May 2015, Vol. 2, No. 3
The Need for Immunotherapeutic Approaches for Lung Cancer
Non–small cell lung cancer is one of the major cancer types for which new immune-based cancer treatments are currently in development
Lung cancer is the second most common cancer in both men and women (not counting skin cancer); in men, prostate cancer is more common, whereas in women, breast cancer is more common.1 The American Cancer Society estimates that approximately 221,200 new cases of lung cancer (115,610 in men and 105,590 in women) will be diagnosed in the United States in 2015, and about 158,040 people (86,380 men and 71,660 women) will die of lung cancer this year.1 Lung cancer is by far the leading cause of cancer death among both men and women; each year, more people die of lung cancer than of colon, breast, and prostate cancers combined (Figure 1).1 Only 17.8% of all patients with lung cancer are alive 5 years or more after diagnosis; the lung cancer 5-year survival rate is lower than that of many other leading cancer sites, such as the colon, breast, and prostate (Figure 1).2 The 5-year survival rate for lung cancer is 54% for cases detected when the disease is still localized; however, only 15% of lung cancer cases are diagnosed at an early stage. For distant tumors, the 5-year survival rate is only 4% (Figure 1).2
Approximately 85% to 90% of lung cancer cases are diagnosed as non–small cell lung cancer (NSCLC), which is further classified into 3 main histologies: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (Figure 2).3 Squamous NSCLC (which is closely associated with tobacco use) is a particularly aggressive form of lung cancer, for which there
is a lack of effective and well- tolerated treatments.4
Targeted Therapies for NSCLC
In recent years, a major paradigm shift has occurred in the management of NSCLC because of advances in the understanding of differences in therapeutic outcomes between tumors of squamous versus nonsquamous histology and the identification of driver mutations that can be targeted with novel agents.5
Historically, patients with advanced NSCLC were treated with a platinum-based doublet chemotherapy without regard to histology. However, in a phase 2 trial of bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, a prohibitive rate of life-threatening pulmonary hemorrhages occurred in the subpopulation of patients with squamous histology.6 Consequently, patients with squamous histology were excluded from subsequent trials of bevacizumab, and the drug is approved by the FDA only for the treatment of nonsquamous NSCLC.7
Advances in the treatment of patients with NSCLC over the past decade have largely involved the development of therapies directed at molecular targets such as mutations in the epidermal growth factor receptor (EGFR) gene or ALK rearrangements.8
Small-Molecule EGFR Inhibitors
In 2004, insight was gained when treatment with the small-molecule tyrosine kinase inhibitor (TKI) gefitinib was associated with superior efficacy in a subgroup of patients with NSCLC whose tumors had certain mutations (ie, deletion of exon 19 or the L858R point mutation of exon 21) in the kinase domain of the EGFR gene.9,10 Mutations in EGFR are present in 10% to 17% of patients with NSCLC from a European background and are more common in women, patients who have never smoked, those of Asian heritage, and those with adenocarcinoma.11-14 Personalized therapy for patients whose tumors have activating EGFR mutations has resulted in better survival outcomes in these biologically selected subgroups.15 Currently, the EGFR TKIs are the standard of care for patients with locally advanced or metastatic NSCLC harboring activating EGFR mutations. A list of the TKIs targeting the EGFR that have been approved by the FDA is shown in Table 1.
Gefitinib was approved for marketing in May 2003 for patients with NSCLC under accelerated approval regulations that allow products to be approved on the basis of a surrogate end point for clinical efficacy. For gefitinib, the surrogate end point was tumor response rate. The response rate in patients taking the drug was approximately 10%. The approved indication was for the treatment of patients who were refractory to chemotherapy (both a platinum drug and docetaxel). However, since the initial approval of gefitinib, erlotinib was approved based on improved overall survival (OS) for treatment of this same patient population.16
The FDA reviewed data from 2 failed clinical studies of gefitinib, one of which was required by the agency as part of the drug’s accelerated approval. This trial enrolled patients with regionally advanced or metastatic NSCLC in whom 1 or 2 prior treatment regimens had failed. In this large study, 1692 patients were randomized to gefitinib or placebo. There was no significant survival benefit in the overall study population or in the patients who had high levels of EGFR. In contrast, the presence of EGFR at high levels appears to predict a good response to erlotinib. In the second trial in patients with stage III NSCLC, after completion of induction and consolidation chemotherapy and radiation therapy, patients were randomized to gefitinib maintenance therapy or placebo. No gefitinib survival benefit could be demonstrated.16
In a randomized, open-label study (N = 174) conducted in Europe, the safety and efficacy of erlotinib as monotherapy were compared with standard platinum-based doublet chemotherapy (cisplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin plus gemcitabine, or carboplatin plus docetaxel) for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. The median progression-free survival (PFS) of patients treated with erlotinib was 10.4 months compared with 5.2 months in the control group (hazard ratio [HR], 0.34; 95% CI, 0.23-0.49; P <.001). The median OS of patients treated with erlotinib was 22.9 months compared with 19.5 months in the control group (HR, 0.93; 95% CI, 0.64-1.35) (Figure 3).17
In a randomized, multicenter, open-label study (N = 345), the efficacy and safety of afatinib were compared with pemetrexed/cisplatin chemotherapy in the first-line treatment of patients with EGFR mutation–positive, metastatic NSCLC. The median PFS of patients treated with afatinib was 11.1 months compared with 6.9 months in the control group (HR, 0.58; 95% CI, 0.43-0.78; P <.001).The median OS of patients treated with afatinib was 28.1 months compared with 28.2 months in the control group (HR, 0.91; 95% CI, 0.66-1.25; P = .55).18
Another study was conducted to evaluate the efficacy of afatinib in 96 patients with EGFR-mutant metastatic NSCLC with acquired resistance to erlotinib or gefitinib.19 Among the 86 patients evaluable for efficacy, the response rate was 11.6%, with a median PFS of 3.9 months and a median OS of 7.3 months. The authors concluded that these results showed that afatinib has only modest efficacy in a real-life population of patients with EGFR-mutant NSCLC with acquired resistance to erlotinib or gefitinib.
