Physicians are at the early stages of realizing the varying mechanisms of resistance to EGFR tyrosine kinase inhibitors and the methods for managing and/or overcoming resistance.
Resistance to targeted therapy with first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with epidermal growth factor receptor (EGFR)–mutant non–small cell lung cancer (NSCLC) is known to occur within 9 to 11 months.1-6 Physicians, however, are only at the early stages of realizing the varying mechanisms of resistance and the methods for managing and/or overcoming resistance.
“The classic EGFR mutations that occur in exon 19 and exon 21 are very responsive to the classic EGFR inhibitors, but it’s recognizant for patients to develop secondary alterations as the tumor tries to escape from the drugs,” Razelle Kurzrock, MD, Distinguished Professor of Medicine, University of California San Diego School of Medicine and director, Center for Personalized Cancer Therapy and Rare Tumor Clinic, associate director, Clinical Science
Leader, Experimental Therapeutics at the UCSD Moores Cancer Center, told Targeted Oncology.
The earlier-generation targeted therapies for EGFR-mutant NSCLC include gefitinib (Iressa) and erlotinib (Tarceva), and chemotherapy was also available to treat these patients. Later, afatinib (Gilotrif) was developed to address resistance to gefitinib and erlotinib, but in the phase 2/3 LUX-Lung 1 trial of afatinib versus placebo, afatinib only achieved a response rate of 7%, which included partial responses (PRs) in patients who progressed on gefitinib or erlotinib.7
In 585 patients, the median overall survival (OS) observed with afatinib was 10.8 months (95% CI 10.0-12.0) compared with the placebo arm, which showed a median OS of 12.0 months (95% CI, 10.2-14.3) (HR, 1.08; 95% CI, 0.86-1.35; P = .74). The median progression-free survival (PFS) was 3.3 months (95% CI 2.79-4.40) in the afatinib arm versus 1.1 months (95% CI, 0.95-1.68) in the placebo arm (HR, 0.38; 95% CI, 0.31-0.48; P <.0001).
The safety analysis showed that adverse events (AEs) were most commonly diarrhea (87%) and rash or acne (78%). Serious treatment-related AEs (TRAEs) occurred in 10% of patients in the afatinib group compared with less than 1% of the placebo group.
Findings from LUX-Lung 1 were the first hint that first-generation TKIs were not as effective as chemotherapy in the second-line setting.7,8
Osimertinib (Tagrisso) was then developed to target the T790M point mutation and first demonstrated superiority in the phase 1 AURA trial of osimertinib monotherapy in 201 patients with EGFR T790M–positive advanced NSCLC who had received prior treatment with an EGFR TKI. A total of 198 patients were evaluable for efficacy and these patients had an ORR of 62% (95% CI, 54%-68%) and a disease control rate (DCR) of 90% (95% CI, 85%-94%). The median duration of response (DOR) was 15.2 months (95% CI, 11.3-not calculable).9
The median PFS observed with osimertinib in AURA was 12.3 months (95% CI, 9.5-13.8). The ORR, PFS, and DOR were considered promising by investigators led by James Chih-Hsin Yang, MD, PhD, of National Taiwan University Hospital.
Diarrhea and rash were the most common adverse events observed in the study, occurring in 43% and 40% of the study population, respectively.
The benefit of osimertinib was validated later in the phase 3 AURA3 clinical trial of osimertinib or platinum-pemetrexed chemotherapy where a median PFS of 10.1 months was observed in the osimertinib arm compared with 4.4 months in the platinum arm, achieving statistical significance (HR, 0.30; 95% CI, 0.23-0.41; P <.001). The ORR observed with osimertinib was 71% versus 31% in the platinum arm (odds ratio [OR], 5.39; 95% CI, 3.47-8.48; P <.001). The median duration of response was 9.7 months (95% CI, 8.3-11.6) in the osimertinib group and 4.1 months (95% CI, 3.0-5.6) in the platinum-pemetrexed group.10
The hazard ratio (HR) for PFS among patients with central nervous system involvement in the AURA3 trial was 0.32, favoring osimertinib. These data ultimately led to the FDA approval of osimertinib as frontline treatment of EGFR T790M–positive NSCLC.
“The best-known exon 20 alteration is T790M, and that was a very resistant alteration until osimertinib came along. Osimertinib is effective in that alteration, and many more physicians are beginning to use osimertinib upfront because it can impact the classic alterations and present the emergences of the T790M, if there is T790M presence,” Kurzrock stated.
