The development of novel therapies has improved the care for patients with non-small cell lung cancer (NSCLC). The identification of activating epidermal growth factor receptor (EGFR) mutation (defined as an exon 19 deletion or an exon 21 L858R point mutation), and development of EGFR tyrosine kinase inhibitors (TKIs) and the identification of anaplastic lymphoma kinase (ALK) rearrangements and development of ALK inhibitors has dramatically changed the treatment paradigm for patients with advanced NSCLC.
Unfortunately, progress for patients with NSCLC without these specific molecular alterations and for those with SCLC has been slower. Several important clinical trials were published in peer-reviewed journals in 2014 that will impact clinical research and care over the next several years.
Erlotinib, gefitinib, and afatinib are first-line therapies for patients with a known EGFR mutation, and the progression-free survival (PFS) observed with these therapies is approximately 10 to 13 months. There is a clinical need to improve first-line therapy. A randomized phase II trial investigated erlotinib alone and with bevacizumab in patients with an activating EGFR mutation.1 The primary endpoint was PFS by independent radiological review (IRR).
Patients assigned to erlotinib and bevacizumab compared with erlotinib alone experienced a statistically significant improvement in PFS (hazard ratio [HR] of 0.54, p=0.0015; median of 16.0 months and 9.7 months, respectively). The most common grade ≥ 3 adverse events in the erlotinib and bevacizumab and erlotinib arms were rash (25% vs. 19%), hypertension (60% vs. 10%), and proteinuria (8% vs. 0%).
The optimal treatment for patients with EGFR-mutant NSCLC who have progressed on EGFR TKI is an area of active investigation. A single-arm phase Ib trial investigated the activity of afatinib and cetuximab in patients who had progressed after erlotinib or gefitinib.2
In the intent-to-treat (ITT) patient population, the objective response rate (ORR) was 29 percent, and the median progression-free survival was 4.7 months. The ORR observed in patients with T790M-positive and -negative NSCLC were 32 and 25 percent, respectively (p=0.341).
The most common grade 3 toxicities observed were rash (20%) and diarrhea (6%), and grade 4 toxicities observed were fatigue, pneumonitis, and lung infiltration, which occurred in two patients.
Crizotinib is approved by the Food and Drug Administration for patients with advanced NSCLC with an ALK rearrangement without regard to line of therapy. Phase III data demonstrating the superiority of crizotinib compared with second-line chemotherapy was available, but phase III data demonstrating the superiority of crizotinib compared with platinum-based chemotherapy was not available until 2014.3 Patients with ALK rearranged NSCLC were randomized to crizotinib or platinum-pemetrexed, and the primary endpoint was PFS by IRR.
Patients assigned to crizotinib compared with chemotherapy experienced a statistically significant longer PFS (HR of 0.45; 95% CI, 0.35 to 0.60; p=0.001; median PFS of 10.9 and 7.0 months, respectively) and higher ORR (74% vs. 45%, p<0.001). Patients assigned to crizotinib experienced a greater reduction in lung cancer symptoms and greater improvement in quality of life. This trial supports the already common practice of using crizotinib in the first-line setting.
Until recently patients who progressed on crizotinib did not have an ALK-directed therapy, but ceritinib, a more potent ALK inhibitor, was approved by the FDA for patients who have progressed on or are intolerant to crizotinib based on a phase I trial with an expansion cohort.4 The maximum tolerated dose was 750 mg daily, and the dose-limiting toxicities (DLTs) observed were diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia.
Among the 114 patients who received ceritinib 400 mg daily, the ORR was 58 percent (95% CI, 48 to 67), and the median PFS was 7.0 months (95% CI, 5.6 to 9.5). Among patients who had or had not previously received crizotinib, the ORR was 56 and 62 percent, respectively, and the PFS was 6.9 and 10.4 months, respectively.
At the 750 mg dose level, 62 percent required at least one dose reduction, and a significant proportion of patients required this dose reduction after the third cycle.