Small-Molecule ALK Inhibitors
More recently, another molecular abnormality, the ALK gene, that drives NSCLC in a different group of patients has been found in 2% to 8% of all patients with NSCLC, predominantly in young (?50 years of age), never/former smokers with adenocarcinoma.11-13,20,21 ALK rearrangements most often consist of a chromosome 2 inversion leading to a fusion with the EML4 gene, resulting in the abnormal expression and activation of this tyrosine kinase in the cytoplasm of cancer cells.20 Two small-molecule ALK inhibitors are currently approved for the treatment of ALK-positive metastatic NSCLC (Table 2).
In a randomized, multicenter, open-label, active-controlled study (N = 347), the efficacy and safety of crizotinib as monotherapy were compared with chemotherapy (pemetrexed or docetaxel) for the treatment of patients with metastatic ALK-positive NSCLC who had been treated previously with 1 platinum-based chemotherapy regimen. The median PFS of patients treated with crizotinib was 7.7 months compared with 3.0 months in the chemotherapy group (HR, 0.49; 95% CI, 0.37-0.64; P <.001). The median OS of patients treated with crizotinib was 20.3 months compared with 22.8 months in the chemotherapy group (HR, 1.02; 95% CI, 0.68-1.54; P = .54) (Figure 4).22
The efficacy of ceritinib was established in a multicenter, single-arm, open-label clinical study (N = 163) in patients with metastatic ALK-positive NSCLC who progressed while receiving, or were intolerant to, crizotinib. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.0 as evaluated by both investigators and a blinded independent central review committee (BIRC). The ORR by investigator assessment was 54.6%, including 1.2% complete responses (CRs); the ORR by BIRC assessment was 43.6%, including 2.5% CRs. The median duration of response was 7.4 months by investigator assessment and 7.1 months by BIRC assessment.23
Another strategy for treating NSCLC is the use of monoclonal antibodies to target angiogenesis (Table 3).
In a randomized, active-controlled, open-label, multicenter study (N = 878), the safety and efficacy of bevacizumab plus paclitaxel/carboplatin were compared with paclitaxel/carboplatin alone as first-line treatment of patients with locally advanced, metastatic, or recurrent nonsquamous NSCLC. The median OS was 12.3 months in the group treated with bevacizumab plus paclitaxel/carboplatin and 10.3 months in the control group (HR, 0.80; 95% CI, 0.68-0.94; P = .013) (Figure 5).24
In another randomized, double-blind, placebo-controlled, 3-arm study (N = 1043), the safety and efficacy of bevacizumab (7.5 or 15.0 mg/kg) plus cisplatin/gemcitabine were compared with placebo plus cisplatin/gemcitabine as first-line treatment of patients with locally advanced, metastatic, or recurrent nonsquamous NSCLC. PFS, the main efficacy outcome measure, was significantly higher in both bevacizumab groups compared with the control group; for the bevacizumab 7.5- mg/kg group, the HR was 0.75 (95% CI, 0.62-0.91; P = .0026); and for the bevacizumab 15.0-mg/kg group, the HR was 0.82 (95% CI, 0.68-0.98; P = .0301). The addition of bevacizumab to cisplatin/gemcitabine chemotherapy failed to demonstrate an improvement in the duration of OS, an additional efficacy outcome measure; for the bevacizumab 7.5-mg/kg group, the HR was 0.93 (95% CI, 0.78-1.11; P = .4203); and for the bevacizumab 15.0-mg/kg group, the HR was 1.03 (95% CI, 0.86-1.23; P = .7613).24
In a multinational, randomized, double-blind study, 1253 patients with NSCLC who had disease progression on or after 1 platinum-based therapy for locally advanced or metastatic disease were randomized 1:1 to received either ramucirumab plus docetaxel or placebo plus docetaxel. The median OS of patients treated with ramucirumab plus docetaxel was 10.5 months compared with 9.1 months in the control group (HR, 0.86; 95% CI, 0.75-0.98; P = .024). The median PFS of patients treated with ramucirumab plus docetaxel was 4.5 months compared with 3.0 months in the control group (HR, 0.76; 95% CI, 0.68-0.86; P <.001) (Figure 6).25
Unmet Need Despite Targeted Therapies
Despite these targeted therapies, the OS in patients with metastatic disease continues to be poor, and the majority of patients with NSCLC are not candidates for these therapies. Patients with EGFR mutations or ALK rearrangements represent only a small percentage of the total population with NSCLC; thus, alternative treatment options are needed to improve the prognosis for patients with lung cancer.15
