The past decade has seen two major changes leading to marked improvements in the outcomes of patients with advanced NSCLC. First, the testing for biomarkers such as EGFR mutations and treatment with highly effective tyrosine kinase inhibitors (TKIs) such as osimertinib,
1
and second, the use of immune checkpoint inhibitors (CPIs) alone2
or with chemotherapy in patients without EGFR or ALK alterations.3
,4
Nevertheless, the utility of CPIs in patients with EGFR mutations (and other driver oncogenes) remains controversial, and most trials using immuno-oncology (IO) have excluded these patients,4
making it very hard to know how best to manage these patients after progression on TKIs.Results from the IMpower150 trial led to the approval by the U.S. Food and Drug Administration of the ABCP (atezolizumab, bevacizumab, carboplatin, and paclitaxel) regimen in 2018 as a treatment option for patients with nonsquamous NSCLC in the metastatic setting.
3
In one of the only phase 3 CPI studies to include patients with EGFR mutations (10% of the trial population), an initial subgroup analysis in this group had improved progression-free survival (PFS) with ABCP over BCP (bevacizumab plus carboplatin and paclitaxel) alone, with a hazard ratio (HR) of 0.59 very similar to the overall intention-to-treat (ITT) population (0.61). In a separate analysis in 2019, the authors concluded that overall survival (OS) was also improved in the EGFR mutation-positive (EGFR mutation+) group with the ABCP regimen.5
On the basis of these subgroup analyses, some oncologists and centers adopted the ABCP regimen as a preferred option after progression on TKI,6
and the European Medicines Agency even extended approval of ABCP to EGFR mutation+ patients.7
Recently, however, the final analysis of the EGFR subgroup was published by Nogami et al.8
in the Journal of Thoracic Oncology. The disappearance of a statistically significant OS benefit in these updated results should be a warning light for practitioners who have adopted routine use of ABCP in this patient population.CPIs have become a routine part of the treatment of patients with metastatic NSCLC, but the use of CPIs in EGFR mutation+ patients has been much less fruitful. Early studies evaluating CPIs in the second-line setting versus docetaxel revealed improvement in OS with the use of IO in the overall population, but this benefit did not translate to the subgroup of patients with EGFR mutations.
9
, 10
, 11
A meta-analysis of these studies confirmed these findings revealing no improvement in the OS of the EGFR mutation subgroup (HR = 1.05, p < 0.81).12
These results and other similar findings led to the exclusion of patients with EGFR mutation+ disease in many IO studies. The positive OS results from the initial EGFR subgroup analysis in the IMpower150 study were therefore an exciting outcome that many were ready to implement into clinical practice.The main objective of the IMpower 150 trial was to evaluate whether the combination of ABCP could improve survival outcomes in metastatic, nonsquamous NSCLC. Patients were randomized to either treatment with ABCP, ACP (atezolizumab plus carboplatin and paclitaxel), or BCP. ABCP and ACP were each separately compared with BCP. The primary analysis population was patients with a wild-type genotype (excluded patients with EGFR or ALK genomic alterations). ABCP improved both OS and PFS in the wild-type and the ITT population indicating the combination could be used in advanced nonsquamous disease. The ACP regimen did not reveal statistically significant benefits.
3
,13
Analyses of key subgroups, including patients with EGFR mutations, were first published in 2019 in Lancet Respiratory Medicine. The three other subgroups evaluated were patients with EGFR-sensitizing mutations, before EGFR TKI use, and baseline liver metastases. Results revealed an improvement in OS with ABCP in the EGFR-sensitizing mutation and liver metastases subgroups (HR = 0.31, 95% confidence interval [CI]: 0.11–0.83 and HR = 0.52, 95% CI: 0.33–0.82). PFS was also statistically improved in both of these subgroups and in patients previously on a TKI. These results marked the first time that a survival benefit was found with CPI use in EGFR positive (EGFR+) patients, and the authors rightfully called for further evaluation of this regimen in EGFR mutation+ disease.
5
The final analysis of the subgroups included approximately 20 additional months of data collection. At that point, all the previously positive findings had lost statistical significance. In the EGFR-sensitizing mutation subgroup, the median OS for ABCP was 29.4 months compared with 18.1 months with BCP, but the CI now crossed one (95% CI: 0.31–1.14). The liver metastases subgroup encountered the same issue on final analysis (95% CI: 0.45–1.02). The ABCP arms for the two other subgroups (all EGFR mutations and previous TKI use) continued to reveal a statistically insignificant trend toward improved survival, and the ACP arms for all four subgroups continued to have similar survival results as the counterpart BCP arms.
