Searching for New Solutions in Treating EGFR-Mutant NSCLC

Worldwide, about 2.2 million people are diagnosed with lung cancer each year; between 80% and 85% of these cases are non–small cell cancer (NSCLC).¹ About 33% of those diagnosed with NSCLC have EGFR mutations, although these are not evenly distributed—those with EGFR-mutant NSCLC are more likely to be Asian, female, and non-smokers.²

As the number of lung cancer cases drops overall due to declining smoking rates, the need for treatments for those with EGFR-mutant driven lung cancer rises in importance. This was reflected by 3 abstracts on potential new regimens featured in an oral abstract session on metastatic lung cancer during the final day of the 2023 American Society of Clinical Oncology Annual Meeting.

For reasons not entirely clear, treatment of patients with EGFR-mutated NSCLC with immune checkpoint inhibitors (ICIs) presents certain challenges;³ following development of tyrosine kinase inhibitor (TKI) resistance, treatment with single-agent immotherapy is not very effective, according to a July 2022 review article in Frontiers in Immunology.⁴ However, the authors wrote, “compared with monotherapy, ICIs combined with chemotherapy can improve efficacy.”

Thus, strategies presented at the ASCO session included both pairing ICIs with additional agents or developing new therapies, including those designed to cross the blood-brain barrier to deal with one of the more challenging effects of lung cancer, brain metastases.

ASCO commentator Jonathan W. Riess, MD, medical director of thoracic oncology, University of California, Davis Comprehensive Cancer Center, saw promise in sunvozertinib, a therapy to treat NSCLC with EGFR Exon20 insertion. But when it came to another therapy, zorifertinib, he did not recommend moving away from osimertinib as first-line therapy for EGFR-mutated lung cancer.

Reiss said the issue of sequencing therapies will also offer challenges for clinicians moving forward.

Pembrolizumab with pemetrexed + platinum chemotherapy. James Yang, MD, PhD, professor and director, Graduate Institute of Oncology,

Yang

National Taiwan University Cancer Center, presented late-breaking results from KEYNOTE-789 (NCT03515837), a randomized phase 3 study of pemetrexed plus platinum chemotherapy with or without pembrolizumab (Keytruda) in patients with TKI-resistant EGFR-mutated metastatic NSCLC.⁵

EGFR-TKI therapies are standard for patients with previously untreated NSCLC with sensitizing EGFR mutations, Yang said. “However, most patients will develop resistance, and at the time of resistance the standard of care is still a combination chemotherapy.”

Although studies in metastatic NSCLC showed overall survival (OS) benefit by combining ICIs with combination therapy, Yang noted “all or most of these studies did not include patients with EGFR mutations,” because in prior studies, use of ICIs in this group was shown to be inferior. However, a prior study showed a signal for a small group of EGFR-mutated patients with PD-L1 expression who received pembrolizumab vs docetaxel.6

“In order to answer this question, it is important to perform this study to figure out the role of immune checkpoint inhibitors adding to chemotherapy  for salvage after EGFR-TKI failure,” Yang said.

Investigators enrolled adults with confirmed stage IV nonsquamous NSCLC, ECOG performance status of 0 or 1, documented EGFR mutation, and progression after EGFR-TKI therapy. Patients were randomized to 35 cycles of pembrolizumab (245 patients) or placebo (247 patients), plus 4 cycles of pemetrexed and carboplatin or cisplatin followed by maintenance pemetrexed. Patients were also stratified by PD-L1 tumor proportion score (TPS), prior osimertinib, and whether or not they were from East Asia.

Progression-free survival (PFS) was assessed at a second interim analysis, and other end points, including overall survival (OS) and safety, were assessed at the final data cutoff in January 2023. Results for median PFS favored pembrolizumab, 5.6 months vs 5.5 months (HR 0.80; 95% CI, 0.65–0.97); P = 0.0122) but did not reach statistical significance. Results for OS also favored pembrolizumab, 15.9 months vs 14.7 months, but did not reach clinical significance (HR 0.84; 95% CI, 0.69–1.02); P = 0.0362. OS rates at 12 months were 61.6% vs 59.4% and at 24 months were 30.6% vs 26.4%, favoring pembrolizumab. Results for OS were improved for patients in the pembrolizumab group among those with PD-L1 TPS ≥1% vs those with PD-L1 TPS < 1% (+4.5 months vs +1.0 month). Grade 3 or higher treatment-related adverse events (AEs) were higher in the pembrolizumab arm.

“Results were consistent with prior findings that TKI-resistant, EGFR-mutant metastatic non-small cell lung cancer derived less benefit from anti-PD-1 or PD-L1 treatment in EGFR wild-type patients, yet there [was] a biomarker that was identified, which is PD-L1 status more than 1%, which deserves further investigation in the future,” Yang said.

