table

Clinical data on targeted agents and radiotherapy combinations in oligopersistent oncogene-addicted NSCLC

Two randomized phase II trials on systemic therapy with or without local ablative therapy (mostly SBRT) to all oligometastatic NSCLC sites were prematurely stopped after interim analyses found a significant PFS improvement in the experimental arms (87,88). In the first of these trials median OS in the local consolidation therapy arm was 41.2 months, compared to 17 months in the observation arm (87). These data support the concept of using local ablative therapies at the best response to systemic treatment, without waiting for inevitable progression, also in oncogene-addicted oligometastatic NSCLC patients.

In the retrospective analysis including NSCLC patients (<20% with targetable molecular aberrations) treated with SBRT for oligometastases, oligoprogression or the dominant primary tumor, median OS in patients receiving early RT to oligometastases and irradiated only at oligoprogression was 39.3 vs. 21.1 months, respectively (89). In a retrospective analysis including EGFR-positive NSCLC patients treated with first line EGFR TKIs, PFS in a subset of patients who underwent additional local treatment (hypofractionated RT, SBRT or surgery) was 36 months, compared to 14 months with TKI alone (P=0.0024) (90). The largest retrospective series included 145 EGFR-positive NSCLC patients with oligoprogressive disease during first line EGFR TKIs (91). Of those, 35% received additionally ablative therapy (RT, surgery or both) targeting all residual disease sites, 38%- targeting the primary tumor or oligometastases, and 27% received no local treatment. The median PFS was 20.6, 15.6 and 13.9 months, respectively, and the median OS was 40.9, 34.1 and 30.8 months, respectively. Importantly, the OS benefit from local therapy was significant only for patients treated to all sites of residual disease, and not for those who received a partial local treatment. Grade ≥3 adverse events included pneumonitis (7.7%) and esophagitis (16.9%). The recently published ATOM phase II trial evaluated the use of SBRT to residual oligopersistent disease after EGFR TKI. The study was closed early due to slow accrual. One-year PFS was 68.8% and median OS reached 43.3 months. No ≥3 grade SBRT related toxicities occurred (92).

Table 5 highlights key clinical trials addressing the role of radiotherapy in oligopersistent oncogene-addicted NSCLC.

Table 5
Table 5 Selected trials of radiotherapy combined with tyrosine kinase inhibitors in oligopersistent oncogene-driven NSCLC
Full table

Summary

Considering the biological rationale supported by preclinical data, combining targeted therapies with RT has long been considered a promising approach in NSCLC. However, none of the targeted therapies so far have demonstrated their added value to CRT, a standard treatment in locally advanced NSCLC. The main reason of these disappointing outcomes is likely due to using TKIs-RT combinations in molecularly unselected patients. The only phase III trial in the field that included molecularly selected (ALK-positive and EGFR-positive) NSCLC patients (RTOG 1306) was prematurely closed due to poor accrual, resulting in the lack of statistical power of the analysis. Another possible explanation of unsuccessful TKIs-RT combination in LA-NSCLC is the hypothetical lack of true synergism between TKIs and chemotherapy if both are combined with concurrent RT, and—potentially—even inhibitory effect of such a trimodality treatment. Indeed, the preclinical data on this strategy has been scarce. Importantly, all available data in this field come from the pre-PACIFIC era, and should be viewed in the context of the new standard of care in locally advanced NSCLC, i.e., CRT followed by consolidation durvalumab.

The side effects of particular targeted therapies while combined with RT are generally specific for their classes. However, since these substances are expected to own radiosensitizing potential, their concomitant use with RT may increase both acute and late thoracic radiation toxicity, such as pulmonary, esophageal, cardiac and skin toxicity.

Combining RT with targeted agents in locally advanced NSCLC still raises questions concerning optimal patient selection, RT timing, duration and fractionation, to mention only a few. These issues can only be answered by large, well-designed multi-center clinical trials dedicated to molecularly-selected populations, with careful long-term safety analyses, and using best available agents in particular classes (e.g., osimertinib for EGFR-positive tumours and alectinib for ALK-positive tumors. Future studies should also be based on more robust data from preclinical research.