Various immunotherapeutic options are being investigated in clinical studies. One approach is checkpoint inhibition, a strategy that involves “taking the brakes off” the immune system by blocking natural mechanisms that serve to limit the immune response.26 One checkpoint inhibitor, nivolumab, was approved by the FDA on March 4, 2015, for the treatment of patients with metastatic squamous NSCLC that had progressed on or after platinum-based chemotherapy. A number of other checkpoint inhibitors, including pembrolizumab, MPDL3280A, MEDI4736, ipilimumab, and tremelimumab, are under investigation. Another strategy is the use of therapeutic vaccines, such as MAGE-A3, PRAME, tecemotide, TG4010, epidermal growth factor vaccine, racotumomab, and belagenpumatucel-L. Immunotherapy is starting to deliver promising results in lung cancer clinical trials, but it will be important to determine if immunotherapies are most effective when used alone or in combination with other agents.
- American Cancer Society. Lung Cancer (Non-Small Cell). www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf. Accessed March 4, 2015.
- Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER website, April 2014.
- American Cancer Society. Lung Cancer (Non-Small Cell). www.cancer.org/can cer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed April 6, 2015.
- McKeage MJ, Jameson MB; AS1404-201 Study Group Investigators. Comparative outcomes of squamous and non-squamous non-small cell lung cancer (NSCLC) patients in phase II studies of ASA404 (DMXAA) – retrospective analysis of pooled data. J Thorac Dis. 2010;2:199-204.
- Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015;4:36-54.
- Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184-2191.
- Stinchcombe TE. Novel agents in development for advanced non-small cell lung cancer. Ther Adv Med Oncol. 2014;6:240-253.
- Savas P, Hughes B, Solomon B. Targeted therapy in lung cancer: IPASS and beyond, keeping abreast of the explosion of targeted therapies for lung cancer. J Thorac Dis. 2013;5(suppl 5):S579-S592.
- Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139.
- Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497-1500.
- Chia PL, Mitchell P, Dobrovic A, et al. Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. Clin Epidemiol. 2014;6:423-432.
- Cardarella S, Johnson BE. The impact of genomic changes on treatment of lung cancer. Am J Respir Crit Care Med. 2013;188:770-775.
- Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311:1998-2006.
- Schettino C, Bareschino MA, Sacco PC, et al. New molecular targets in the treatment of NSCLC. Curr Pharm Des. 2013;19:5333-5343.
- Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958-967.
- US Food and Drug Administration. Information for Healthcare Professionals: Gefitinib (marketed as Iressa). www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafe tyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfes sionals/ucm085197.htm. Accessed April 8, 2015.
- Tarceva [package insert]. South San Francisco, CA: Genentech USA, Inc; 2014.
- Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.
- Landi L, Tiseo M, Chiari R, et al. Activity of the EGFR-HER2 dual inhibitor afatinib in EGFR-mutant lung cancer patients with acquired resistance to reversible EGFR tyrosine kinase inhibitors. Clin Lung Cancer. 2014;15:411-417.
- Gridelli C, Peters S, Sgambato A, et al. ALK inhibitors in the treatment of advanced NSCLC. Cancer Treat Rev. 2014;40:300-306.
- Casaluce F, Sgambato A, Maione P, et al. ALK inhibitors: a new targeted therapy in the treatment of advanced NSCLC. Target Oncol. 2013;8:55-67.
- Xalkori [package insert]. New York, NY: Pfizer Labs; 2015.
- Zykadia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
- Avastin [package insert]. South San Francisco, CA: Genentech, Inc; 2014.
- Cyramza [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.
- Zielinski C, Knapp S, Mascaux C, et al. Rationale for targeting the immune system through checkpoint molecule blockade in the treatment of non-small-cell lung cancer. Ann Oncol. 2013;24:1170-1179.
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