Immunotherapy combinations in EGFR-mutated NSCLC
While the armamentarium of therapies for metastatic non-small-cell lung cancer (NSCLC) has evolved to include various targeted therapies and immunotherapeutic agents, combinations with optimal efficacy and tolerability remain to be elucidated. At the 8th Joint Scientific Meeting of the Royal College of Radiologists (RCR) and Hong Kong College of Radiologists (HKCR) and 27th Annual Scientific Meeting of HKCR, Professor Tai-Chung Lam of the Department of Clinical Oncology, the University of Hong Kong, discussed the use of immunotherapy-based combinations for the management of EGFR-mutated NSCLC, with an emphasis on the role of the anti–PD-L1 antibody, atezolizumab.
“EGFR-positive NSCLC is prevalent in Hong Kong and East Asia, with relatively high numbers of nonsmokers frequently being diagnosed with aggressive disease,” said Lam.
“In Hong Kong, the current first-line standard of care [SoC] for patients with advanced EGFR-positive NSCLC is a first- or second-generation EGFR tyrosine kinase inhibitor [TKI], or a third-generation EGFR TKI. In the second-line setting, the SoC is a third-generation EGFR-TKI for patients with T790M-positive disease, whereas those with T790M-negative disease will receive platinum-based chemotherapy with or without the addition of bevacizumab,” Lam noted.
Immunotherapy in EGFR-mutated NSCLC
Single-agent immunotherapy for the treatment of EGFR-mutated advanced NSCLC has been investigated in large trials such as KEYNOTE-010 and CheckMate-057. “However, in KEYNOTE-010, pembrolizumab [2 mg/kg] did not demonstrate a significant difference in progression-free survival [PFS] vs docetaxel, with a hazard ratio [HR] of 0.88. In CheckMate-057, the PFS HR for nivolumab vs docetaxel was 1.08,” said Lam. [N Engl J Med 2015;373:1627-1639; Lancet 2016;387:1540-1550]
“While the results of preclinical studies investigating the utility of EGFR TKIs and immune checkpoint inhibitors (ICIs) in the treatment of EGFR-positive NSCLC were promising, these trials also showed high toxicity levels,” Lam noted. [J Thorac Oncol 2016;11:S115; J Thorac Oncol 2016;11:S79; Ann Oncol 2016;27(suppl 9):ix139-ix156] “The high toxicity rates, coupled with efficacy that was not significantly better than that of EGFR TKI monotherapy, led to investigations into the potential augmentation of immunotherapeutic effects through combining ICIs with chemotherapy, and subsequently combining those with bevacizumab, a VEGF inhibitor,” he said. [J Thorac Oncol 2019;14:124-129]
Atezolizumab activity enhanced by adding bevacizumab
“A key unmet need in today’s clinical practice lies in identifying an effective treatment regimen for EGFR-mutant NSCLC patients who have disease progression beyond TKI therapy,” said Lam. “This is where bevacizumab can play an important role due to its antiangiogenic and immunomodulatory effects.”
Atezolizumab demonstrated an overall survival (OS) benefit vs docetaxel in patients with previously treated metastatic NSCLC and has shown promising efficacy in combination with platinum-doublet chemotherapy in chemotherapy-naive patients. [Lancet 2017;389:255-265; J Clin Oncol 2017;35(Suppl 15):abstract 9092]
“The idea that atezolizumab’s antitumour activity could be enhanced by bevacizumab’s reversal of VEGF-mediated immunosuppression formed the basis of the IMpower150 study,” said Lam. [Lancet Respir Med 2019;7:387-401]
Results of the IMpower150 study showed that atezolizumab in combination with bevacizumab, carboplatin and paclitaxel [ABCP] significantly improved PFS and OS in patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression EGFR or ALK mutation status. [N Engl J Med 2018;378:2288-2301]
“These were very encouraging findings. Further analyses were then performed to investigate the efficacy of the ABCP regimen in different subgroups, including patients with sensitizing EGFR mutations,” Lam noted.
ABCP improves survival in patents with sensitizing EGFR mutations
The subgroup analyses demonstrated improved PFS with ABCP vs BCP in patients with sensitizing EGFR mutations (HR, 0.41; 95 percent confidence interval [CI], 0.23 to 0.75), including in those who had received prior EGFR-TKI therapy (HR, 0.42; 95 percent CI, 0.22 to 0.80). [Lancet Respir Med 2019;7:387-401]
“The PFS improvement with ABCP vs BCP in patients with sensitizing EGFR mutations was not carried across with ACP vs BCP [HR, 1.01; 95 percent CI, 0.61 to 1.70],” noted Lam. [Lancet Respir Med 2019;7:387-401] “Without the bevacizumab-induced tumour vasculature normalization and increased sensitivity to ICI therapy, it may not have been possible for atezolizumab to improve overall PFS in this subgroup of patients.”
The ABCP regimen also improved OS vs BCP in patients with sensitizing EGFR mutations. (Figure) “The OS HR for ABCP vs BCP in all EGFR-positive patients was 0.61. However, the upper bound of 95 percent CI crossed 1, and this may have been due to the small sample size and insufficient power,” said Lam. (Figure) [Lancet Respir Med 2019;7:387-401]
“Overall, there was an obvious trend for improvement in survival with the ABCP vs BCP regimen, especially in patients with sensitizing EGFR mutations who have progressed on TKI therapy,” he reiterated.
Switching chemo partner helps manage toxicities
“The safety of four-drug regimens is one of the most common concerns among physicians,” said Lam. “Paclitaxel, a component of the four-drug regimen evaluated in the IMpower150 study, is generally considered to be more toxic than pemetrexed, which is more commonly used locally.”
With this in mind, Lam and colleagues conducted a phase II single-arm study in Hong Kong to investigate the safety and efficacy of ABC plus pemetrexed in EGFR-mutated NSCLC patients who had failed EGFR TKI therapy.
“Study enrollment was only completed in May 2019, and mature PFS data are not yet available. However, preliminary results indicate that 6-month PFS and OS rates are approximately 80 percent and 100 percent, respectively. To date, more than 280 cycles of treatment have been administered in 40 patients, and we have observed very few immune-related adverse events, with only one patient withdrawing from the study,” said Lam.
“The combination of platinum-based chemotherapy and an anti-VEGF agent with a PD-L1 inhibitor is a promising salvage regimen for EGFR-mutated NSCLC after failure of EGFR TKI therapy. While further investigation is needed to ascertain the safety of four-drug regimens, there are promising data on the horizon demonstrating a favourable toxicity profile of ABC in combination with pemetrexed,” Lam concluded.