The Food and Drug Administration approved several new treatments for patients with non-small cell lung cancer (NSCLC) in 2015, which made it an exciting year for lung cancer patients and doctors. The most significant advance was the validation of immunotherapy as second-line therapy for NSCLC, which will help a large number of patients.
Nivolumab was investigated in two Phase III trials in patients with squamous and non-squamous histology. The Phase III trial in patients with squamous NSCLC enrolled patients who had experienced disease progression after platinum-based therapy. Patients assigned to the nivolumab arm compared with the docetaxel arm experienced a statistically significant higher objective response rate (ORR) (20% vs. 9%), longer progression-free survival (PFS), and longer overall survival (OS) (Hazard ratio (HR) of 0.59, p<0.001; median OS of 9.2 and 6.0 months, respectively).1
The Phase III trial in non-squamous histology enrolled patients who had experienced disease progression after platinum-based therapy and patients with an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement with disease progression after the appropriate tyrosine kinase inhibitor (TKI). Patients assigned to nivolumab compared with docetaxel experienced a statistically significant higher ORR (19% vs 12%) and longer OS (HR of 0.73, p=0.002; median OS of 12.2 and 9.4, respectively).2
The role of PD-L1 expression for selection of patients for nivolumab is unclear, and PD-L1 testing is not required for nivolumab use.
Pembrolizumab was investigated in a Phase I trial with expansion cohorts in NSCLC, and PD-L1 biomarker development and validation were incorporated in the trial design.3 NSCLC tumors were divided into three categories based on PD-L1 tumor expression (≥ 50%, 1-49%, and <1%) using the Dako 22C3 monoclonal antibody testing.
Approximately 25 percent of tumor samples had PD-L1 tumor expression of 50 percent or more. The ORR, the median PFS, and the median OS observed in patients with PD-L1 tumor expression of 50 percent or more was 45 percent, 6.3 months, and not reached (95% CI, 13.7 to not reached).
Based on this trial the FDA approved pembrolizumab for patients who had progressed on a platinum-based therapy and for patients with an EGFR mutation or ALK rearrangement with disease progression after the appropriate TKI with PD-L1 tumor expression of at least 50 percent.
A Phase III trial compared pembrolizumab 2 mg/kg and 10 mg/kg with docetaxel in patients with disease progression after platinum-doublet chemotherapy or with EGFR-mutant or ALK-rearranged NSCLC with disease progression after the appropriate TKI and with PD-L1 tumor expression of one percent or more.4 The primary endpoints were OS and PFS in the total study population and in patients with PD-L1 expression of at least 50 percent.
Of the tumor samples evaluated, 66 percent had PDL1 tumor expression of at least one percent, and 28 percent had 50 percent or more. In the total study population the OS was significantly longer in patients assigned to pembrolizumab 2 mg/kg compared with docetaxel (HR of 0.71, p=0.0008) and for pembrolizumab 10 mg/kg compared with docetaxel (HR=0.61, p<0.0001).
The median OS in the pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, and docetaxel arms were 10.4, 12.7, and 8.5 months, respectively. Pembrolizumab 2 mg/kg and pembrolizumab 10 mg/kg when compared with docetaxel did not meet the prespecified criterion for a statistically significant difference in PFS.
A statistically significant higher ORR was observed with pembrolizumab 2 mg/kg compared with docetaxel and 10 mg/kg compared with docetaxel (18% in both pembrolizumab arms vs. 9% in the docetaxel arm).
In the analysis of patients with PD-L1 tumor expression of 50 percent or more, a statistically significant higher ORR, longer PFS, and longer OS was observed with pembrolizumab 2 mg/kg compared with docetaxel and pembrolizumab 10 mg/kg compared with docetaxel. The benefit of pembrolizumab was more pronounced in this subset.
Patients with an activating EGFR mutation receive first-line therapy with an EGFR TKI, and generally experience an ORR of approximately 70 to 80 percent and a median PFS of 10 to 12 months. Approximately 50 to 60 percent of patients will have an EGFR exon 20 T790M mutation as the primary mechanism of resistance.
