New modalities of cancer treatment for NSCLC: focus on immunotherapy

Figures & data

Figure 1 Immune evasion or immunosuppressive strategies used by tumor cells.

Notes: Tumors use numerous strategies to evade immune responses.^18–23 (A) Cancer cells can downregulate expression of MHC molecules that present tumor antigens to T-cells, and suppress tumor antigen presentation by professional APC, thereby avoiding recognition by T-cells. (B) Tumors create an immunosuppressive environment by recruitment and retention of suppressive Tregs and MDSCs, or (C) by secretion of immune-regulating or suppressive cytokines (IL-4, IL-5, IL-6, IL-10, and IL-13 and transforming growth factor-beta) and mediators (prostaglandins, indoleamine 2,3-dioxygenase. (D) Dysregulation of T-cell checkpoint pathways, including expression of PD-L1 by tumors, sends negative signals to tumor-specific T cells, causing T cell inactivation.

Abbreviations: APC, antigen-presenting cells; IL, interleukin; MDSCs, myeloid-derived suppressor cells; MHC, major histocompatibility complex; Tregs, T-regulatory cells.

Figure 2 Targeted therapy approaches in NSCLC. Targeted therapies work by inactivating proteins essential for tumor growth and survival. Both EGF receptor tyrosine kinase and ALK can be mutated and overactive in some patients with NSCLC, although not typically in the same patients. Erlotinib and afatinib inhibit the tyrosine kinase on the intracellular region of the EGF receptor and prevent growth signaling. Crizotinib inhibits the kinase activity of ALK, located in the cell cytoplasm, to prevent growth signaling. Bevacizumab binds and inactivates vascular endothelial growth factor (VEGF) secreted by the tumor into the intracellular space, thereby limiting blood vessel formation to the tumor.

Abbreviations: ALK, anaplastic lymphoma kinase; EGF, epidermal growth factor; NSCLC, non-small cell lung cancer.

Table 1 Clinical results of ipilimumab in combination with chemotherapy in patients with chemotherapy-naïve advanced (stage 3b or 4) NSCLC

	Phased ipilimumab	Concurrent ipilimumab	Chemotherapy control
Time to immune-related progression, median	5.7 months	5.5 months	4.6 months
Progression-free survival (WHO criteria), median	5.1 months	4.1 months	4.2 months
Overall survival, median	12.2 months	9.7 months	8.3 months
Overall survival at one year	50%	42%	39%

Note: Data from Lynch et al.⁶²

Abbreviations: NSCLC, non-small cell lung cancer; WHO, World Health Organization.

Figure 3 Concept of immunotherapy in NSCLC. (A) APCs display tumor antigens and B7 (CD80/CD86) molecules to CD8+ T-cells. CTLA-4 and CD28 are expressed on T-cells and compete for binding to B7. CTLA-4 has a higher affinity for B7 and CTLA-4:B7 binding leads to T-cell deactivation. (B) Anti-CTLA-4 antibodies prevent CTLA-4:B7 binding and allow CD28:B7 binding leading to T-cell activation. (C) Binding of PD-1 on T-cells to PD-L1 (or PD-L2; not depicted) on tumor cells causes T-cell deactivation. (D) Anti-PD-1 antibodies (or anti-PD-L1 antibodies, not shown) prevent PD-1:PD-L1 binding and restore T-cell activation and killing of tumor cells via release of cytolytic molecules.

Abbreviations: APCs, antigen-presenting cells; MHC, major histocompatibility complex; NSCLC, non-small cell lung cancer; CTLA4, cytotoxic T-lymphocyte-associated antigen-4.

Table 2 Initial Phase I efficacy results for nivolumab monotherapy in evaluable patients with NSCLC

Nivolumab dose (mg/kg)	Objective response rate, %			Stable disease ≥24 weeks, %			Progression-free survival rate at 24 weeks, %
	Squamous (n=18)	Nonsquamous (n=56)	All NSCLC (n=76)a	Squamous (n=18)	Nonsquamous (n=56)	All NSCLC (n=76)a	Squamous (n=18)	Nonsquamous (n=56)	All NSCLC (n=76)a
1.0	0	0	6	0	8	6	0	14	16
3.0	50	23	32	0	15	11	50	37	41
10.0	43	13	18	0	6	5	43	21	24
All doses	33	12	18	0	9	7	33	22	26

Notes:

a Two patients had unknown histologic type. From N Engl J Med, Topalian SL, Hodi FS, Brahmer JR, et al, Safety, activity, and immune correlates of anti-PD-1 antibody in cancer, 366, 2443–2454. Copyright © (2012) Massachusetts Medical Society. Adapted with permission from Massachusetts Medical Society.¹²

Abbreviation: NSCLC, non-small-cell lung cancer.

