ASCO 2017 Report — Lung Cancer
ASCO 2017 Report — Lung Cancer
- Anne S. Tsao, MD
Highlights of new treatments for patients with non–small-cell lung cancer and malignant pleural mesothelioma
- Anne S. Tsao, MD
At this year's annual meeting of the American Society of Clinical Oncology (ASCO 2017), held June 3 to 7 in Chicago, investigators discussed the latest findings in cancer research. The editors of NEJM Journal Watch Oncology and Hematology were on hand to report highlights of the conference. Here, Associate Editor, Anne S. Tsao, MD, reviews key presentations on new treatments for patients with non–small-cell lung cancer (NSCLC) and malignant pleural mesothelioma. All meeting abstracts can be viewed in the ASCO meeting library.
Osimertinib for EGFR T790M-Mutated NSCLC
Osimertinib, an oral, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with central nervous system (CNS) penetrance, is currently FDA-approved for patients with EGFR T790M-mutated NSCLC. The prior AURA3 trial by Mok and colleagues (NEJM JW Oncol Hematol Feb 2017) showed superior efficacy of osimertinib versus platinum-pemetrexed in patients with EGFR T790M-mutated disease who had failed one prior EGFR TKI.
Now, these investigators have conducted a subgroup analysis of 46 patients in the AURA3 trial with CNS metastases (abstract 9005), of whom 30 received osimertinib and 16 received chemotherapy.
Compared with chemotherapy, osimertinib was associated with a higher CNS objective response rate (ORR; 70% vs. 31%; odds ratio, 5.13; P=0.015), longer median duration of response (8.9 vs. 5.7 months), and greater median best percentage change from baseline (−43% vs. −16%). The CNS median progression-free survival (PFS) was prolonged with osimertinib (11.7 vs. 5.6 months; P=0.004) and was seen in patients with baseline CNS metastases (8.5 vs. 4.2 months, hazard ratio, 0.32; P<0.001) and in those without baseline CNS metastases (10.8 vs. 5.6 months; HR, 0.40; P<0.001). In the 7 patients with baseline leptomeningeal metastases, 2 had a complete leptomeningeal response with osimertinib and 2 had partial response.
This study demonstrates that osimertinib has good CNS penetrance and superior CNS efficacy compared with chemotherapy in refractory EGFR-mutated NSCLC. The osimertinib CNS response was rapid (~6 weeks), was protective against cumulative CNS progression, and can be effective against leptomeningeal disease. It is anticipated that osimertinib will likely change the EGFR-mutation space once results of the front-line FLAURA trial are known, and it will likely become the preferred front-line regimen.
Dacomitinib vs. Gefitinib for Advanced EGFR-Mutated NSCLC
Mok and colleagues conducted the ARCHER 1050 trial (abstract LBA9007) to compare gefitinib with dacomitinib, a second-generation irreversible EGFR TKI in 452 treatment-naive NSCLC patients with EGFR-activating mutations. Patients were not allowed to have CNS metastases and were stratified by Asian ethnicity and type of EGFR mutation (exon 19 vs. exon 21 L858).
In the intent-to-treat population, dacomitinib versus gefitinib improved median PFS (14.7 vs. 9.2 months; HR, 0.59; P<0.0001). Whereas ORR was similar with dacomitinib or gefitinib (74.9% and 71.6%, respectively), the duration of response was significantly longer with dacomitinib (14.8 vs. 8.3 months; P<0.0001). Dacomitinib was associated with a higher rate of any grade diarrhea, paronychia, dermatitis acneiform, and stomatitis, whereas gefitinib was associated with a higher rate of any grade alanine aminotransferase increase. Dacomitinib was also associated with a higher rate of treatment-related serious adverse events (9.3% vs. 4.5%), higher discontinuation rate due to toxicity (9.7% vs. 6.7%), and more dose modifications (66.1% vs 8%).
Although this trial supports the use of dacomitinib in the first-line setting, it is anticipated that this landscape will soon change rapidly with use of osimertinib (see above summary), as it has CNS penetrance and also covers EGFR T790M. It therefore remains unclear whether dacomitinib will play a major role in the EGFR-mutation space.
Alectinib vs. Crizotinib for Advanced ALK-Positive NSCLC
The prior standard of care for ALK-positive NSCLC was to administer crizotinib, a first-generation ALK inhibitor that does not have significant CNS penetrance. Alectinib, a next-generation ALK inhibitor with CNS penetrance, is already FDA approved for use in crizotinib-refractory ALK-positive NSCLC patients. Now, Shaw and colleagues have conducted the ALEX study (abstract LBA9008) to compare first-line alectinib versus crizotinib in 303 treatment-naive patients with ALK-positive disease. Between 38% and 42% of patient had baseline brain metastases.
Median PFS was superior with alectinib versus crizotinib (not reached vs. 11.1 months; HR 0.47; P<0.0001), as were independent radiographic review median PFS (25.7 vs. 10.4 months; HR 0.5; P<0.0001), and time to CNS progression (HR, 0.16; P<0.0001). ORR was similar with alectinib and crizotinib (83% and 76%, respectively), but alectinib was associated with a longer duration of response (not reached vs. 11.1 months; HR, 0.36). The PFS subgroup analysis favored alectinib in all groups analyzed and appeared to yield a neuroprotective benefit in patients with no preexisting brain metastases. Patients with baseline CNS disease who received alectinib achieved a higher CNS response (81% vs. 50%) and longer median CNS duration of response (17.3 vs. 5.5 months). Alectinib was associated with less grade ≥3 toxicity (41% vs. 50%), a lower rate of dose reductions (16% vs. 21%), and fewer dose interruptions (18% vs. 25%).
