MEETING HIGHLIGHT
Adopting durvalumab consolidation therapy: A breakthrough for non-small cell lung cancer treatment
Despite recent advances in oncology, drug resistance and disease relapse have remained a significant unmet need among non-small cell lung cancer (NSCLC). Recently, the development of novel therapeutics including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have made multiple breakthroughs in the treatment of NSCLC. In a virtual meeting and clinical debate, “Durvalumab in EGFRm Stage III NSCLC – To Offer or Not to Offer?”, Dr. Victor Lee summarized the key studies of NSCLC treatments, including the phase 3 PACIFIC trial of an anti-programmed cell death receptor ligand 1 (PD-L1) drug, durvalumab. Dr. Oscar Chan and Dr. Jonathan Nyaw then discussed the applications and other considerations of the durvalumab regimen among stage 3 Epidermal Growth Factor Receptor mutated (EGFRm) NSCLC patients in the clinical setting.
Introduction
EGFRm lung cancer occurs in 15-20% of patients with adenocarcinoma and is most commonly associated with nonsmokers and those of Asian ethnicity.1 Because EGFR-mutated tumors tend to be dependent on the EGFR activity to stimulate downstream signaling pathways, an opportunity exists to treat such tumors with oral TKIs that block EGFR. In EGFR-mutated NSCLC, first-, second- and third-generation EGFR-TKIs have demonstrated improved response rates (ORR), progression-free survival (PFS) and better tolerability compared with the standard therapy, with median overall survival (OS) rates now succeeding 4 years.2 However, a majority of patients confer primary resistance to first and second generation TKIs, and develop progressive disease after 10-14 months of treatment.4 ICIs were developed to inhibit the immunosuppressive effects of the programmed death 1 receptor (PD-1)/PD-L1 pathway and to activate the immune response against tumor antigens.3 ICI have revolutionized systemic treatment of patients with EGFR wild-type (WT) NSCLC in the setting of first and latter treatment lines, mainly due to their unique ability of long-term tumor control in a subset of patients.2 In EGFR-mutated tumors patient subgroup, second and third-line phase III trials have shown lower activity than WT population, and its role remains yet to be further investigated and refined in EGFR-mutated NSCLC.2 After all, durvalumab in EGFRm stage III NSCLC – to offer or not to offer?
Notable development of osimertinib in EGFRm NSCLC
Osimertinib is a 3rd generation TKI that was developed to overcome resistance from the EGFR T790M mutation which was common among 1st and 2nd generation TKIs.5 A pre-specified exploratory analysis among resected EGFRm NSCLC patients in the ADAURA trial found a much lower probability (<1%; 95% CI: 0.002-0.025) of observing central nervous system recurrence at 18 months with adjuvant osimertinib than with placebo (9%; 95% (9%; 95% CI: 0.06-0.125).6 Furthermore, the phase 3 FLAURA China study (n=136) found that the osimertinib arm had 7.4 months longer median overall survival (OS) when compared to the comparator TKI (gefitinib/erlotinib) arm in patients with advanced EGFRm NSCLC.7
Durvalumab as a pan-mutational treatment option for NSCLC
PACIFIC is a phase 3 trial studied durvalumab in all comer’s (regardless of PD-L1 expression and EGFR mutation status) setting among patients with unresectable, Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (n=713).8 After 12 months of intravenous treatment, patients who received durvalumab showed a significant improvement in PFS over placebo [stratified hazards ratio (HR) for disease progression or death=0.52; 95% CI: 0.42-0.65, p<0.0001] as well as a significant improvement in OS at 24 months (stratified HR for death=0.68, 99.7% CI: 0.47-0.997, p=0.0025) after randomization that is consistent in all prespecified subgroups, including PD-L1 expression levels and EGFR mutation status.8,9 Dr. Lee added, “Almost all subgroup analyses were in favor of OS and PFS [for durvalumab].”
Durvalumab continued to demonstrate durable PFS and has sustained OS benefit after 5 years of treatment.10 With a median OS of 47.5 months, the OS benefit in the durvalumab arm was approximately 18 months longer than the placebo arm at 29.1 months (HR=0.72; 95% CI: 0.59-0.89; Figure 1).10 Furthermore, durvalumab significantly prolonged median PFS of 16.9 vs. 5.6 months (HR=0.55; 95% CI: 0.45-0.68; Figure 2).10
Durvalumab - To give or not to give?