In the phase 3 head-to-head FLAURA trial (NCT02296125), osimertinib was compared with gefitinib and erlotinib in 556 patients. The interim analysis of FLAURA showed significant improvement with osimertinib versus gefitinib and erlotinib. The median PFS was 18.9 months with compared with 10.2 months in the standard TKI arm (HR, 0.46; 95% CI, 0.37-0.57; P <.001). The 2 arms showed similar objective response rates of 80% in the osimertinib arm versus 76% in the standard arm (OR, 1.27; 95% CI, 0.85-1.90; P = .24). Response in the FLAURA study lasted for a median duration of 17.2 months (95% CI, 13.8-22.0) with osimertinib, compared with 8.5 months (95% CI, 7.3-9.8) with standard EGFR TKI therapy.11
The most common any-grade adverse events (AEs) were rash/acne occurring in 58% of patients in the osimertinib arm versus 78% in the standard EGFR EKI arm, following by diarrhea (58% vs 57%, respectively), dry skin (36% vs 36%), and paronychia (35% vs 33%), respectively. Grade 3 or higher AEs were more abundant in the standard EGFR TKI group versus the osimertinib arm (45% vs 34%).
In a paper published in Critical Reviews in Oncology/Hematology, Li et al (including co-author Kurzrock) highlighted the novel options for patients with EGFR exon 20 insertions who confer resistance to the available therapies in the treatment paradigm. The paper suggests that the issue with using agents like osimertinib in the case of these insertions is not efficacy, but rather the inability of these agents to bind to the intended targets, thereby necessitating the need for such new approaches.12
Poziotinib, a novel EGFR/HER2 TKI, has demonstrated promise in terms of tumor size reductions and durable responses in previously treated patients with EGFR exon 20 mutations, specifically those with an insertion between M766 and D770, according to results from a cohort of the ZENITH20-1 clinical trial (NCT03318939).13
“The reason the exon 20 insertions have been difficult to impact is because the kinase domain becomes a very small pocket,” Kurzrock explained. “The classic drugs are too big to fit into that pocket. But, poziotinib is a small compound that can fit into the pocket and induce responses.”
In 115 patients in the intent-to-treat population with a median of 2 prior lines of therapy, the ORR was 14.8% (95% CI, 8.9%-22.6%), and the DCR was 68.7% (95% CI, 59.4%-77.0%). The median DOR was 7.4 months (95% CI, 3.7-9.7). Reductions in tumor size were observed in 65% of patients in the intent-to-treat population. The median PFS was 4.2 months (95% CI, 3.7-6.6).
Eighty-eight patients were evaluable for response and in that group, the confirmed ORR was 19.3%, and the DCR was 80.7% (95% CI, 70.9%-88.3%). The median DOR among evaluable patients was consistent with the intent-to-treat population at 7.4 months (95% CI, 3.7-9.7). The median PFS in the evaluable group was 4.1 months (95% CI, 3.7-5.5).
Tumor shrinkage in the evaluable population was observed in 84% of patients, showing the strong clinical activity with poziotinib.
In terms of safety and tolerability, the profile of poziotinib in ZENITH20-1 was consistent with second-generation EGFR TKIs. The most common grade 3 TRAEs were diarrhea (25%), rash (28%), stomatitis (9%), and paronychia (6%).
“There’s a lot of variety in the response, depending on what clinical trial you refer to. The response ranged from as high as 60% and as low as 15%. But, poziotinib was one of the first drugs that showed that you can actually hit and impact this insertion.”
Another novel EGFR and HER2 inhibitor, mobocertinib (TAK-788), demonstrated antitumor activity in patients with NSCLC harboring an EGFR exon 20 insertion, according to early results from a phase 1/2 clinical trial (NCT02716116).14,15
Out of 26 patients in an expanded cohort of the study, the ORR was 46% (95% CI, 24%-63%) and the DCR was 86% (95% CI, 67%-96%). Responses included 54 partial responses and 35 cases of stable disease. Progressive disease was observed in 1 patient and 2 patients were not evaluable for response.
The most common any-grade treatment-emergent AEs observed with mobocertinib included diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%). The most frequent grade 3 or higher treatment-emergent AEs were diarrhea (26%) as well as hypokalemia, nausea, and stomatitis, which occurred in 7% of patients each.
Although the drug is novel, the concept of using EGFR antibodies dates back over a decade. Kurzrock shared a story of a patient who derived benefit from a similar drug, cetuximab (Erbitux), during a protocol treatment study conducted at The University of Texas MD Anderson Cancer Center, where Kurzrock used to work.
