Challenges of Systemic Therapy for Patients with EGFR-mutated Lung Cancer After Progression on Targeted Therapy

Palliative systemic treatment regimens for patients with metastatic EGFR-mutated non-small cell lung cancer (NSCLC) have improved dramatically throughout the past several decades with the development of EGFR-targeted tyrosine kinase inhibitors (TKI); the current standard of practice being first-line therapy with osimertinib, a third-generation EGFR-TKI, based on the results of the FLAURA trial.1

Although efforts have been made to further optimize the results of first-line targeted therapy for this population—for example by adding chemotherapy, as is being explored in FLAURA-2,2 or with other targeted agents, such as the amivantamab and lazertinib combination seen in MARIPOSA3—data has yet to demonstrate an overall survival benefit compared to osimertinib monotherapy. Thus, providers continue to face challenging treatment decisions for these patients following progression.

The issue of acquired resistance remains a concern in patients treated with a first-line EGFR-TKI. After determining the resistance mechanism, some patients may have a modification in targeted therapy to pursue another period of disease control. However, for most the patients, there is no option for a targeted second-line treatment.4 In these cases, conventional chemotherapy-based systemic treatment is left for further palliative treatment, but the question remains; which regimen performs best in this patient population with EGFR-mutated lung cancer?

Systemic Regimens After Progression

In trying to answer this question, we analyzed data from patients in the Netherlands treated in Erasmus MC, Rotterdam, and Antoni van Leeuwenhoek, Amsterdam.5 We included 171 lines of chemotherapy, of which 106 lines were given as first-line chemotherapy after progression on an EGFR-TKI. Most patients were treated with platinum/pemetrexed. Other systemic regimens consisted of carboplatin/paclitaxel/bevacizumab/atezolizumab (also known as the IMPOWER150 regimen), paclitaxel/bevacizumab, and carboplatin/paclitaxel/bevacizumab. The progression free survival (PFS) and overall survival (OS) of the first-line regimens did not show a statistically significant difference between the regimens. However, in our study, patients benefited from chemotherapy regimens with a median PFS of 5.2 months from platinum/pemetrexed and 5.9 months from carboplatin/paclitaxel/bevacizumab/atezolizumab, and a median overall survival of 15.3 months of first-line chemotherapy regimens.5 This suggests that chemotherapy after EGFR-TKI provides substantial survival benefit for patients, without a preference for a specific regimen, according to our findings.

Other studies have also investigated the efficacy of systemic treatment after progression on EGFR-TKI. In China, Yu and colleagues evaluated chemotherapy and immunotherapy versus chemotherapy and anti-angiogenic agents retrospectively.6 They reported no significant difference in PFS (7.6 vs. 6.9 months) in the patients with at least one assessment of response. However, the regimens were not further specified, and the authors also acknowledged inconsistencies in the prescribed agents.

A retrospective cohort treated with the IMPOWER150 regimen in Australia showed a median time to treatment failure of 5.2 months and a median OS of 10.5 months in the patients withEGFR–mutated NSCLC.7 However, not all patients were pretreated with an EGFR-TKI, and a significant part of the cohort was treated with pemetrexed instead of paclitaxel (42%). Additionally, about half the patients received lower chemotherapy dosages.

Another study performed by White and colleagues in the US compared the duration on treatment of patients with chemotherapy, chemotherapy and immunotherapy (pembrolizumab), or chemotherapy and anti-angiogenic agents (bevacizumab).8 Although the duration on treatment did not differ significantly (5.0 vs. 5.2 vs. 6.0 months respectively), they found a shorter OS in the patients treated with chemotherapy and pembrolizumab when adjusted for baseline ECOG performance status and brain metastasis, which argues against the use of pembrolizumab compounds in chemotherapy regimens after progression on EGFR-TKI.

In contrast, a study from Chen and colleagues from China reported a significantly longer PFS and OS for patients treated with chemotherapy and pembrolizumab compared to chemotherapy alone, with a hazard ratio of 0.64 [95% CI 0.46-0.89] and 0.49 [95% CI 0.31-0.75] respectively.9

Immunotherapy

While treatment with checkpoint inhibitors (CPI) has become the backbone of treatment in patients with NSCLC, its use in patients with EGFR-mutated NSCLC remains controversial. Early studies evaluating checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab) in the second-line setting reported no OS benefit for patients with EGFR-mutated NSCLC. This led to the exclusion of patients with EGFR-mutated NSCLC from almost all immunotherapy studies.10 Post-hoc analysis of the PACIFIC trial showed that adjuvant durvalumab did not lead to better outcomes compared to placebo in patients with EGFR-mutated NSCLC after chemo-radiation.11