Osimeritinib (AZD9291) is a third-generation EGFR TKI that has activity against the activating EGFR mutation, the T790M resistance mutation, and relative sparing of the EGFR wild-type receptor on normal tissues.
A Phase I trial with expansion cohorts revealed that in patients with EGFR-mutant NSCLC with a confirmed T790M mutation the ORR was 61 percent and the median PFS was 9.6 months.5
At the 80 mg dose level the most common grade 3 adverse events were diarrhea (1%), decreased appetite (1%), anemia (3%), and dyspnea (1%). QT prolongation and pneumonitis-like events occurred in 11 patients and six patients in the study population, respectively.
Historically patients have undergone repeat tumor biopsy for detection of the T790M mutation, but there is interest in using peripheral blood sample testing for detection of the T790M mutation. However, there are concerns about the sensitivity for detection of the T790M mutation, and it is unknown if the activity of osimertinib is similar in patients with T790M mutation detected on tumor biopsy and peripheral blood testing.
There are now three EGFR TKIs approved for use as first-line therapy in patients with EGFR-mutant NSCLC with the recent FDA approval of gefitinib. Most physicians select an EGFR TKI based on personal preference and experience, whether the EGFR mutation is an exon 19 of 21 L858R mutation, the rate of adverse events, and patient preference.
A randomized trial compared afatinib 40 mg daily with gefitinib 250 mg daily in patients with EGFR-mutant NSCLC defined as exon 19 and 21 L858R mutations (n=319).6
Patients assigned to afatinib compared with gefitinib experienced a statistically significant higher ORR (70% vs. 56%, p=0.0083), longer PFS by independent radiologically review (HR of 0.73, p=0.0165; median 11.0 and 10.9 months), and longer time to treatment failure (HR of 0.73, p=0.0073; median 13.7 and 11.5 months).
The median values for PFS are similar, but the Kaplan Meier curve for PFS demonstrates the benefit of afatinib. The benefit was similar in patients with EGFR exon 19 and exon 21 L858R mutations. The rates of grade 3 or higher diarrhea, rash, stomatitis, and paronychia were 12, 9, 4, and 2 percent, respectively; 42 percent of patients in the afatinib arm had an adverse event leading to dose reduction. This trial challenges the common perception that all EGFR TKIs have similar efficacy.
Alectinib, a second-generation ALK inhibitor, was investigated in patients who had previously received crizotinib.7 The ORR and median PFS by independent radiological review were 50 percent and 8.9 months, respectively. Many patients who receive first-line crizotinib have disease progression in the central nervous system (CNS). The CNS ORR and disease control rate observed with alectinib in patients with brain metastases were 57 and 83 percent, respectively.
The most common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%). The rate of grade 3 or higher adverse events was low (all ≤3%); 21 percent of patients required a dose reduction and/or interruption mainly due to laboratory abnormalities. Alectinib's activity after crizotinib, for patients with CNS disease, and favorable toxicity profile make it a valuable new therapy.
As we look ahead to 2016, numerous trials of immunotherapy in NSCLC are ongoing, and current investigations into biomarkers predictive of benefit will be crucial for further development of these therapies.
New therapies for our patients with NSCLC with EGFR mutations and ALK rearrangements may become available in 2016, which will continue the progress in these molecularly defined patient populations.
Several trials investigating immunotherapy and novel agents in small cell lung cancer are ongoing, and will be watched closely given the limited progress of systemic therapy for this disease.
1. 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; 373:123–135.
2. 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; 373:1627–1639.
3. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372:2018–2028.
4. Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. The Lancet [epub available ahead of print]
5. Janne PA, Ramalingam SS, Yang JC-H, et al. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2014;32(suppl; abstr 8009)
6. Park K, Tan E-H, Zhang L, et al.Afatinib (A) vs gefitinib (G) as first-line treatment for patients (pts) with advanced non-smallcell lung cancer (NSCLC) harboring activating EGFR mutations: results of the global, randomized, open-label, Phase IIb trial LUX-Lung 7 Presented at: ESMO Asia 2015 Congress, 2015
7. Ou SI, Ahn JS, De Petris L, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol [epub available ahead of print].