“Little was known about EGFR exon 20 insertions back in that time-period. We administered cetuximab in combination with erlotinib to the patient. Of course, we now know erlotinib is completely ineffective for this insertion. But, to everyone’s surprise, the patient had an excellent response, she shared.
“By the time I left MD Anderson 4 years later, the patient was still responding. I didn’t understand why he responded until a year and half later during a molecular tumor board discussion,” Kurzrock added.
During the tumor board, computer modeling revealed that although erlotinib would not work in patients with EGFR exon 20 insertions, an EGFR antibody would work.
“We ended up treating the patient at UCSD with cetuximab. The patient had a nice response that lasted for about a year. Since then, we’ve treated several other patients at UCSD with an EGFR antibody,” Kurzrock told Targeted Oncology.
In the management of disease, particularly resistance to EGFR TKIs in patients, genomic testing plays an important role.
“Genomic testing is critical, in general. It is also critical for the management of lung cancer,” Kurzrock noted. “For many decades, the way we diagnosed cancer was by where the cancer originated from using the light microscope. It’s a great instrument, but there are limits to how you can use it. It doesn’t tell you exactly what is wrong with the cell that is causing the cancer.
“Doing genomic sequencing is also vital because that’s how you know what drug to give. If you want to know if the patients had an immediate mutation or what type of mutation a patient has, you have to do genomic sequencing. There’s no other way to get that information.”
Importantly, Kurzrock expressed that molecular testing is just as important in the later-line settings as it is in the front-line setting because patients can develop other mutations and build new mechanisms of resistance.
The recommendations for overcoming resistance to EGFR TKI vary, depending on the mutation. Overall, oncologists are encouraged to follow the data from clinical trials.
“It depends on the mutation the patient has. If you have a T790M mutation, the drug is osimertinib. That is approved. If they have an exon 20 insertion, my recommendation would be the off-label use of the EGFR antibody cetuximab. Oncologists could also refer to a clinical trial,” Kurzrock stated. “The 2 drugs of interest in clinical trials are poziotinib and TAK-788.”
1. Yang JJ, Zhou Q, Yan HH, et al. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer. 2017;116:568-574. doi:10.1038/bjc.2016.456
2. Killock D. Lung cancer: a new generation of EGFR inhibition. Nat Rev Clin Oncol. 2015;12(7):373. doi:10.1038/nrclinonc.2015.93
3. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334. doi:10.1200/JCO.2012.44.2806
4. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. doi:10.1016/S1470-2045(11)70393-X
5. Zhou C, Wu YL, Chen G, et al. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015;26(9):1877-1883. doi:10.1093/annonc/mdv276
6. Maemondo M, Inoue A, Kobayashi K, et al; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-2388. doi:10.1056/NEJMoa0909530
7. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012;13:528-538. doi:10.1016/S1470- 2045(12)70087-6
8. Lovly CM, Iyengar P, Gainor JF. Managing Resistance to EFGR- and ALK-Targeted Therapies. American Society of Clinical Oncology Educational Book. 2017:37:607-618. doi:10.1200/EDBK_176251
9. Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in Pretreated T790M-Positive Advanced Non–Small-Cell Lung Cancer: AURA Study Phase II Extension Component. J Clin Oncol. 2017;35(12):1288-1296. doi:10.1200/JCO.2016.70.3223
10. Mok TS, Wu L, Ahn J, et al; AURA3 Investigators. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. N Engl J Med. 2017;376:629-640. doi:10.1056/NEJMoa1612674
11. Sonia JC, Vansteenkiste OJ, Reungwetwattana T, et al; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
12. Li AM, Boichard A, Felip E, Kurzrock R. New therapeutic approaches to overcoming resistant EGFR exon 20 alterations. Crit Rev Oncol/Hematol. 2020;151:102990. doi:10.1016/j.critrevonc.2020.102990
13. Le X, Goldman J, Clarke JM, et al. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J Clin Oncol. 2020;38(suppl):9514. doi:10.1200/JCO.2020.38.15_suppl.9514
14. Janne PA, Neal JW, Camidge D, et al. Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions. J Clin Oncol. 2019;37(suppl 15):9007. doi:10.1200/JCO.2019.37.15_suppl.9007
15. Takeda Announces U.S. FDA Breakthrough Therapy Designation for Mobocertinib (TAK-788) for the Treatment of NSCLC Patients with EGFR Exon 20 Insertion Mutations [news release]. Cambridge, MA & Osaka, Japan: Takeda Pharmaceutical Company Limited; April 27, 2020. https://bwnews.pr/2KFC7vj. Accessed April 27, 2020.