The heterogeneity of oligoprogression definitions and limited clinical experience do not allow for firm conclusions regarding the role of RT in oligoprogressive oncogene-driven NSCLC patients managed with targeted therapy. Nonetheless, this strategy is already considered a standard clinical practice, supported by European Society of Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) guidelines. The use of consolidation RT in advanced oligopersistent oncogene-driven NSCLC creates the possibility to interfere with the natural course of the disease, resulting in progression delay. However, the real benefit from combining targeted agents with RT in oligoprogressive or oligopersistent oncogene-driven NSCLC still warrants confirmation in well-designed trials. These trials will necessitate advanced functional imaging (to confirm real oligoprogression and rule out polyprogression) and biomarker analysis of material obtained through tissue or liquid biopsy. Careful patient selection and the identification of reliable factors that predict a biologically favorable oligometastatic disease seem crucial. A few trials with the focus on oligoprogressive or oligopersistent oncogene-driven NSCLC are currently ongoing. The Canadian STOP-NSCLC (NCT02756793) phase II trial enrolls NSCLC patients with up to five progressing metastases during TKI or maintenance chemotherapy. Patients are randomized to SBRT to progressing sites while continuing primary systemic therapy, or systemic therapy alone (continuing the same drug beyond progression, switching to another agent, or observation). In the European HALT trial, EGFR-positive or ALK-positive NSCLC patients undergoing TKI treatment are randomized to TKI continuation with or without SBRT. In both studies the primary end point is PFS. In the ongoing NCT02314364 phase II trial, EGFR-positive, ALK-positive or ROS1-positive NSCLC patients after 6 months on TKIs without disease progression receive SBRT to residual extracranial (up to five) disease sites. The primary end point is frequency of distant failure. The ongoing US NCT02759835 trial, with PFS as the primary endpoint, includes oligoprogressive EGFR-positive NSCLC patients treated with a third generation EGFR TKI osimertinib.

Combining SBRT with targeted therapies in oligometastatic oncogene-driven NSCLC holds great promise for prolonging PFS and OS, at least in some subsets of patients. While waiting for the results of trials, physicians are encouraged to offer SBRT with risk-adapted dose fractionation to carefully selected oncogene-addicted oligoprogressive/oligopersistent NSCLC patients in the course of targeted therapy.


Acknowledgments

Funding: None.


Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research for the series “Radiotherapy in thoracic malignancies”. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-552). The series “Radiotherapy in thoracic malignancies” was commissioned by the editorial office without any funding or sponsorship. Rafal Dziadziuszko served as the unpaid Guest Editor of the series. Jacek Jassem served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Translational Lung Cancer Research from Oct 2017 to Sep 2021. Dr. Wrona reports other from Pfizer, other from BMS, other from Roche, other from Takeda, outside the submitted work. Dr. Dziadziuszko reports personal fees and other from Roche, personal fees and other from AstraZeneca, personal fees from Novartis, personal fees from Pfizer, personal fees from MSD, personal fees from Takeda, personal fees from Boehringer-Ingelheim, personal fees from FoundationMedicine, outside the submitted work. Dr. Jassem reports Speaker: AstraZeneca, Roche, Pfizer; Advisory roles: AstraZeneca, BMS, Pfizer, MSD, Takeda; Travel support: Roche, Pfizer. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