Results for Zorifertinib. Yi-Long Wu, MD, professor at Guangdong Lung Cancer Institute, presented results from EVEREST

Wu

(NCT03653546), the randomized phase 3 study of first-line zorifertinib, a next-generation EGFR-TKI inhibitor, vs first-generation gefitinib or erlotinib in EGFR-mutant NSCLC with central nervous system (CNS) metastasis.⁷

Zorifertinib is being developed by Alpha Biopharma, which paid for the study.

“As you know, more than 50% of patients with non-small cell lung cancer and the EGFR-mutant patients develop brain metastases during their lifetime, “ Wu said, noting these patients have a very poor prognosis. Thus, developing therapies that can demonstrate intercranial antitumor activity represents a critical need.

“Approved EGFR-TKIs show variable penetration across the brain barrier, with the ratio of the [cerebrospinal fluid] concentration to free plasma concentration ranging from 0.066 to 0.21,” he said.

Zorifertinib has shown promise in having higher blood brain barrier penetration in phase 1 and phase 2 trials, and Wu presented the first phase 3 results, comparing the efficacy and safety of first-line zorifertinib with that of earlier generation TKIs in patients with advanced EGFR-mutated lung cancer and confirmed CNS metastatis. Patients in EVEREST had no prior system or radiotherapy and more than 1 brain lesion. They were randomized to zorifertinib, 200 mg given twice a day, vs gefitinib or erlotinib given once a day.

The trial randomized 439 patients at 58 sites in China, Taiwan, South Korea, and Singapore; 220 received zorifertinib and 215 received a first-generation TKI.

The primary end point was PFS, which was assessed by blinded independent central review (BICR) per RECIST 1.1 criteria. After median follow-up was 20.4 months, a 28% improvement in PFS, which study authors called “significantly superior,” was seen in the zorifertinib group. Those taking the study drug had a PFS of 9.6 months compared with 6.9 months in the control group (HR 0.719; 95% CI, 0.580-0.893); P = .0024.

The objective response rate (ORR) was 68.6% for zorifertinib vs 58.4% for the control group (P = .027), “with a trends toward longer median duration of response favoring zorifertinib (8.2 months vs 6.8 months, P = .0997). OS data are not mature. Any grade treatment-related adverse events (TRAEs) was similar between the 2 groups (97.7% vs 94.0%). Grade 3 or higher TRAEs occurred in 65.9% of the zorifertinib group vs 18.3% of the control group; common events were skin and subcutaneous tissue events, gastrointestinal events and abnormal liver function. No new safety signals arose. Wu said this was consistent with second-generation EGFR TKIs.

“In conclusion, EVEREST is the first randomized, controlled, open label, multiple national study designed specifically to address the unmet medical need for the patient with the EGFR-mutant non-small cell lung cancer and brain metastasis,” he said.

Sunvozertinib in NSCLC With EGFR Exon 20 Insertions. Mengzhao Wang, MD, of Peking University Medical College and the Chinese Academy of

Medical Science, presented the first pivotal study results in WU-KONG6 (NCT05712902), which is evaluating sunvozertinib for this subset of patients.⁸

“EGFR exon20 insertion occur in about 2% of [cases in] non-small cell lung cancer,” Wang said. "Sonvozertinib is a rationally designed, oral potent EGFR inhibitor targeting EGFR exon20 Insertion, as well as other EGFR mutations."

The therapy, being developed by Dizal, has received Breakthrough Therapy designations in both the United States and China, leading to 2 single-arm pivotal studies—WU-KONG6 in China and a multinational study, WU-KONG1 (NCT0397402) in the rest of Asia, Europe, the United States, Australia, and other countries. A randomized phase 3 study is ongoing as well.

Patients in WU-KONG6 received a 300 mg dose per day, with the tumor assessed every 6 weeks. Primary end point was response rate as assessed by BICR; secondary end points are duration of response, PFS, OS, and safety. A total of 104 with exon20 insertions were enrolled; however, 7 patients did not have the mutation confirmed in a central lab, so only 97 were included in the efficacy analysis. Wang noted that 32% had baseline brain metastasis, and the median prior therapies was 2; all had failed 2 platinum-based chemotherapy regimens.

What’s next? Reiss discussed each trial, noting that a meta-analysis found that “efficacy of single-agent, PD-1, PD-L1, immune checkpoint blockade in EGFR-mutant lung cancer is suboptimal."⁹

Reiss

The review found, “for EGFR wild type, there was an impressive survival benefit, but for EGFR-mutant lung cancer, it faired no better than docetaxel.”

