Breathing New Life Into Hypoxia-Targeted Therapies for Non–Small Cell Lung Cancer

Breathing New Life Into Hypoxia-Targeted Therapies for Non–Small Cell Lung Cancer Clinical outcomes for non–small cell lung cancer (NSCLC) have remained dismal despite therapeutic advancements including the incorporation of adjuvant chemotherapy in resected stage IB–IIIA NSCLC (5% gain in survival) (1), combining concurrent chemotherapy with radiotherapy (CRT) in locally advanced unresectable NSCLC (improves survival over RT or sequential chemotherapy and RT) (2,3), and replacing chemotherapy with immune checkpoint inhibitors (immunotherapies) for stage IV NSCLC (4–8). Further efforts to improve treatment outcomes by combining molecularly targeted therapies with existing therapies, such as vascular or epidermal growth factor receptor (EGFR) targeting, have been excessively toxic (9) or unsuccessful (10). The same is true for hypoxia targeting. While hypoxia is an important hallmark of cancer, conferring resistance to conventional therapies, promoting a more aggressive and metastatic phenotype, and targeting tumor hypoxia through a myriad of approaches have shown promise in early studies but have largely been disappointing in definitive clinical trials (11). In order for hypoxia targeting to be relevant for therapy in NSCLC, we need to learn from past failures in order to be successful in future efforts. The review by Salem and colleagues in this issue of the Journal summarizes a research framework on which future trials in NSCLC could be designed (12). The authors provide an excellent overview of the biology of hypoxia and the current status of hypoxia targeting in NSCLC. Substantial tumor hypoxia exists in NSCLC, even in early-stage tumors (13), thus forming a strong rationale to leverage this unique aspect of the tumor microenvironment. While hypoxia targeting holds promise to improve outcomes in head and neck cancers (14), such clinical evidence is lacking in NSCLC. Studies that appeared promising initially were not confirmed in subsequent phase III trials (11). Human tumors have widely variable and dynamic levels of oxygenation, thus complicating efforts to target a hypoxic population of cells. Overall, this area of clinical–translational investigation is hampered by the lack of a widely accepted method for determining tumor hypoxia and general agreement regarding what constitutes clinically significant hypoxia. Regardless, it is generally accepted that the differential level of hypoxia observed in human tumors relative to normal tissues could be exploited to improve the therapeutic index of hypoxic drug targeting. Because hypoxia promotes tumor aggressiveness and metastatic spread, trial designs should take into account how best to sequence hypoxia-targeted drugs with standard cancer therapies. Potential synergistic combinations and synthetic lethality may be identified in small “window of opportunity” trials, with pathologic assessment of response, before advancement into definitive randomized trials. The authors appropriately point out the importance of patient selection through hypoxia biomarkers, which may be achieved through imaging (hypoxia positron emission tomography or magnetic resonance imaging), gene expression profiling of tumor samples, or blood-based assays. Salem etal. propose four clinical scenarios for development, but there appears to be no consensus strategy toward successful implementation. In early-stage NSCLC, metastatic recurrence is a major barrier to achieving cures after surgery or stereotactic ablative RT (SABR). However, there are limited data to support that targeting hypoxia itself will decrease metastatic recurrence. The same rationale applies for locally advanced and advanced NSCLC, where hypoxia-targeted approaches may be combined with RT alone, CRT, chemotherapy, or biologic agents. Unfortunately, these approaches have largely been explored, generally resulting in negative results. Image-guided radiation dose painting to boost hypoxic regions within the tumor during RT is another proposed strategy to enhance tumoricidal effects. While technically feasible, there is little evidence that such techniques would yield better outcomes because hypoxic regions may fluctuate throughout the course of RT and dose escalation studies of up to 90 Gy to the tumor still result in high rates of local recurrence (15). One hypothesis is that hypoxia targeting may be effective only if the most severely hypoxic tumors are selected for treatment. However, as