Although both osimertinib and durvalumab are promising antitumor agents for NSCLC, combination therapy involving both treatments is not feasible due to a higher toxicity profile, which leads to a clinical debate between the choice of prescribing osimertinib or durvalumab for patients with NSCLC.
While Dr. Chan introduced durvalumab as a game changer in patients with unresectable stage 3 NSCLC after CRT, only a minority of patients in the PACIFIC trial had EGFRm, which means that the PACIFIC data may not be powerful enough to show efficacy in EGFR mutation subgroups. Dr. Chan also pointed out the “Lung cancer is a diverse disease with different biology,” reminded Dr. Chan, “we should be moving away from the old one-size-fits-all approaches.” From his personal experience, Dr. Chan expressed concern regarding durvalumab’s efficacy in stage 4 NSCLC patient; consolidation osimertinib could be an alternative due to its good central nervous system penetration, low toxicity, easy administration, and potential larger magnitude of PFS improvement among stage 3 NSCLC patients.
On the contrary, Dr. Nyaw pointed out that the subgroup analysis of PACIFIC did not show statistically significant benefit in both PFS and OS in the EGFR mutant subgroup. However, since there were only a small percentage of patients in the PACIFIC trial with EGFR mutation, it is uncertain that durvalumab would not benefit these patients. Therefore, durvalumab should still be regarded as the standard of care in unresectable stage 3 NSCLC regardless of the EGFR mutation status. The balance of benefits and risks must be considered in the durvalumab treatment decision, especially when stage 3 NSCLC patients generally have a higher risk of relapse in the first 2 years after initial treatment.
On the other hand, osimertinib could be a potential alternative and was shown to have a lower risk of disease recurrence (11%) when compared to placebo (46%) in the ADAURA study. Notably, 10% of the resected EGFRm NSCLC patients on placebo experienced brain metastasis which was not observed among osimertinib treated patients. LAURA, a Phase 3 trial assessing the potential benefit of starting osimertinib earlier in the treatment paradigm in patients with unresectable, Stage III, EGFRm NSCLC who did not progress after CRT is currently undergoing.
Moreover, durvalumab is now reimbursed in the public sector, making it more accessible to patients. In terms of safety, there were no significant differences in global health status and physical functioning between patients in the durvalumab arm and the placebo arm. Based on these study data, Dr. Nyaw asserted that “Adjuvant durvalumab has demonstrated significant improvement in the overall survival and is now regarded as the standard of care after stage 3 lung cancer post chemoradiotherapy”. Based on the discussion, Dr. Nyaw concluded that the PACIFIC data did not refute the potential benefits of durvalumab in EGFRm lung cancer, and durvalumab should be considered regardless of EGFR mutation status.
Practical application of durvalumab treatment
When considering the combination treatment of osimertinib and durvalumab for EGFRm stage 3 NSCLC patients, Dr. Nyaw highlighted that the combination should not be given as there is currently no data to demonstrate its safety. Dr. Chan agreed and pointed out that in the phase 1 TATTON study, patients on combination therapy had a higher than 30% chance of interstitial lung disease which led to the study’s termination.
In the case of a T4 lung cancer patient with attempted resection and lobectomy that had completed chemoradiation but ended up with gross residual disease, Dr. Chan commented that a T4 disease is already a stage 3 disease and the decision to undergo surgery might not have been appropriate. Instead, CRT should be initiated with a follow up of durvalumab. Dr. Nyaw agreed and commented that despite the patient being operated unnecessarily, he is still a good candidate for adjuvant durvalumab.
Conclusion
In patients with locally advanced NSCLC, durvalumab consolidation treatment has shown significant improvements in ORR, PFS, and OS when compared to placebo. The side effects of durvalumab were also manageable. Based on the phase 3 clinical trial, consolidation therapy with durvalumab after CRT is now considered the standard of care for NSCLC patients in all comer setting. Ongoing clinical trials are investigating concurrent ICI/CRT regimens and may further transform the treatment landscape for unresectable stage 3 NSCLC patients, including those with driver mutations.