Table 3 Examples of select adverse events reported with immune checkpoint inhibitors^{12,13,25,62,65,72,73,75,76,85,86}

Category	Adverse events
Dermatologic	Pruritus, rash, vitiligo, urticaria, alopecia, pruritic rash, macular rash, hypopigmentation, erythema, erythematous rash
Gastrointestinal	Diarrhea, colitis, nausea, abdominal pain
Endocrine	Hypothyroidism, hyperthyroidism, hypopituitarism, hypophysitis, adrenal insufficiency, altered hormone levels
Hepatic	Hepatitis, increased liver function enzymes
Pulmonary	Pneumonitis, pulmonary edema
Ocular	Uveitis, episcleritis, eye pruritus
Pancreatic	Elevated lipase levels, hyperglycemia
Infusion-related	Infusion-related reaction or hypersensitivity
General	Fatigue, headache, decreased appetite, arthralgia

BabaTHanagiriTIchikiYLack and restoration of sensitivity of lung cancer cells to cellular attack with special reference to expression of human leukocyte antigen class I and/or major histocompatibility complex class I chain related molecules A/BCancer Sci200798111795180217725806

 PubMed Web of Science ®Google Scholar

ShimizuKNakataMHiramiYYukawaTMaedaATanemotoKTumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancerJ Thorac Oncol20105558559020234320

 PubMed Web of Science ®Google Scholar

LynchTJBondarenkoILuftAIpilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II studyJ Clin Oncol201230172046205422547592

 PubMed Web of Science ®Google Scholar

TopalianSLHodiFSBrahmerJRSafety, activity, and immune correlates of anti-PD-1 antibody in cancerN Engl J Med2012366262443245422658127

 PubMed Web of Science ®Google Scholar

WolchokJDKlugerHCallahanMKNivolumab plus ipilimumab in advanced melanomaN Engl J Med2013369212213323724867

 PubMed Web of Science ®Google Scholar

HodiFSO’DaySJMcDermottDFImproved survival with ipilimumab in patients with metastatic melanomaN Engl J Med2010363871172320525992

 PubMed Web of Science ®Google Scholar

BrahmerJRHornLAntoniaSJNivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with non-small cell lung cancer (NSCLC): overall survival and long-term safety in a phase 1 trialAbstract MO18.03 presented at the 15th International Association for the Study of Lung Cancer World Conference on Lung CancerOctober 27–30, 2013Sydney, Australia

 Google Scholar

HamidORobertCDaudASafety and tumor responses with lambrolizumab (anti-PD-1) in melanomaN Engl J Med2013369213414423724846

 PubMed Web of Science ®Google Scholar

GaronEBBalmanoukianAHamidOPreliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC)Abstract MO18.02 presented at the 15th International Association for the Study of Lung Cancer World Conference on Lung CancerOctober 27–30, 2013Sydney, Australia

 Google Scholar

BrahmerJRTykodiSSChowLQSafety and activity of anti-PD-L1 antibody in patients with advanced cancerN Engl J Med2012366262455246522658128

 PubMed Web of Science ®Google Scholar

HornLHerbstRSSpigelDRAn analysis of the relationship of clinical activity to baseline EGFR status, PD-L1 expression and prior treatment history in patients with non-small cell lung cancer (NSCLC) following PD-L1 blockade with MPDL3280A (anti-PDL1)Abstract MO18.01 presented at the 15th International Association for the Study of Lung Cancer World Conference on Lung CancerOctober 27–30, 2013Sydney, Australia

 Google Scholar

HerbstRSGordonMSFineGDA study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumorsJ Clin Oncol201331Suppl Abstr 3000

 Google Scholar

WeberJSKählerKCHauschildAManagement of immune-related adverse events and kinetics of response with ipilimumabJ Clin Oncol201230212691269722614989

 PubMed Web of Science ®Google Scholar