the authors state, all current hypoxia biomarkers are fraught with inadequate experience, suboptimal signals, or irreproducibility. This task, although supported by robust preclinical data, remains daunting, and perhaps an approach focused on recent immunologic advances may be warranted. For NSCLC, standard of care (SOC) therapies have evolved rapidly, with the US Food and Drug Administration approving three immune checkpoint inhibitors in the past two years to replace cytotoxic chemotherapy in both first- and second-line settings for metastatic NSCLC (4–8). This trend will likely continue for locally advanced disease as consolidation and maintenance therapy after completing CRT (16). Immunotherapies may even play a pivotal role in early-stage diseases either before or after completing surgery or SABR (17). The authors suggest an approach where all three treatments (hypoxia-targeted therapy/immunotherapy/RT) could be incorporated into a “hypoimmuno trial.” Tumor hypoxia results in an immunosuppressive microenvironment, and therefore targeting hypoxia could synergize with immunotherapies, either alone or in combination with RT (SABR or conventional RT), CRT, or cytotoxic chemotherapy. However, evaluating a combination of agents may best be studied initially in resectable NSCLC, where hypoxia drugs can be administered preoperatively for one or two cycles, along with immunotherapy, so that pathologic and immunologic response data may be incorporated into future trial design. These early responses could be analyzed along with companion hypoxia imaging to identify robust predictive biomarkers. If a promising signal is observed, eventually such combinations could be tested in more advanced disease settings, with assessment of progression or survival. Interestingly, hypoxia also upregulates immunosuppressive proteins like CD73 or adenosine receptors (18) or suppressive cell types such as T-regulatory cells or myeloid-derived suppressor cells (19). Determining levels of tumor hypoxia may even help direct the type of immune-targeted therapies to utilize for best combinatorial effects. While hypoxia-targeted therapies have had a disappointing past, combining this approach with emerging immunotherapies in NSCLC creates exciting opportunities that will advance our understanding of the biology of tumor hypoxia. Innovative trials with correlative predictive biomarker assessments and end points will surely invigorate this approach, ultimately leading to the development of novel therapies for our patients. Note The authors have no relevant conflicts of interest to disclose. References 1 Pignon JP, Tribodet H, Scagliotti GV, et al.   Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol.  2008; 26( 21): 3552– 3559. Google Scholar CrossRef Search ADS PubMed  2 Dillman RO, Seagren SL, Propert KJ, et al.   A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med.  1990; 323( 14): 940– 945. Google Scholar CrossRef Search ADS PubMed  3 Curran WJJr, Paulus R, Langer CJ, et al.   Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: Randomized phase III trial RTOG 9410. J Natl Cancer Inst.  2011; 103( 19): 1452– 1460. Google Scholar CrossRef Search ADS PubMed  4 Reck M, Rodriguez-Abreu D, Robinson AG, et al.   Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med.  2016; 375( 19): 1823– 1833. Google Scholar CrossRef Search ADS PubMed  5 Fehrenbacher L, Spira A, Ballinger M, et al.   Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): A multicentre, open-label, phase 2 randomised controlled trial. Lancet (London, England).  2016; 387( 10030): 1837– 1846. Google Scholar CrossRef Search ADS PubMed  6 Borghaei H, Paz-Ares L, Horn L, et al.   Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med.  2015; 373( 17): 1627– 1639. Google Scholar CrossRef Search ADS PubMed  7 Herbst RS, Baas P, Kim DW, et al.   Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet (London, England).  2016; 387( 10027): 1540– 1550. Google Scholar CrossRef Search ADS PubMed  8 Brahmer J, Reckamp KL, Baas P, et al.   Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med.  2015; 373( 2): 123– 135. Google Scholar CrossRef Search ADS PubMed  9 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( 1): 43– 48. Google Scholar CrossRef Search ADS PubMed  10 Bradley J, Masters G, Hu C, et al.   An intergroup randomized phase III comparison of standard-dose (60 Gy) vs high-dose (74 Gy) chemoradiotherapy (CRT) +/- cetuximab (cetux) for stage III non-small cell lung cancer (NSCLC): Results on cetux from RTOG 0617. J Thorac Oncol.  