References

  1. Greenhalgh J, Dwan K, Boland A, et al. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. Cochrane Database Syst Rev 2016;CD010383 [Crossref] [PubMed]
  2. Zhang Q, Qin N, Wang J, et al. Crizotinib versus platinum-based double-agent chemotherapy as the first line treatment in advanced anaplastic lymphoma kinase-positive lung adenocarcinoma. Thorac Cancer 2016;7:3-8. [Crossref] [PubMed]
  3. Auperin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181-90. [Crossref] [PubMed]
  4. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16:187-99. [Crossref] [PubMed]
  5. Blais N, Kassouf E. Maintenance therapies for non-small cell lung cancer. Front Oncol 2014;4:213. [Crossref] [PubMed]
  6. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:1919-29. [Crossref] [PubMed]
  7. Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 2018;379:2342-50. [Crossref] [PubMed]
  8. Bentzen SM, Harari PM, Bernier J. Exploitable mechanisms for combining drugs with radiation: concepts, achievements and future directions. Nat Clin Pract Oncol 2007;4:172-80. [Crossref] [PubMed]
  9. Lammering G, Hewit TH, Valerie K, et al. EGFRvIII-mediated radioresistance through a strong cytoprotective response. Oncogene 2003;22:5545-53. [Crossref] [PubMed]
  10. Lammering G, Hewit TH, Holmes M, et al. Inhibition of the type III epidermal growth factor receptor variant mutant receptor by dominant-negative EGFR-CD533 enhances malignant glioma cell radiosensitivity. Clin Cancer Res 2004;10:6732-43. [Crossref] [PubMed]
  11. Lammering G, Valerie K, Lin PS, et al. Radiation-induced activation of a common variant of EGFR confers enhanced radioresistance. Radiother Oncol 2004;72:267-73. [Crossref] [PubMed]
  12. Lee SM. Is EGFR expression important in non-small cell lung cancer? Thorax. vol 2. England2006. p. 98-9.
  13. Das AK, Sato M, Story MD, et al. Non-small-cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. Cancer Res 2006;66:9601-8. [Crossref] [PubMed]
  14. Das AK, Chen BP, Story MD, et al. Somatic mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) abrogate EGFR-mediated radioprotection in non-small cell lung carcinoma. Cancer Res 2007;67:5267-74. [Crossref] [PubMed]
  15. Milas L, Fan Z, Andratschke NH, et al. Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys 2004;58:966-71. [Crossref] [PubMed]
  16. Nyati MK, Morgan MA, Feng FY, et al. Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer 2006;6:876-85. [Crossref] [PubMed]
  17. Schmidt-Ullrich RK, Mikkelsen RB, Dent P, et al. Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 1997;15:1191-7. [Crossref] [PubMed]
  18. Herbst RS, Bunn PA Jr. Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 2003;9:5813-24. [PubMed]
  19. Bianco C, Bianco R, Tortora G, et al. Antitumor activity of combined treatment of human cancer cells with ionizing radiation and anti-epidermal growth factor receptor monoclonal antibody C225 plus type I protein kinase A antisense oligonucleotide. Clin Cancer Res 2000;6:4343-50. [PubMed]
  20. Bonner JA, Raisch KP, Trummell HQ, et al. Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation in head and neck cancers. J Clin Oncol 2000;18:47S-53S. [PubMed]
  21. Petty WJ, Dragnev KH, Memoli VA, et al. Epidermal growth factor receptor tyrosine kinase inhibition represses cyclin D1 in aerodigestive tract cancers. Clin Cancer Res 2004;10:7547-54. [Crossref] [PubMed]
  22. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567-78. [Crossref] [PubMed]
  23. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21-8. [Crossref] [PubMed]