All these trials suggest that CPIs are ineffective in patients with EGFR-mutated NSCLC. The only exception may be atezolizumab. In the IMPOWER150 trial, 10% of the patients had an EGFR mutation. A subgroup analysis from IMPOWER150 reported a survival benefit for patients treated with chemotherapy combined with bevacizumab and atezolizumab (known as ABCP) compared to chemotherapy with bevacizumab. The differences were numerically in favor of ABCP but not statistically significant. However, this subgroup was not appropriately powered for formal statistical testing.12, 13

Based on these results, the European Medicines Agency extended approval for ABCP to EGFR-mutated NSCLC patients. Until there is better evidence, ABCP will remain controversial in this patient population where all other CPIs seem ineffective. In addition, ORIENT-31, a phase-3 study, evaluated cisplatin, pemetrexed, sintilimab and bevacizumab biosimilar IBI305 in patients with EGFR-mutated NSCLC previously treated with an EGFR-TKI. They reported significantly better PFS when compared to chemotherapy, however the immature OS data have shown no significant differences yet.14

The results of KEYNOTE-789 were presented at American Society of Clinical Oncology Annual Meeting in 2023, however the manuscript is still awaited. Patients with stage IV EGFR-mutated lung cancer with progression after EGFR-TKI were randomized to pembrolizumab plus chemotherapy or chemotherapy alone. The trial did not show an improvement in PFS or OS for the experimental arm, and thus did not support the implementation of pembrolizumab plus chemotherapy in clinical practice for patients with an EGFR-mutation.15

Future Directions

Even though many studies have been performed evaluating different treatments after osimertinib resistance, to this day there is no clear answer to the question of which treatment strategy is best for which patients.

Compared to TKI treatment in EGFR-mutated NSCLC, the response rate and duration of response of subsequent chemotherapy are relatively low. This is the reason many trials are evaluating other treatment options after first-line EGFR-TKI. These options range from adding agents (such as monoclonal antibodies, chemotherapy, immunotherapy, or targeted therapy directed at bypass mechanisms) to antibody drug conjugates (ADCs) and further exploration of anti-angiogenic agents and CPIs.

Recently, FLAURA2 reported superior PFS in first-line chemotherapy with osimertinib when compared to osimertinib monotherapy. The OS data remain immature, but a second interim OS analysis showed a trend toward OS benefit for the combination arm compared to osimertinib monotherapy.16 See FLAURA 2 Post-progression Outcomes Demonstrate Consistent Benefit, Favor Combination Arm, for more information.  FLAURA2 was not designed to investigate whether the combination of chemotherapy and osimertinib is superior to sequential osimertinib and chemotherapy because second-line chemotherapy was not mandatory in the osimertinib arm and only 54% of the patients in the osimertinib arm were subsequently treated with chemotherapy.2

The results of studies evaluating drugs targeting osimertinib resistance have been underwhelming. Response chances are limited, and duration of response seems to be relatively short. MET-amplification is the most common resistance mechanism after first-line osimertinib. Trials targeting MET-amplification with MET-TKIs are a good example of limited response rates and response duration.17

Results of the ORCHARD study (NCT03944772) may provide further data on these matters. This open-label, multicenter, multi-drug, biomarker-directed phase 2 platform study evaluates different drugs and drug combinations in patients who progressed after first-line osimertinib. Hopefully, the results will soon provide some direction regarding the optimal post-progression treatment for this population.

Promising results have been reported in the MARIPOSA2 study, where chemotherapy was compared to amivantamab (an EGFR and MET bispecific antibody) plus chemotherapy, with or without lazertinib. The combination of amivantamab with chemotherapy and lazertinib was superior to chemotherapy alone in terms of PFS. However, the combination had more toxicity compared to chemotherapy alone, and the overall survival analysis remains to be seen.3

Another group of cytotoxic drugs that is increasingly being investigated are antibody drug conjugates (ADCs). ADCs consist of a monoclonal antibody (mAB) and cytotoxic payload. When a mAB binds to the target antigen of the cells in the tumor, they deliver the cytotoxic payload, causing the cell to die. Currently ADCs targeting HER3, MET, and EGFR are being investigated, as well as combinations of ADCs with TKIs.18 Learn more about the latest in ADC research here.

Physicians and patients alike question which drugs to choose after osimertinib resistance. Should you choose a targeted therapy as the next treatment whenever possible? Or is cytotoxic therapy a safer choice? What is the best sequence of treatment? Does it matter which and how many resistance mechanisms are present?

Answers to these questions will hopefully come soon. In the past decade we have made impressive advancements in the treatment of EGFR-mutated NSCLC, however there is still much to be learned and investigated. We eagerly await what the future holds.

References

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