Alecitinib was investigated in a phase I/II trial in patients with ALK-rearranged NSCLC who had progressed on or were intolerant of crizotinib. The recommended dose for phase II trials was 600 mg twice a day, and the DLTs were grade 3 neutropenia and headache. The most common grade 3 or 4 adverse events were adverse liver function tests, neutropenia, and hypophosphatemia. The ORR as assessed by the investigator was 55 percent, and objective responses were seen for central nervous system metastases.
ROS1 rearrangements occur in approximately one percent of patients with NSCLC, and ROS1-rearranged NSCLC represents a unique subset of NSCLC. Crizotinib is an inhibitor of the ROS1 tyrosine kinase. Fifty patients tested positive for ROS1 and the majority of patients on the trial had the ROS1 rearrangement detected using a break-apart fluorescence in situ hybridization (FISH) test. Patients were enrolled in an expansion cohort of a crizotinib phase I trial. The ORR observed was 72 percent (95% CI, 58 to 84), and the median PFS was 19.2 months (95% CI, 14.4 to not reach).5 No unexpected toxicities were observed.
This study demonstrates the value of testing for ROS1 rearrangements and crizotinib as a therapeutic agent.
A multivariate serum protein test (Veristrat®) can classify patients based on treatment outcome with EGFR TKI; patients are categorized as “poor” or “good.” A phase III trial prospectively tested second-line patients in a blinded manner, and patients were stratified based on test classification and randomized to erlotinib or second-line chemotherapy (pemetrexed or docetaxel).6 The primary endpoint was OS, and the primary hypothesis was the existence of interaction between protein test classification and treatment.
The OS was not significantly different in the two treatment arms in the ITT patient population, and a statistically significant interaction between proteomic classification and treatment was observed (p=0.031).
Patients with proteomic classification of poor assigned to erlotinib compared with chemotherapy experienced a worse OS (HR of 1.72, 95% CI, 1.08 to 2.64; p=0.022; median of 3.0 and 6.4 months, respectively). Patients with proteomic classification of good assigned to erlotinib compared with chemotherapy experienced a similar OS (HR of 1.06, 95% CI, 0.77 to 1.46; p=0.714; median 10.9 and 11.0 months, respectively).
This test should be used in the second-line setting in EGFR wild-type patients, and patients with a proteomic status of poor should not receive second-line erlotinib.
One challenge in performing molecular profiling of NSCLC is the need for sufficient tumor tissue, and patients may undergo repeat biopsy to determine EGFR mutation and ALK rearrangement status at time of diagnosis or at the time of disease progression to detect resistance mutations (e.g., EGFR exon 20 T790M).
There has been increased interested in developing “liquid” biopsies using peripheral blood samples.7,8 The optimal technique for liquid biopsies and clinical situation is yet to be determined. There is also increased use of immunohistochemistry (IHC) for the detection of ALK rearrangements as an alternative to FISH testing.9
These techniques of assessing the molecular characteristics of NSCLC may become widely available in the near future.
EGFR Mutation and ALK Rearrangement-negative NSCLC
A phase III trial compared docetaxel with ramucirumab, a monoclonal antibody against vascular endothelial growth factor receptor 2, or placebo in patients who had progressed after first-line platinum-based therapy.10 Patients were not restricted based on histology, and the primary endpoint was OS. Patients assigned to the ramucirumab compared with placebo arm experienced a statistically significant longer OS (HR of 0.86, 95% CI, 0.75 to 0.98; p=0.023; median 10.5 and 9.9 months, respectively), PFS (HR of 076, 95% CI, 0.68 to 0.86; p< 0.0001; median 4.5 and 3.0 months, respectively) and ORR (23% vs. 14%, P<0.0001).
Common grade ≥ 3 adverse events in the ramucirumab and placebo arms were neutropenia (49% vs. 40%), febrile neutropenia (16% vs. 10%), fatigue (14% vs. 10%), and hypertension (6% vs. 2%). The rate of grade 3 pulmonary hemorrhage was similar (1% in both arms). The global quality-of-life analysis showed that the time to deterioration did not differ between the treatment arms.
Approximately a quarter of patients enrolled had squamous histology and the rates of gastrointestinal tract bleeding and pulmonary hemorrhage did not differ according to histology.