  24. Raben D, Helfrich B, Chan DC, et al. The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res 2005;11:795-805. [PubMed]
  25. Hughes S, Liong J, Miah A, et al. A brief report on the safety study of induction chemotherapy followed by synchronous radiotherapy and cetuximab in stage III non-small cell lung cancer (NSCLC): SCRATCH study. J Thorac Oncol 2008;3:648-51. [Crossref] [PubMed]
  26. Jatoi A, Schild SE, Foster N, et al. A phase II study of cetuximab and radiation in elderly and/or poor performance status patients with locally advanced non-small-cell lung cancer (N0422). Ann Oncol 2010;21:2040-4. [Crossref] [PubMed]
  27. Jensen AD, Munter MW, Bischoff HG, et al. Combined treatment of nonsmall cell lung cancer NSCLC stage III with intensity-modulated RT radiotherapy and cetuximab: the NEAR trial. Cancer 2011;117:2986-94. [Crossref] [PubMed]
  28. Hallqvist A, Wagenius G, Rylander H, et al. Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: satellite--a phase II study from the Swedish Lung Cancer Study Group. Lung Cancer 2011;71:166-72. [Crossref] [PubMed]
  29. Ramalingam SS, Kotsakis A, Tarhini AA, et al. A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer. Lung Cancer 2013;81:416-21. [Crossref] [PubMed]
  30. Dilling TJ, Extermann M, Kim J, et al. Phase 2 study of concurrent cetuximab plus definitive thoracic radiation therapy followed by consolidation docetaxel plus cetuximab in poor prognosis or elderly patients with locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2014;90:828-33. [Crossref] [PubMed]
  31. Blumenschein GR Jr, Paulus R, Curran WJ, et al. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. J Clin Oncol 2011;29:2312-8. [Crossref] [PubMed]
  32. Govindan R, Bogart J, Stinchcombe T, et al. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol 2011;29:3120-5. [Crossref] [PubMed]
  33. Liu D, Zheng X, Chen J, et al. Induction chemotherapy with cetuximab, vinorelbine-cisplatin followed by thoracic radiotherapy and concurrent cetuximab, vinorelbine-cisplatin in patients with unresectable stage III non-small cell lung cancer. Lung Cancer 2015;89:249-54. [Crossref] [PubMed]
  34. Vokes EE, Herndon JE 2nd, Crawford J, et al. Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431. J Clin Oncol 2002;20:4191-8. [Crossref] [PubMed]
  35. van den Heuvel MM, Uyterlinde W, Vincent AD, et al. Additional weekly Cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell lung carcinoma: efficacy and safety outcomes of a randomized, multi-center phase II study investigating. Radiother Oncol 2014;110:126-31. [Crossref] [PubMed]
  36. Walraven I, van den Heuvel M, van Diessen J, et al. Long-term follow-up of patients with locally advanced non-small cell lung cancer receiving concurrent hypofractionated chemoradiotherapy with or without cetuximab. Radiother Oncol 2016;118:442-6. [Crossref] [PubMed]
  37. Kruser TJ, Armstrong EA, Ghia AJ, et al. Augmentation of radiation response by panitumumab in models of upper aerodigestive tract cancer. Int J Radiat Oncol Biol Phys 2008;72:534-42. [Crossref] [PubMed]
  38. Edelman MJ, Hu C, Le QT, et al. Randomized Phase II Study of Preoperative Chemoradiotherapy +/- Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa, N2+) Non-Small Cell Lung Cancer: NRG Oncology RTOG 0839. J Thorac Oncol 2017;12:1413-20. [Crossref] [PubMed]
  39. Boland W, Bebb G. The emerging role of nimotuzumab in the treatment of non-small cell lung cancer. Biologics 2010;4:289-98. [PubMed]
