Genetic Testing is Essential in NSCLC Prior to Induction Therapy

Suresh S. Ramalingam, MD, FASCO

Suresh S. Ramalingam, MD

Because of the risk associated with the type of upfront treatment selected for patients with non—small cell lung cancer (NSCLC), testing for driver mutations is essential before beginning frontline therapy. Treatments could add to the toxicity of targeted therapies, as well as spark resistance to these therapeutic options, according to Suresh S. Ramalingam, MD, at the14th AnnualNew 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,BRAFV600E,ROS1,RET, andNTRK.

“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.

EGFR-Mutated NSCLC

In patients withEGFR-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 untreatedEGFRmutation—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 comparatorEGFRTKI group.^1,3Because crossover was allowed, &ldquo;The control group had one of the highest OS [rates] we have seen for the EGFR first-line setting, and despite this, we&rsquo;ve seen an overall improvement in survival with osimertinib,&rdquo; Ramalingam said.

Osimertinib is the preferred first-line treatment forEGFR-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 advancedEGFR-positive NSCLC, according to data from the phase III ARCHER 1050 trial.⁴Data 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 metastaticEGFR-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 withEGFRmutations was 11.2 months versus 20.9 months, and the median OS was 38.8 months versus 52.2 months, respectively.⁶

ALK-Positive NSCLC

The second-generation ALK inhibitor alectinib (Alecensa) has become the preferred drug in theALK-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

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 advancedROS1-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&ldquo;These results were impressive, and they have driven practice for a very long time,&rdquo; Ramalingam said.

More recently, entrectinib (Rozlytrek) received FDA approval for adult and pediatric patients &ge;12 years of age with solid tumors that harborROS1alterations orNTRKfusions. 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 withROS1fusion—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

BRAFMutations

Oncologists should keep in mind that &ldquo;not allBRAF-mutations are the same,&rdquo; Ramalingam stressed.BRAFV600E 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 withBRAFV600E 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- andNTRK-Positive NSCLC

Two key agents in development for treatment of patients withRET-positive NSCLC include selpercatinib (LOXO-292), which has achieved an ORR of 77% (95% CI, 58%-90%);¹²and BLU-667, which induced an ORR of 50%.^1,13Both agents have received breakthrough designations from the FDA.

&ldquo;They have very good tolerability&hellip;and we hope to have them available for our patients in the very near future,&rdquo; Ramalingam said.

For patients withNTRKfusion—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.¹⁴Furthermore, entrectinib was found to induce an ORR of 57% (95% CI, 43-71) in efficacy-evaluable patients withNTRKfusion—positive disease.¹⁵

References:

1. Ramalingam S. Choosing the best first-line therapy: oncogene-driven NSCLC. Presented at: 14th Annual New York Lung Cancers Symposium; November 9, 2019; New York, New York.
2. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.N Engl J Med. 2018;378(2):113-125. doi: 10.1056/NEJMoa1713137.
3. Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR—TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): final overall survival analysis.Ann Oncol. 2019;30(suppl 5):mdz394.076. doi: 10.1093/annonc/mdz394.076.
4. Mok T, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): a randomized, open-label phase III trial.J Clin Oncol. 2017;35(suppl 18, abstr LBA9007). doi: 10.1200/JCO.2017.35.18_suppl.LBA9007.
5. Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations.J Clin Oncol. 2018;36(22):2244-2250. doi: 10.1200/JCO.2018.78.7994.
6. Nakamura A, Inoue A, Morita S, et al. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009).J Clin Oncol. 2018;36(suppl 15, abstr 9005). doi: 10.1200/JCO.2018.36.15_suppl.9005.
7. Camidge DR, Peters S, Mok T, et al. Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC.J Clin Oncol. 2018;36(suppl 15, abstr 9043). doi: 10.1200/JCO.2018.36.15_suppl.9043.
8. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer.N Engl J Med. 2018;379(21):2027-2039. doi: 10.1056/NEJMoa1810171.
9. Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer.N Engl J Med. 2014;371(21):1963-1971. doi: 10.1056/NEJMoa1406766.
10. Barlesi F, Drilon A, De Braud F, et al. Entrectinib in locally advanced or metastatic ROS1 fusion-positive non—small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract 109O.
11. Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicenter phase 2 trial.Lancet Oncol. 2016;17(7):984-993. doi: 10.1016/S1470-2045(16)30146-2.
12. Drilon AE, Subbiah V, Oxnard GR, et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers.J Clin Oncol. 2018;36(suppl 15; abstr 102). doi: 10.1200/JCO.2018.36.15_suppl.102.
13. Subbiah V, Taylor M, Lin J, et al. Highly potent and selective RET inhibitor, BLU-667, achieves proof of concept in a phase I study of advanced, RET-altered solid tumors. Presented at: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. Abstract CT043.
14. Lassen UN, Albert CM, Kummar S, et al. Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach.Ann Oncol. 2018;29(suppl 8). doi: 10.1093/annonc/mdy279.397.
15. Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA17.