A phase III trial compared docetaxel with nintedanib or placebo in patients who had experienced disease progression after first-line platinum-based therapy. The primary endpoint was PFS by IRR, and OS was a secondary endpoint.11
Patients assigned to the nintedanib compared with placebo arm experienced a statistically significant longer PFS (HR of 0.79, 95% CI, 0.68-.02; p=0.0019; median 3.4 and 2.7 months, respectively), and similar OS (HR of 0.94, 95% CI, 0.83 to 1.05; p=0.272; median 10.1 and 9.1 months, respectively). A statistically significant longer OS was observed in patients with adenocarcinoma histology (HR of 0.83; 95% CI, 0.70 to 0.99; p=0.0359; median 12.6 and 10.3 months, respectively).
The future development of nintedanib will be in patients with adenocarcinoma histology.
Ramucirumab or nintedanib are currently not approved by the FDA, a biomarker to select patients likely to benefit is not available for either agent, and the OS benefit observed is modest.
Small Cell Lung Cancer
First-line therapy for extensive-stage SCLC is platinum-etoposide and prophylactic cranial irradiation, but patients frequently have persistent intra-thoracic disease or experience intra-thoracic disease progression.
A phase III trial investigated the role of thoracic radiation therapy (TRT) of 30 Gy in 10 fractions) compared with no TRT.12 Patients were required to have responded to chemotherapy and have a performance status of 0 to 2. The primary endpoint was the one-year OS rate. The one-year OS rate was not significantly different between the TRT and no-TRT groups (HR for OS of 0.84, 95% CI, 0.69 to 1.01; p=0.066 and 1-year OS rate of 33% and 28%, respectively).
A secondary analysis revealed an improvement in the two-year OS rate in TRT compared with the no-TRT group (13% vs. 3%, p=0.004). The most common grade 3 adverse events in TRT were fatigue 4.5%, esophagitis (1.6%), dyspnea (1.2%), insomnia (1.2%), and headache (1.2%). This trial suggests that the benefit of consolidation TRT after first-line therapy is limited.
Looking Ahead to 2015
While it is difficult to anticipate the future developments for lung cancer, especially given the increasing pace or target identification and drug development, additional data on several novel agents are highly anticipated in 2015. Preliminary data demonstrating the activity of “third generation” EGFR TKI in patients who had progressed on EGFR TKI and had an exon T790M resistance mutation were presented in 2014. These agents spare the EGFR wild-type receptor and have a low rate of typical EGFR-associated toxicities of rash and diarrhea.
Several checkpoint inhibitors targeting the PD-1/PD-L1 interaction have revealed promising results in heavily treated patients with NSCLC. Several checkpoint inhibitors are being studied in different disease settings, and these agents may have a role in a broad population of patients with NSCLC.
These two classes of agents have the potential to immediately impact the care of patients with advanced NSCLC.
1. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. Oct 2014;15(11):1236–1244.
2. Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer discovery. Sep 2014;4(9):1036–1045.
3. Solomon BJ, Mok T, Kim DW, et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med. Dec 4 2014;371(23):2167–2177.
4. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. Mar 27 2014;370(13):1189–1197.
5. Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. Nov 20 2014;371(21):1963–1971.
6. Gregorc V, Novello S, Lazzari C, et al. Predictive value of a proteomic signature in patients with non-small-cell lung cancer treated with second-line erlotinib or chemotherapy (PROSE): a biomarker-stratified, randomised phase 3 trial. Lancet Oncol. Jun 2014;15(7):713–721.
7. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. May 2014;20(5):548–554.
8. Oxnard GR, Paweletz CP, Kuang Y, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res. Mar 15 2014;20(6):1698–1705.
9. Wynes MW, Sholl LM, Dietel M, et al. An international interpretation study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators. J Thorac Oncol. May 2014;9(5):631–638.
10. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. Aug 23 2014;384(9944):665–673.
11. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. Feb 2014;15(2):143–155.
© 2015 by Lippincott Williams & Wilkins, Inc.
12. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. Sep 14 2014.
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