These tumors, Reiss said, were characterized by a suppressed immune microenvironment, low PD-L1 expression, low tumor mutational burden, low tumor-infiltrating lymphocytes and low T-cell clonality. So, for these reasons, among others, patients were excluded from teh first-line pivotal studies, including KEYNOTE 189,¹⁰ that showed a substantial and significant PFS and OS benefit, adding pembrolizumab to platinum-pemetrexed chemotherapy," he said.

KEYNOTE 789 attempts to fill some knowledge gaps, but Reiss said the minor improvement seen by add pembrolizumab to the combination stands in contrast to the “wide gap” in the curves in KEYNOTE 189.^5,10

He went through a roster of studies that showed adding immunotherapy for EGFR-mutant lung cancer has either resulted in a negative outcome, or in a benefit so marginal that “the juice is not worth the squeeze.”

But there are other studies to watch, he said, notably those that add anti-angiogenesis agents. And the search for better biomarkers should continue. “We saw in KEYNOTE 789, stratified by PD-L1 status, for overall survival, the PD-L1 positive patients seemed to do a bit better."

"There are other strategies in terms of combining with chemotherapy in addition to immunotherapy,” Reiss said, taking note of the recent announcement that FLAURA2 study, which compares first-line osimertinib with osimertinib-platinum-pemetrexed, had met its primary end point.¹¹

“We really need to study exceptional responders and study why patients with EGFR-mutant lung cancers are IO refractory, because that represents a lot of patients we could impact with IO treatments.”

On zorifertinib, Reiss observed that while the study results were statistically significant, the control arm was a first-generation TKI. Today, standard of care is osimertinib, which has demonstrated a PFS and OS benefit vs first-generation TKIs in the FLAURA trial, with a median PFS Of 15.2 months.^12,13 “Of course, there are cross trial comparisons but zorifertinib was 9.6 months,” he said.

Nothing that osimertinib may not be available everywhere, Reiss said. “I would say in terms of our next-generation TKIs, we need to globalize the best therapies worldwide."

References

1. American Cancer Society. What is lung cancer? Types of lung cancer. January 12, 2023. Accessed June 25, 2023. https://bit.ly/44cTOK9
2. Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-78993. doi: 10.18632/oncotarget.12587.
3. To KKW, Fong W, Cho WCS. Immunotherapy in treating EGFR-mutant lung cancer: current challenges and new strategies. Front Oncol 2021;11 https://doi.org/10.3389/fonc.2021.635007
4. Shi C, Wang Y, Xue J, et a. Immunotherapy for EGFR-mutant advanced non-small cell lung cancer: current status, possible mechanisms and application prospects. 2022;13 https://doi.org/10.3389/fimmu.2022.940288
5. Yang JCH, Lee DH, Lee JS, et al. Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: Phase 3 KEYNOTE-789 study. J Clin Oncol 2023;41(suppl 17):abstr LBA9000. doi: 10.1200/JCO.2023.41.17_suppl.LBA9000
6. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7.
7. Yi-Long Wu, Qing Zhou, Jie Wang, et al. Randomized phase 3 study of first-line AZD3759 (zorifertinib) versus gefitinib or erlotinib in EGFR-mutant (EGFRm+) non–small-cell lung cancer (NSCLC) with central nervous system (CNS) metastasis. J Clin Oncol. 2023;41(suppl 16): abstr 9001. doi: 10.1200/JCO.2023.41.16_suppl.9001

8. Wang M, Fan Y, Sun M, et al. Sunvozertinib for the treatment of NSCLC with EGFR Exon20 insertion mutations: The first pivotal study results. J Clin Oncol. 2023;41(suppl 16): abstr 9002. DOI: 10.1200/JCO.2023.41.16_suppl.9002

9. Dong ZY, Zhang JT, Liu SY, et al. EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer. Oncoimmunology. 2017;6(11):e1356145. doi: 10.1080/2162402X.2017.1356145.

10. Rodriguez-Abreu D, Powell SF, Hochmair MJ, et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021;32(7):881-895. doi: 10.1016/j.annonc.2021.04.00

11. Tagrisso plus chemotherapy demonstrated strong improvement in progression-free survival for patients with EGFR-mutated advanced lung cancer in FLAURA2 Phase III trial. News release. AstraZeneca.May 17, 2023. Accessed June 25, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemo-improved-pfs-in-lung-cancer.html

12. Soria JC, Ohe Y, Vansteenkiste J, et al. for the 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.

13. Ramalingam SS. Vansteenkiste J, Planchard D, et al. for the FLAURA investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi: 10.1056/NEJMoa1913662.