2013; 8( S2). 11 Williamson SK, Crowley JJ, Lara PNJr, et al.   Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol.  2005; 23( 36): 9097– 9104. Google Scholar CrossRef Search ADS PubMed  12 Salem A, Asselin M-C, Reymen B, et al.   Targeting hypoxia to improve non-small cell lung cancer outcome. J Natl Cancer Inst.  2018; 110( 1): 14– 30. Google Scholar CrossRef Search ADS   13 Le QT, Chen E, Salim A, Cao H, Kong CS, Whyte R, et al.   An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers. Clin Cancer Res.  2006; 12( 5): 1507– 1514. Google Scholar CrossRef Search ADS PubMed  14 Janssens GO, Rademakers SE, Terhaard CH, et al.   Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: Results of a phase III randomized trial. J Clin Oncol.  2012; 30( 15): 1777– 1783. Google Scholar CrossRef Search ADS PubMed  15 Bradley J, Graham MV, Winter K, et al.   Toxicity and outcome results of RTOG 9311: A phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys.  2005; 61( 2): 318– 328. Google Scholar CrossRef Search ADS PubMed  16 AstraZeneca. Imfinzi significantly reduces the risk of disease worsening or death in the phase III PACIFIC trial for stage III unresectable lung cancer. https://wwwastrazenecacom/media-centre/press-releases/2017/imfinzi-significantly-reduces-the-risk-of-disease-worsening-or-death-in-the-phase-iii-pacific-trial-for-stage-iii-unresectable-lung-cancer-12052017html. Accessed July 5, 2017. 17 Bernstein MB, Krishnan S, Hodge JW, Chang JY. Immunotherapy and stereotactic ablative radiotherapy (ISABR): A curative approach? Nat Rev Clin Oncol.  2016; 13( 8): 516– 524. Google Scholar CrossRef Search ADS PubMed  18 Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1alpha driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol.  2016; 29: 90– 96. Google Scholar CrossRef Search ADS PubMed  19 Kumar V, Gabrilovich DI. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology.  2014; 143( 4): 512– 519. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

Breathing New Life Into Hypoxia-Targeted Therapies for Non–Small Cell Lung Cancer

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Oxford University Press
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© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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0027-8874
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1460-2105
D.O.I.
10.1093/jnci/djx163
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Abstract

Clinical outcomes for non–small cell lung cancer (NSCLC) have remained dismal despite therapeutic advancements including the incorporation of adjuvant chemotherapy in resected stage IB–IIIA NSCLC (5% gain in survival) (1), combining concurrent chemotherapy with radiotherapy (CRT) in locally advanced unresectable NSCLC (improves survival over RT or sequential chemotherapy and RT) (2,3), and replacing chemotherapy with immune checkpoint inhibitors (immunotherapies) for stage IV NSCLC (4–8). Further efforts to improve treatment outcomes by combining molecularly targeted therapies with existing therapies, such as vascular or epidermal growth factor receptor (EGFR) targeting, have been excessively toxic (9) or unsuccessful (10). The same is true for hypoxia targeting. While hypoxia is an important hallmark of cancer, conferring resistance to conventional therapies, promoting a more aggressive and metastatic phenotype, and targeting tumor hypoxia through a myriad of approaches have shown promise in early studies but have largely been disappointing in definitive clinical trials (11). In order for hypoxia targeting to be relevant for therapy in NSCLC, we need to learn from past failures in order to be successful in future efforts. The review by Salem and colleagues in this issue of the Journal summarizes a research framework on which future trials in NSCLC could be designed (12). The authors provide an excellent overview of the biology of hypoxia and the current status of hypoxia targeting in NSCLC. Substantial tumor hypoxia exists in NSCLC, even in early-stage tumors (13), thus forming a strong rationale to leverage this unique aspect of the tumor microenvironment. While hypoxia targeting holds promise to improve outcomes in head and neck cancers (14), such clinical evidence is lacking in NSCLC. Studies that appeared promising initially were not confirmed in subsequent phase III trials (11). Human tumors have widely variable and dynamic levels of oxygenation, thus complicating efforts to target a