Breathing New Life Into Hypoxia-Targeted Therapies for Non–Small Cell Lung Cancer
JNCI J Natl Cancer Inst (
Breathing New Life Into Hypoxia-Targeted Therapies for Non-Small Cell Lung Cancer
Steven H. Lin 0 1 2
Albert C. Koong 0 1 2
0 The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions , please
1 Houston , Texas 77030 , USA
2 Affiliation of authors: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX , USA
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) (
), combining concurrent
chemotherapy with radiotherapy (CRT) in locally advanced unresectable
NSCLC (improves survival over RT or sequential chemotherapy
and RT) (
), and replacing chemotherapy with immune
checkpoint inhibitors (immunotherapies) for stage IV NSCLC (
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 (
). 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 (
). 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 (
). 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 (
), 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 (
), such clinical evidence is
lacking in NSCLC. Studies that appeared promising initially were
not confirmed in subsequent phase III trials (
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
Salem et al. 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 (
). 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
). This trend will likely continue for locally advanced disease
as consolidation and maintenance therapy after completing
). Immunotherapies may even play a pivotal role in
early-stage diseases either before or after completing surgery or
). 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 (
suppressive cell types such as T-regulatory cells or
myeloidderived suppressor cells (
). 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.
The authors have no relevant conflicts of interest to disclose.
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 .
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 nonsmall-cell lung cancer . N Engl J Med . 1990 ; 323 ( 14 ): 940 - 945 .
3. Curran WJ Jr, 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 .
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 .
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 .
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 .
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 .
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 .
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 .
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) þ/- 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 PN Jr, 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 .
12. Salem A , Asselin M-C , Reymen B , et al. Targeting hypoxia to improve nonsmall cell lung cancer outcome . J Natl Cancer Inst . 2018 ; 110 ( 1 ): 14 - 30 .
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 .
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 .
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 .
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 /imfinzisignificantly-reduces-the-risk-of-disease-worsening-or-death-in-the-phase-iiipacific-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 .
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 .
19. Kumar V , Gabrilovich DI . Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment . Immunology . 2014 ; 143 ( 4 ): 512 - 519 .