  40. Bebb G, Smith C, Rorke S, et al. Phase I clinical trial of the anti-EGFR monoclonal antibody nimotuzumab with concurrent external thoracic radiotherapy in Canadian patients diagnosed with stage IIb, III or IV non-small cell lung cancer unsuitable for radical therapy. Cancer Chemother Pharmacol 2011;67:837-45. [Crossref] [PubMed]
  41. Choi HJ, Sohn JH, Lee CG, et al. A phase I study of nimotuzumab in combination with radiotherapy in stages IIB-IV non-small cell lung cancer unsuitable for radical therapy: Korean results. Lung Cancer 2011;71:55-9. [Crossref] [PubMed]
  42. Zhou LL LJ, Gong R-M, et al. A phase II trial of nimotuzumab in combination with chemoradiotherapy in locally advanced lung squamous cell carcinoma. J Thorac Oncol 2011;6:
  43. Ball D, Burmeister B, Mitchell P, et al. P2-162: Phase I trial of gefitinib in combination with concurrent carboplatin, paclitaxel and radiation therapy in patients with stage III non small cell lung cancer (“CRITICAL”). J Thorac Oncol 2007;2:S633-S4. [Crossref]
  44. Center B, Petty WJ, Ayala D, et al. A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer. J Thorac Oncol 2010;5:69-74. [Crossref] [PubMed]
  45. Stinchcombe TE, Morris DE, Lee CB, et al. Induction chemotherapy with carboplatin, irinotecan, and paclitaxel followed by high dose three-dimension conformal thoracic radiotherapy (74 Gy) with concurrent carboplatin, paclitaxel, and gefitinib in unresectable stage IIIA and stage IIIB non-small cell lung cancer. J Thorac Oncol 2008;3:250-7. [Crossref] [PubMed]
  46. Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008;26:2450-6. [Crossref] [PubMed]
  47. Ready N, Janne PA, Bogart J, et al. Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol 2010;5:1382-90. [Crossref] [PubMed]
  48. Niho S, Ohe Y, Ishikura S, et al. Induction chemotherapy followed by gefitinib and concurrent thoracic radiotherapy for unresectable locally advanced adenocarcinoma of the lung: a multicenter feasibility study (JCOG 0402). Ann Oncol 2012;23:2253-8. [Crossref] [PubMed]
  49. Hotta K, Sasaki J, Saeki S, et al. Gefitinib Combined With Standard Chemoradiotherapy in EGFR-Mutant Locally Advanced Non-Small-Cell Lung Cancer: The LOGIK0902/OLCSG0905 Intergroup Study Protocol. Clin Lung Cancer 2016;17:75-9. [Crossref] [PubMed]
  50. Akamatsu H, Harada H, Tokunaga S, et al. A Phase II Study of Gefitinib With Concurrent Thoracic Radiotherapy in Patients With Unresectable, Stage III Non-small-cell Lung Cancer Harboring EGFR Mutations (WJOG6911L). Clin Lung Cancer 2019;20:e25-7. [Crossref] [PubMed]
  51. Choong NW, Mauer AM, Haraf DJ, et al. Phase I trial of erlotinib-based multimodality therapy for inoperable stage III non-small cell lung cancer. J Thorac Oncol 2008;3:1003-11. [Crossref] [PubMed]
  52. Wang J, Xia TY, Wang YJ, et al. Prospective study of epidermal growth factor receptor tyrosine kinase inhibitors concurrent with individualized radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e59-65. [Crossref] [PubMed]
  53. Lilenbaum R, Samuels M, Wang X, et al. A phase II study of induction chemotherapy followed by thoracic radiotherapy and erlotinib in poor-risk stage III non-small-cell lung cancer: results of CALGB 30605 (Alliance)/RTOG 0972 (NRG). J Thorac Oncol 2015;10:143-7. [Crossref] [PubMed]
  54. Martinez E, Martinez M, Rico M, et al. Feasibility, tolerability, and efficacy of the concurrent addition of erlotinib to thoracic radiotherapy in locally advanced unresectable non-small-cell lung cancer: a Phase II trial. Onco Targets Ther 2016;9:1057-66. [Crossref] [PubMed]
  55. Komaki R, Allen PK, Wei X, et al. Adding Erlotinib to Chemoradiation Improves Overall Survival but Not Progression-Free Survival in Stage III Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2015;92:317-24. [Crossref] [PubMed]
