The recent World Conference on Lung Cancer (WCLC), held in Sydney, Australia, had the theme of "Next-Generation Lung Cancer Care," reflecting, as the organizers said, "the need for collaboration and cooperation in producing the best possible outcomes in the treatment of lung cancer." The presentations are available online: http://wclc.iaslc.org.
This brief review focuses on a few select presentations covering immunotherapy with checkpoint inhibitors, epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors, and thoracic radiation.
Immunotherapy with Checkpoint Blockade
Immunotherapy with checkpoint blockade has attracted considerable attention over the past few years. Updated results of the Phase I study using nivolumab (anti-PD-1) in patients with non-small cell lung cancer (NSCLC) were presented at this meeting.
The fully human IgG4 PD-1 immune checkpoint inhibitor antibody nivolumab restores anti-tumor T cell activity by preventing interaction with its ligands PD-L1 and PD-L2. In this study, the overall response rate in 129 patients treated at three different dose levels was 17 percent, with an estimated median duration of response of 74 weeks. The median overall survival was 9.9 months in this heavily pre-treated population.
More importantly, durable responses were observed, with responses ongoing in nearly half of responders. Nearly 50 percent of responders demonstrated benefit within eight weeks of starting therapy. Of the seven responders who discontinued therapy for reasons other than disease progression, six continue to have no evidence of disease progression despite not receiving therapy.
This phenomenon of durable response even in patients who discontinue checkpoint blockade is being observed repeatedly with other agents that inhibit PD-1 or PD-L1. Nivolumab is associated with immune-related side effects affecting the skin, gastrointestinal tract, lung, liver, and kidneys, but all appear to be mostly manageable.
Randomized controlled trials are now under way to define the role of niovlumab in patients with NSCLC.
Activating Mutations in the EGFR Receptor
Activating mutations in the EGFR are typically associated with dramatic and at times durable response to EGFR TK inhibitors such as gefitinib, erlotinib, and afatinib. Exon 19 deletions and L858R mutations are the two most common EGFR mutations known to be sensitive to EGFR TK inhibitors in patients with metastatic non-small-cell lung cancer (NSCLC).
With the advent of next-generation sequencing, several uncommon mutations in the EGFR TK domain are being reported. It is unclear whether EGFR TK inhibitors are active in patients with "uncommon" EGFR TK mutations. At the meeting, Ping Yang and colleagues presented data from three trials regarding the efficacy of afatinib in this group of patients. Seventy-five patients from three prospective studies (LUX-Lung 2, 23 patients; LUX-Lung 3, 26 patients; and LUX-Lung 6, 26 patients) who had uncommon EGFR mutations received afatinib either as frontline therapy (62 patients) or after chemotherapy (13 patients).
Patients were divided into three subgroups (a) T790M group, 14 patients; Exon 20 insertions (23 patients); and the larger "other" group that included various mutations including L861Q, G719X, G719X+S768I, and G719X+L861Q (38 patients). The response rates (71%) and median duration of response (11.1 months with 95% CI 1.3-35+ months) with afatinib in the "other" group is similar to what has been reported historically with EGFR TK inhibitors in patients with exon 19 deletion and L858R.
The response rate was low in patients with de novo EGFR T790M mutations and exon 20 insertions, though some patients have had durable responses even lasting up to 13.8 months. Afatinib was recently approved for use in the treatment of EGFR-mutant NSCLC in the United States. Hopefully, we will learn a lot more about specific mutations and responses to targeted therapies through prospective clinical trials and registries (http://mycancergenome.org).
Despite having impressive responses, though, most patients with EGFR TK mutation eventually die from relapsed NSCLC. A common mechanism of resistance is the emergence of the T790M mutation. There are no effective therapies for patients with acquired resistance to EGFR TK inhibitors including those with EGFR T790M NSCLC.
At the meeting, Jean Charles Soria and colleagues reported the results of an ongoing first-in-human dose-finding study of CO-1686 in patients with EGFR-mutant NSCLC who have had progressive disease following EGFR TK inhibitors.
CO-1686 is a novel and selective inhibitor of cells harboring key EGFR-activating and T790M-resistance mutant cells. At the time of presentation, 56 patients (93% of whom had either exon 19 deletion or L858R) had been enrolled, receiving a dose of 150 mg once a day to 900 mg twice daily. Among these 56 patients, 39 tumors (70%) were positive for T790M and 12 were negative (21%). The investigators reported a response rate of 67 percent in evaluable T790M-mutant patients treated at 900 mg bid.
The majority of these patients had progressed on EGFR TKI immediately preceding treatment with CO-1686, suggesting clinical benefit perhaps from directly inhibiting the growth of T790M mutant cells. In keeping with the selectivity of this compound for EGFR mutants, skin rash was not seen in this study. Adverse events attributed to the study drug included nausea, vomiting, fatigue, diarrhea, and decreased appetite.
Studies are ongoing with an improved oral formulation. These results, though preliminary, are indeed very promising.
AZD9291 is an irreversible, potent, and selective TK inhibitor of activating and resistance (T790M) mutations in patients with advanced NSCLC. Promising response rates were reported from an ongoing Phase I study. Of 35 patients with EGFR-mutant NSCLC, 15 had a partial response and nine of 18 patients with EGFR T790M NSCLC had a partial response.
Although these results have to be confirmed, these two compounds show considerable promise in the treatment of patients with EGFR T790M NSCLC.
Several retrospective studies and some Phase I and II studies had reported promising results with 74 Gy of thoracic radiation in patients with locally advanced NSCLC. Results of the Radiation Therapy Oncology Group (RTOG) 0324 trial showed a two-year survival rate of 49 percent in patients with stage III NSCLC with the addition of cetuximab to chemoradiation in patients with locally advanced NSCLC.
RTOG 0617 is an intergroup Phase III study comparing standard dose (60 Gy) with high-dose (74 Gy) chemoradiotherapy with or without cetuximab in patients with stage III NSCLC. This study randomized patients in a 2x2 factorial design. Patients received paclitaxel and carboplatin chemotherapy regimen.
When a planned interim analysis revealed no benefit with high-dose radiation, enrollment was discontinued. The presentation at the conference focused on the efficacy of cetuximab in this setting, since the results with regard to high-dose versus standard-dose radiation were presented at the most recent ASCO Annual Meeting. Of 465 patients evaluated, 237 received cetuximab.
There was no difference in overall survival (primary objective) or progression-free survival. The 18-month overall survival rates were 67.1 percent (95% CI: 56.8-75.5) and 67.9 percent (95% CI: 57.6-76.2), respectively, in the standard-dose arm with or without cetuximab. The 18-month overall survival rates were 58 percent (95% CI: 47.6-67.1) and 52.3 percent (95% CI: 41.5-62.0), respectively, in the high-dose arm with or without cetuximab.
The addition of cetuximab to chemoradiation increased overall grade 3-5 toxicities. There was a suggestion that cetuximab may have a more beneficial effect in patients with high EGFR expression than in patients with low EGFR expression. However, this issue needs to be studied more carefully. Currently there is no role for cetuximab or high-dose (74 Gy) radiation in patients with locally advanced NSCLC.
In summary, I am very optimistic that outcomes for patients with lung cancer will continue to improve in the coming years, perhaps more dramatically for some. There is considerable promise that immune checkpoint inhibitors and EGFR inhibitors targeting specifically T790M will alter the clinical practice in the very near future.
Our understanding of the altered genomic landscape of lung cancer continues to evolve. The new genre of large early-phase studies targeting specific molecular subsets is quite promising.