Suresh S. Ramalingam, MD, FASCO, highlights current and emerging therapies for 6 key actionable driver mutations in non–small cell lung cancer.
Suresh S. Ramalingam, MD, FASCO
Testing for driver mutations is essential before initiating therapy in patients with non—small cell lung cancer (NSCLC), because there is a risk that the type of upfront treatment chosen may add to toxicity and spur resistance to targeted therapy options, Suresh S. Ramalingam, MD, FASCO, said at the 14th Annual New York Lung Cancers Symposium®.1
“Once you go in the wrong direction, there can be significant costs,” said Ramalingam, the Roberto C. Goizueta Chair for Cancer Research, professor, Department of Hematology and Medical Oncology, and deputy director of the Winship Cancer Institute of Emory University.
In his presentation, Ramalingam highlighted current and emerging therapies for 6 key actionable driver mutations in NSCLC: EGFR (exon 19/21), ALK, BRAF V600E, ROS1, RET, and NTRK.
“If you have to start treatment and you don’t have time to wait [for next-generation sequencing (NGS) results], then I would suggest starting patients on a chemotherapy doublet alone,” explained Ramalingam. “By the time the results come back, if you have to shift gears and switch them to targeted therapy after [immunotherapy] exposure has already happened, there is a high incidence of regression no matter which targeted agent you’re considering—some more than others.” Starting off with a less-than-ideal therapy can also complicate the toxicity picture, he added.
For patients with actionable mutations, targeted therapy is the preferred frontline treatment “regardless of PD-L1 expression levels,” said Ramalingam.
In patients with EGFR-mutated NSCLC, osimertinib (Tagrisso) has shown potency in comparison with earlier-generation EGFR TKIs, Ramalingam noted. The phase III FLAURA trial randomized 556 patients with previously untreated EGFR mutation—positive (exon 19 del or L858R) advanced NSCLC to receive either osimertinib or standard EGFR TKI therapy with gefitinib (Iressa) or erlotinib (Tarceva). In the primary analysis, median progression-free survival (PFS), the primary end point, was 18.9 months for osimertinib versus 10.2 months for standard EGFR TKIs (HR, 0.46; 95% CI, 0.37-0.57; P <.001).2
The trial was not powered for overall survival (OS), but Ramalingam noted that a nearly 7-month advantage in OS was seen with osimertinib. The median OS was 38.6 months for the osimertinib group versus 31.8 months for the comparator EGFR TKI group.1,3 Because crossover was allowed, “The control group had one of the highest OS [rates] we have seen for the EGFR first-line setting, and despite this, we’ve seen an overall improvement in survival with osimertinib,” Ramalingam said.
Osimertinib is the preferred first-line treatment for EGFR-positive NSCLC, according to the National Comprehensive Cancer Network guidelines.
Also in this setting, dacomitinib (Vizimpro) outperformed gefitinib with regard to median PFS benefit (14.7 months vs 9.2 months; HR, 0.59; 95% CI, 0.47-0.74; P <.0001) for the first-line treatment of patients with advanced EGFR-positive NSCLC, according to data from the phase III ARCHER 1050 trial.4 Data presented at the 2018 ASCO Annual Meeting demonstrated that at a median follow-up of 31.3 months, the median OS with dacomitinib was 34.1 months versus 26.8 months with gefitinib.5
Looking ahead to potential therapeutic advances in this setting, Ramalingam noted that various trials are evaluating EGFR TKIs in combination with angiogenesis inhibitors. One such trial is EA5182 (NCT02803203), which is comparing osimertinib with osimertinib plus bevacizumab (Avastin) in untreated patients with metastatic EGFR-positive NSCLC. Furthermore, studies of chemotherapy plus gefitinib have shown wide margins of improvement in median PFS and OS, Ramalingam added.
For example, in the phase III NEJ009 study, the median PFS for gefitinib versus chemotherapy plus gefitinib in advanced NSCLC with EGFR mutations was 11.2 months versus 20.9 months, and the median OS was 38.8 months versus 52.2 months, respectively.6
The second-generation ALK inhibitor alectinib (Alecensa) has become the preferred drug in the ALK-positive space and shows good tolerability, Ramalingam said. In the phase III ALEX trial, the median PFS was 11.1 months for crizotinib versus not yet reached for alectinib (HR, 0.47; 95% CI, 0.34-0.65; P <.001), and the number of adverse events was 102 (68%) versus 62 (41%), respectively.1,7
Brigatinib has also shown strong activity in this space, particularly in patients who have received prior chemotherapy. In the phase III ALTA-1L trial, brigatinib was associated with a 51% lower risk of disease progression or death than crizotinib (HR, 0.49; P <.001) in patients with prior chemotherapy in the locally advanced or metastatic setting. For patients who did not receive chemotherapy, median PFS was not reached for brigatinib versus 9.8 months for crizotinib.1,8
ROS1-positive NSCLC accounts for up to 2% of patients with actionable mutations in NSCLC, Ramalingam said. Crizotinib, 1 of 2 FDA-approved agents in this space, has demonstrated strong antitumor activity in patients with advanced ROS1-positive NSCLC. According to findings reported in 2014, the objective response rate (ORR) was 72% (95% CI, 58-84) and the median PFS was 19.2 months (95% CI, 14.4-not reached). Notably, 44% of patients in the study had received 2 or more prior lines of therapy.9 “These results were impressive, and they have driven practice for a very long time,” Ramalingam said.
More recently, entrectinib (Rozlytrek) received FDA approval for adult and pediatric patients ≥12 years of age with solid tumors that harbor ROS1 alterations or NTRK fusions. The decision was based on findings from an integrated analysis of the phase II STARTRK-2, phase I STARTRK-1, and the phase I ALKA-372-001 trials, which showed a clinical benefit rate of 77.4% (95% CI, 63.8-87.7) in patients with ROS1 fusion—positive NSCLC. Patients responded whether or not they had central nervous system (CNS) disease, Ramalingam noted. For those with CNS disease at baseline (n = 23) versus those without CNS disease (n = 30), the ORR was 73.9% (95% CI, 51.6-89.8) versus 80.0% (95% CI, 61.4-92.3), respectively.1,10
Oncologists should keep in mind that “not all BRAF-mutations are the same,” Ramalingam stressed. BRAF V600E mutations account for approximately 41% of mutations in this class but patients whose tumors harbor non-V600E mutations are not likely to respond to BRAF inhibitors, he noted. For patients with BRAF V600E mutated NSCLC, dabrafenib (Tafinlar) in combination with trametinib (Mekinist) has shown to be an effective regimen. Data from an open-label, phase II trial showed that treatment with the combination led to a response rate of 63.2% (95% CI, 49.3-75.6), a median PFS of 14 months, and a median OS of 24 months.1,11
RET- and NTRK-Positive NSCLC
Two key agents in development for treatment of patients with RET-positive NSCLC include selpercatinib (LOXO-292), which has achieved an ORR of 77% (95% CI, 58%-90%);12 and BLU-667, which induced an ORR of 50%.1,13 Both agents have received breakthrough designations from the FDA.
“They have very good tolerability…and we hope to have them available for our patients in the very near future,” Ramalingam said.
For patients with NTRK fusion—positive cancers, the TRK inhibitors larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) have both shown promise, added Ramalingam. For example, larotrectinib was found to induce an ORR of 80%, according to pooled trial results presented at the 2018 ESMO Congress.14 Furthermore, entrectinib was found to induce an ORR of 57% (95% CI, 43-71) in efficacy-evaluable patients with NTRK fusion—positive disease.15