The ALEX trial has reshaped the ALK-positive NSCLC front-line setting to now include alectinib as the preferred therapy. These positive PFS data are consistent with the J-ALEX study (Lancet 2017; 390:29) of alectinib conducted in Japan, albeit at a lower dose. Alectinib is now the preferred front-line option largely due to the high CNS penetrance and well-tolerated safety profile. It remains to be seen what the resistance mechanisms are to alectinib and whether other ALK inhibitors will be able to salvage alectinib-refractory patients. Of particular interest will be brigatinib and lorlatinib.
Adjuvant Gefitinib vs. Vinorelbine Plus Cisplatin for Stage II–IIIA EGFR-Mutated NSCLC
In the ADJUVANT trial (abstract 8500), Wu and colleagues randomized 220 stage II–IIIA (N1-N2) resectable NSCLC patients with an activating EGFR mutation (del exon 19 or exon 21 L858) to gefitinib versus cisplatin plus vinorelbine for 4 cycles.
Disease-free survival (DFS) was significantly longer with gefitinib than with cisplatin plus vinorelbine (28.7 vs. 18 months; HR, 0.6; P=0.005). Gefitinib was associated with higher rates of any grade rash, liver function test elevation, and diarrhea but markedly less grade ≥3 toxicity (12.3% vs. 48.3%). No cases of interstitial lung disease were observed in either arm. The quality-of-life analysis favored the gefitinib arm.
This trial provides compelling prospective data that adjuvant EGFR TKIs may provide clinical benefit versus chemotherapy for patients with resectable stage II–III EGFR-mutated NSCLC. However, overall survival (OS) results will need to be analyzed. Also, the manner in which the patients were staged remains unknown, and the comparison arm used an older adjuvant chemotherapy regimen (cisplatin-vinorelbine), whereas in the U.S., it is common to give newer regimens such as cisplatin-pemetrexed to non-squamous NSCLC patients. Although these results were positive, adjuvant oral EGFR TKIs should replace chemotherapy only in the setting of clinical trial and should not yet be given as standard of care.
Nintedanib for Malignant Pleural Mesothelioma
Since the MAPS trial (NEJM JW Oncol Hematol Mar 2016) showed PFS and OS benefit from adding bevacizumab to cisplatin-pemetrexed in malignant pleural mesothelioma (MPM), there has been a renewed interest in front-line triplet MPM regimens.
In the LUME-Meso study (abstract 8506), Nowak and colleagues randomized 87 patients with epithelioid or biphasic MPM to cisplatin-pemetrexed with or without the oral VEGFR, PDGFR, FGFR TKI nintedanib.
The addition of nintedanib improved the ORR (57% vs. 44%; OR, 1.66) and median duration of response (6 vs. 4 months). Nintedanib also significantly improved median PFS (9.4 vs. 5.7 months; HR, 0.54; P=0.010) and demonstrated a trend for improvement in median OS (18.3 and 14.2 months, respectively), with OS benefit across most subgroups, except for patients with biphasic histology. Nintedanib had a higher rate of dose reductions (27.3% vs. 17.1%) but a lower rate of treatment discontinuation due to toxicity (6.8% vs. 17.1%).
This trial provides supportive evidence that anti-angiogenics with platinum-pemetrexed in MPM are effective. However, it remains unclear whether the oral TKIs (nintedanib, cediranib) will have better efficacy than the monoclonal antibody bevacizumab and whether there is a predictive biomarker that can identify patients who are likely to have the greatest benefit. The LUME-Meso trial has been expanded into a phase III registration trial. If the study is positive, it will change standard of care in the front-line setting for MPM.
Editor Disclosures at Time of Publication
Disclosures for Anne S. Tsao, MD at time of publication Consultant / Advisory board Genentech BioOncology; Boehringer Ingelheim Pharmaceuticals; ARIAD Pharmaceuticals, Inc.; Bristol-Myers Squibb; TRM Oncology; EMD Serono; Merck & Co.; Novartis Pharmaceuticals; Roche Laboratories Speaker’s bureau Physician Education Resource; Research to Practice Grant / Research support Southwest Oncology Group; Medimmune; National Institutes of Health/National Cancer Institute; Millennium; American Cancer Society; Genentech; AstraZeneca; Takeda Oncology; Seattle Genentics; Epizyme; ARIAD Pharmaceuticals; Polaris Pharmaceuticals Leadership positions in professional societies American Medical Association (Member); American Association for Cancer Research (Member); AACR–Women in Cancer Research (Member); American Society of Clinical Oncology (Member); International Mesothelioma Interest Group (Member); SWOG SWOG – Southwest Oncology Group (Member); International Association for the Study of Lung Cancer (Communications Committee Chair); American Radium Society (Chair); Radiation Therapy Oncology Group (Member); Mesothelioma Applied Research Foundation (Member); National Cancer Institute–Thoracic Malignancy Steering Committee (Member)