8
Does this mean that ABCP should not be used routinely for patients with advanced EGFR mutation+ disease? On the basis of the updated results, there would seem to be no compelling evidence that the ABCP combination should be a preferred regimen for EGFR mutation+ patients outside of a clinical trial. One could even argue that treating EGFR+ patients with ABCP on the basis of the initial analysis may have been premature given that this subgroup was small and was removed from the ITT analysis, and thus not included in the Food and Drug Administration label. Only 123 of 1202 patients in the study had an EGFR mutation, and even fewer patients had a sensitizing mutation (91) or were previously treated with a TKI (78). In addition, even though these were prespecified subgroups, the authors acknowledged that the results are exploratory and are not appropriately powered for formal statistical testing.
This lack of power is why the IMpower150 subgroup data by itself should not be used to change clinical practice, although it is certainly compelling enough that the positive trends should still pique interest. The difference between the median OS of the ABCP and BCP arms in both of these subgroups is sizable and clinically significant (11 mo and 9 mo, respectively). The ACP arms, in contrast, had a similar OS compared with BCP. The difference between the ABCP and ACP results suggests that the addition of bevacizumab is potentially making difference. The investigators had hypothesized that bevacizumab would make the tumor environment more susceptible to IO.
The major takeaway from the updated results is that we need larger studies evaluating the efficacy of programmed death-ligand 1 with chemotherapy (and possibly antiangiogenics) in EGFR mutation+ patients. The wait may not be too much longer as two trials focusing on patients with EGFR mutation+ nonsquamous NSCLC after progression on a TKI should have results presented soon. The global ORIENT-31 study is evaluating the quadruple regimen of sintilimab plus bevacizumab and platinum chemotherapy, with an estimated accrual of approximately 600 patients divided between three arms. Interestingly, patients will only have stage IIIB or IIIC disease that is not amenable resection or chemoradiation. It has already been announced in a news release that the study met its first primary end point of improved PFS at a first interim analysis.
14
A second trial looking at this question is the ongoing KEYNOTE-789 study of platinum and pemetrexed with or without pembrolizumab in previously TKI-treated advanced EGFR mutation+ patients.15
The IMpower150 trial is a good example of the importance of subgroup analyses in formulating testable hypotheses, but also in the importance of evaluating final data before making formal practice changes on the basis of these subgroups. It has also highlighted that we still do not have a clear role yet for CPIs in the treatment of EGFR+ disease. At the same time, it did provide a possible strategy out of this dilemma, and the upcoming phase 3 trials likely will put this issue to rest soon. Although the IMpower150 results did not have the same impact as initially thought, it still played an important part in investigating the chemotherapy and CPI combinations in patients with EGFR mutations.
CRediT Authorship Contribution Statement
Bharathi Muthusamy: Writing—original draft.
Nathan Pennell: Writing—review and editing.
References
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- Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639
- Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-a meta-analysis.J Thorac Oncol. 2017; 12: 403-407
- IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC.J Thorac Oncol. 2021; 16: 1909-1924
- Genetic classification of lung adenocarcinoma based on array-based comparative genomic hybridization analysis: its association with clinicopathologic features.Clin Cancer Res. 2005; 11: 6177-6185
- P1.01-81 phase 3 study of pemetrexed-platinum with or without pembrolizumab for TKI-resistant/EGFR-mutated advanced NSCLC: KEYNOTE-789.J Thorac Oncol. 2018; 13: S494
Article info
Publication history
Accepted:
November 12,
2021
Received:
November 10,
2021
Footnotes
Disclosure: Dr. Pennell reports having paid consulting for Merck, Genentech, AstraZeneca, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Amgen, Mirati, Eli Lilly, Inivata, G1 Therapeutics, Xencor, and Janssen. Dr. Muthusamy declares no conflict of interest.
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- IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or BrainJournal of Thoracic OncologyVol. 17Issue 2
- PreviewFinal overall survival (OS) analyses are presented for EGFR mutations and liver or brain metastases subgroups in the phase 3 IMpower150 study (NCT02366143) evaluating atezolizumab plus bevacizumab plus carboplatin and paclitaxel (ABCP) or atezolizumab plus carboplatin and paclitaxel (ACP) versus bevacizumab plus carboplatin and paclitaxel (BCP).
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