  56. Brognard J, Clark AS, Ni Y, et al. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 2001;61:3986-97. [PubMed]
  57. De Bacco F, Luraghi P, Medico E, et al. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J Natl Cancer Inst 2011;103:645-61. [Crossref] [PubMed]
  58. Bai RY, Ouyang T, Miething C, et al. Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood 2000;96:4319-27. [Crossref] [PubMed]
  59. Chen Z, Sasaki T, Tan X, et al. Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. Cancer Res 2010;70:9827-36. [Crossref] [PubMed]
  60. Tumati V, Kumar S, Yu L, et al. Effect of PF-02341066 and radiation on non-small cell lung cancer cells. Oncol Rep 2013;29:1094-100. [Crossref] [PubMed]
  61. Sun Y, Nowak KA, Zaorsky NG, et al. ALK inhibitor PF02341066 (crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK. Mol Cancer Ther 2013;12:696-704. [Crossref] [PubMed]
  62. Dai Y, Wei Q, Schwager C, et al. Synergistic effects of crizotinib and radiotherapy in experimental EML4-ALK fusion positive lung cancer. Radiother Oncol 2015;114:173-81. [Crossref] [PubMed]
  63. Ramaswamy G. NCT01822496. ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Available online: https://clinicaltrials.gov/ct2/show/NCT01822496 Accessed February 02,2020.
  64. Ou SH, Weitz M, Jalas JR, et al. Alectinib induced CNS radiation necrosis in an ALK+NSCLC patient with a remote (7 years) history of brain radiation. Lung Cancer 2016;96:15-8. [Crossref] [PubMed]
  65. Zhu VW, Nagasaka M, Kubota T, et al. Symptomatic CNS Radiation Necrosis Requiring Neurosurgical Resection During Treatment with Lorlatinib in ALK-Rearranged NSCLC: A Report of Two Cases. Lung Cancer (Auckl). New Zealand: (c) 2020 Zhu et al.; 2020. p. 13-8.
  66. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:58-62. [Crossref] [PubMed]
  67. Gao H, Xue J, Zhou L, et al. Bevacizumab radiosensitizes non-small cell lung cancer xenografts by inhibiting DNA double-strand break repair in endothelial cells. Cancer Lett 2015;365:79-88. [Crossref] [PubMed]
  68. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 2003;300:1155-9. [Crossref] [PubMed]
  69. Hoang T, Dahlberg SE, Schiller JH, et al. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol 2012;30:616-22. [Crossref] [PubMed]
  70. Lind JS, Senan S, Smit EF. Pulmonary toxicity after bevacizumab and concurrent thoracic radiotherapy observed in a phase I study for inoperable stage III non-small-cell lung cancer. J Clin Oncol 2012;30:e104-8. [Crossref] [PubMed]
  71. Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 2010;28:43-8. [Crossref] [PubMed]
  72. Socinski MA, Stinchcombe TE, Moore DT, et al. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small-cell lung cancer: results of a phase I/II trial. J Clin Oncol 2012;30:3953-9. [Crossref] [PubMed]
  73. Wozniak AJ, Moon J, Thomas CR Jr, et al. A Pilot Trial of Cisplatin/Etoposide/Radiotherapy Followed by Consolidation Docetaxel and the Combination of Bevacizumab (NSC-704865) in Patients With Inoperable Locally Advanced Stage III Non-Small-Cell Lung Cancer: SWOG S0533. Clin Lung Cancer 2015;16:340-7. [Crossref] [PubMed]
  74. Kao J, Chen CT, Tong CC, et al. Concurrent sunitinib and stereotactic body radiotherapy for patients with oligometastases: final report of a prospective clinical trial. Target Oncol 2014;9:145-53. [Crossref] [PubMed]
  75. Zhai Y, Ma H, Hui Z, et al. HELPER study: A phase II trial of continuous infusion of endostar combined with concurrent etoposide plus cisplatin and radiotherapy for treatment of unresectable stage III non-small-cell lung cancer. Radiother Oncol 2019;131:27-34. [Crossref] [PubMed]