hypoxic population of cells. Overall, this area of clinical–translational investigation is hampered by the lack of a widely accepted method for determining tumor hypoxia and general agreement regarding what constitutes clinically significant hypoxia. Regardless, it is generally accepted that the differential level of hypoxia observed in human tumors relative to normal tissues could be exploited to improve the therapeutic index of hypoxic drug targeting. Because hypoxia promotes tumor aggressiveness and metastatic spread, trial designs should take into account how best to sequence hypoxia-targeted drugs with standard cancer therapies. Potential synergistic combinations and synthetic lethality may be identified in small “window of opportunity” trials, with pathologic assessment of response, before advancement into definitive randomized trials. The authors appropriately point out the importance of patient selection through hypoxia biomarkers, which may be achieved through imaging (hypoxia positron emission tomography or magnetic resonance imaging), gene expression profiling of tumor samples, or blood-based assays. Salem etal. propose four clinical scenarios for development, but there appears to be no consensus strategy toward successful implementation. In early-stage NSCLC, metastatic recurrence is a major barrier to achieving cures after surgery or stereotactic ablative RT (SABR). However, there are limited data to support that targeting hypoxia itself will decrease metastatic recurrence. The same rationale applies for locally advanced and advanced NSCLC, where hypoxia-targeted approaches may be combined with RT alone, CRT, chemotherapy, or biologic agents. Unfortunately, these approaches have largely been explored, generally resulting in negative results. Image-guided radiation dose painting to boost hypoxic regions within the tumor during RT is another proposed strategy to enhance tumoricidal effects. While technically feasible, there is little evidence that such techniques would yield better outcomes because hypoxic regions may fluctuate throughout the course of RT and dose escalation studies of up to 90 Gy to the tumor still result in high rates of local recurrence (15). One hypothesis is that hypoxia targeting may be effective only if the most severely hypoxic tumors are selected for treatment. However, as the authors state, all current hypoxia biomarkers are fraught with inadequate experience, suboptimal signals, or irreproducibility. This task, although supported by robust preclinical data, remains daunting, and perhaps an approach focused on recent immunologic advances may be warranted. For NSCLC, standard of care (SOC) therapies have evolved rapidly, with the US Food and Drug Administration approving three immune checkpoint inhibitors in the past two years to replace cytotoxic chemotherapy in both first- and second-line settings for metastatic NSCLC (4–8). This trend will likely continue for locally advanced disease as consolidation and maintenance therapy after completing CRT (16). Immunotherapies may even play a pivotal role in early-stage diseases either before or after completing surgery or SABR (17). The authors suggest an approach where all three treatments (hypoxia-targeted therapy/immunotherapy/RT) could be incorporated into a “hypoimmuno trial.” Tumor hypoxia results in an immunosuppressive microenvironment, and therefore targeting hypoxia could synergize with immunotherapies, either alone or in combination with RT (SABR or conventional RT), CRT, or cytotoxic chemotherapy. However, evaluating a combination of agents may best be studied initially in resectable NSCLC, where hypoxia drugs can be administered preoperatively for one or two cycles, along with immunotherapy, so that pathologic and immunologic response data may be incorporated into future trial design. These early responses could be analyzed along with companion hypoxia imaging to identify robust predictive biomarkers. If a promising signal is observed, eventually such combinations could be tested in more advanced disease settings, with assessment of progression or survival. Interestingly, hypoxia also upregulates immunosuppressive proteins like CD73 or adenosine receptors (18) or suppressive cell types such as T-regulatory cells or myeloid-derived suppressor cells (19). Determining levels of tumor hypoxia may even help direct the type of immune-targeted therapies to utilize for best combinatorial effects. While hypoxia-targeted therapies have had a disappointing past, combining this approach with emerging immunotherapies in NSCLC creates exciting opportunities that will advance our understanding of the biology of tumor hypoxia. Innovative trials with correlative predictive biomarker assessments and end points will surely invigorate this approach, ultimately leading to the development of novel therapies for our patients. Note The authors have no relevant conflicts of interest to disclose. References 1 Pignon JP, Tribodet H, Scagliotti GV, et al.   Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol.  2008; 26( 21): 3552– 3559. Google Scholar CrossRef Search ADS PubMed  2 Dillman RO, Seagren SL, Propert KJ, et al.   A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med.  1990; 323( 14): 940– 945. Google Scholar CrossRef Search ADS PubMed  3 Curran WJJr, Paulus R, Langer CJ, et al.   Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: Randomized phase III trial RTOG 9410. J Natl Cancer Inst.  2011; 103( 19): 1452– 1460. Google Scholar CrossRef Search ADS PubMed  4 Reck M, Rodriguez-Abreu D, Robinson AG, et al.   Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med.  2016; 375( 19): 1823– 1833. Google Scholar CrossRef Search ADS PubMed  5 Fehrenbacher L, Spira A, Ballinger M, et al.   Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): A multicentre, open-label, phase 2 randomised controlled trial. Lancet (London, England).  2016; 387( 10030): 1837– 1846. Google Scholar CrossRef Search ADS PubMed  6 Borghaei H, Paz-Ares L, Horn L, et al.   Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med.  2015; 373( 17): 1627– 1639. Google Scholar CrossRef Search ADS PubMed  7 Herbst RS, Baas P, Kim DW, et al.   Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet (London, England).  2016; 387( 10027): 1540– 1550. Google Scholar CrossRef Search ADS PubMed  8 Brahmer J, Reckamp KL, Baas P, et al.   Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med.  2015; 373( 2): 123– 135. Google Scholar CrossRef Search ADS PubMed  9 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( 1): 43– 48. Google Scholar CrossRef Search ADS PubMed  10 Bradley J, Masters G, Hu C, et al.   An intergroup randomized phase III comparison of standard-dose (60 Gy) vs high-dose (74 Gy) chemoradiotherapy (CRT) +/- cetuximab (cetux) for stage III non-small cell lung cancer (NSCLC): Results on cetux from RTOG 0617. J Thorac Oncol.  2013; 8( S2). 11 Williamson SK, Crowley JJ, Lara PNJr, et al.   Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol.  2005; 23( 36): 9097– 9104. Google Scholar CrossRef Search ADS PubMed  12 Salem A, Asselin M-C, Reymen B, et al.   Targeting hypoxia to improve non-small cell lung cancer outcome. J Natl Cancer Inst.  2018; 110( 1): 14– 30. Google Scholar CrossRef Search ADS   13 Le QT, Chen E, Salim A, Cao H, Kong CS, Whyte R, et al.   An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers. Clin Cancer Res.  2006; 12( 5): 1507– 1514. Google Scholar CrossRef Search ADS PubMed  14 Janssens GO, Rademakers SE, Terhaard CH, et al.   Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: Results of a phase III randomized trial. J Clin Oncol.  2012; 30( 15): 1777– 1783. Google Scholar CrossRef Search ADS PubMed  15 Bradley J, Graham MV, Winter K, et al.   Toxicity and outcome results of RTOG 9311: A phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys.  2005; 61( 2): 318– 328. Google Scholar CrossRef Search ADS PubMed  16 AstraZeneca. Imfinzi significantly reduces the risk of disease worsening or death in the phase III PACIFIC trial for stage III unresectable lung cancer. https://wwwastrazenecacom/media-centre/press-releases/2017/imfinzi-significantly-reduces-the-risk-of-disease-worsening-or-death-in-the-phase-iii-pacific-trial-for-stage-iii-unresectable-lung-cancer-12052017html. Accessed July 5, 2017. 17 Bernstein MB, Krishnan S, Hodge JW, Chang JY. Immunotherapy and stereotactic ablative radiotherapy (ISABR): A curative approach? Nat Rev Clin Oncol.  2016; 13( 8): 516– 524. Google Scholar CrossRef Search ADS PubMed  18 Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1alpha driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol.  2016; 29: 90– 96. Google Scholar CrossRef Search ADS PubMed  19 Kumar V, Gabrilovich DI. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology.  2014; 143( 4): 512– 519. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Journal

JNCI: Journal of the National Cancer InstituteOxford University Press

Published: Jul 19, 2017

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