  76. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 2012;7:1807-14. [Crossref] [PubMed]
  77. Campo M, Al-Halabi H, Khandekar M, et al. Integration of Stereotactic Body Radiation Therapy With Tyrosine Kinase Inhibitors in Stage IV Oncogene-Driven Lung Cancer. Oncologist 2016;21:964-73. [Crossref] [PubMed]
  78. Patel SH, Rimner A, Foster A, et al. Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib. Lung Cancer 2017;108:109-14. [Crossref] [PubMed]
  79. Wang Z, Zhu XX, Wu XH, et al. Gefitinib combined with stereotactic radiosurgery in previously treated patients with advanced non-small cell lung cancer. Am J Clin Oncol 2014;37:148-53. [Crossref] [PubMed]
  80. Iyengar P, Kavanagh BD, Wardak Z, et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. J Clin Oncol 2014;32:3824-30. [Crossref] [PubMed]
  81. Yu HA, Sima CS, Huang J, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013;8:346-51. [Crossref] [PubMed]
  82. Conforti F, Catania C, Toffalorio F, et al. EGFR tyrosine kinase inhibitors beyond focal progression obtain a prolonged disease control in patients with advanced adenocarcinoma of the lung. Lung Cancer 2013;81:440-4. [Crossref] [PubMed]
  83. Gan GN, Weickhardt AJ, Scheier B, et al. Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib. Int J Radiat Oncol Biol Phys 2014;88:892-8. [Crossref] [PubMed]
  84. Qiu B, Liang Y, Li Q, et al. Local Therapy for Oligoprogressive Disease in Patients With Advanced Stage Non-small-cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutation. Clin Lung Cancer 2017;18:e369-73. [Crossref] [PubMed]
  85. Xu Q, Liu H, Meng S, et al. First-line continual EGFR-TKI plus local ablative therapy demonstrated survival benefit in EGFR-mutant NSCLC patients with oligoprogressive disease. J Cancer 2019;10:522-9. [Crossref] [PubMed]
  86. Borghetti P, Bonu ML, Giubbolini R, et al. Concomitant radiotherapy and TKI in metastatic EGFR- or ALK-mutated non-small cell lung cancer: a multicentric analysis on behalf of AIRO lung cancer study group. Radiol Med 2019;124:662-70. [Crossref] [PubMed]
  87. Gomez DR, Tang C, Zhang J, et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol 2019;37:1558-65. [Crossref] [PubMed]
  88. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2018;4:e173501 [Crossref] [PubMed]
  89. Merino Lara T, Helou J, Poon I, et al. Multisite stereotactic body radiotherapy for metastatic non-small-cell lung cancer: Delaying the need to start or change systemic therapy? Lung Cancer 2018;124:219-26. [Crossref] [PubMed]
  90. Elamin YY, Gomez DR, Antonoff MB, et al. Local Consolidation Therapy (LCT) After First Line Tyrosine Kinase Inhibitor (TKI) for Patients With EGFR Mutant Metastatic Non-small-cell Lung Cancer (NSCLC). Clin Lung Cancer 2019;20:43-7. [Crossref] [PubMed]
  91. Xu Q, Zhou F, Liu H, et al. Consolidative Local Ablative Therapy Improves the Survival of Patients With Synchronous Oligometastatic NSCLC Harboring EGFR Activating Mutation Treated With First-Line EGFR-TKIs. J Thorac Oncol 2018;13:1383-92. [Crossref] [PubMed]
  92. Chan OSH, Lam KC, Li JYC, et al. ATOM: A phase II study to assess efficacy of preemptive local ablative therapy to residual oligometastases of NSCLC after EGFR TKI. Lung Cancer 2020;142:41-6. [Crossref] [PubMed]
Cite this article as: Wrona A, Dziadziuszko R, Jassem J. Combining radiotherapy with targeted therapies in non-small cell lung cancer: focus on anti-EGFR, anti-ALK and anti-angiogenic agents. Transl Lung Cancer Res 2021;10(4):2032-2047. doi: 10.21037/tlcr-20-552