|Year : 2022 | Volume
| Issue : 5 | Page : 68-79
Role of immunotherapy in metastatic EGFRm NSCLC: Is it relevant?
Boman Dhabhar1, Tarini P Sahoo2, JK Akshay3
1 Department of Medical Oncology, Fortis Hospital, Mulund, Mumbai, Maharashtra, India
2 Consultant Medical Oncology, Silver Line Hospital, Bhopal, Madhya Pradesh, India
3 Medical Advisor, AstraZeneca Pharma India Ltd, Bangalore, Karnataka, India
|Date of Submission||12-Jan-2021|
|Date of Decision||02-Apr-2021|
|Date of Acceptance||14-Oct-2021|
|Date of Web Publication||24-Mar-2022|
Tarini P Sahoo
Consultant Medical Oncology, Silver Line Hospital, Bhopal, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
EGFR-TKIs have changed the landscape of metastatic NSCLC treatment with a significant improvement in survival of EGFRm patients compared to wild-type EGFR. Even with the newer third generation EGFR TKIs like, Osimertinib, which has proven efficacy against the resistance mutation of EGFRm T790M, progression eventually occurs. There are limited treatment options for patients with metastatic EGFRm NSCLC with other acquired resistance. Therefore, novel therapeutic combination strategies are being researched to overcome potential resistance to EGFR-TKI-targeted therapy. The ICIs targeting the programmed cell death-1 pathway in patients with EGFRm NSCLC were greatly anticipated based on preclinical studies showing increased PD-L1 expression. In clinical settings, this increased expression did not translate into a survival benefit. Treatment with ICIs failed to positively affect EGFRm patients because of multiple reasons: nonsynonymous tumor mutational burden, lower PD-L1 expression in tumors, and cancer cells utilizing alternate immune escape mechanisms. The NCCN guidelines currently do not recommend immunotherapy in patients with metastatic EGFRm NSCLC. Recently, a subgroup analysis in the IMpower150 study provided a signal for overall survival of atezolizumab with bevacizumab plus chemotherapy in EGFRm-TKI progressed patients. Based on these encouraging findings, several combinations of ICIs and EGFR-TKIs are being evaluated in TKI-failed EGFRm patients. These regimens might provide a favorable therapeutic effect by combining higher response rates of TKIs and durable disease control of ICIs. However, further research is warranted to understand the exact underlying molecular and cellular mechanisms responsible for the clinical benefits. In this article, we explored the TKI failed metastatic EGFRm NSCLC, reviewed the available clinical data of ICI use in metastatic EGFRm NSCLC, and discussed its emerging role as a combination regimen in this patient population.
Keywords: Epidermal growth factor receptors, immune checkpoint inhibitors, non-small cell lung cancer, programed cell death-1, programmed cell death ligand-1, tyrosine kinase inhibitors
|How to cite this article:|
Dhabhar B, Sahoo TP, Akshay J K. Role of immunotherapy in metastatic EGFRm NSCLC: Is it relevant?. Indian J Cancer 2022;59, Suppl S1:68-79
| » Introduction|| |
Lung cancer is the leading cause of cancer-related deaths worldwide, with 2.09 million new cases and 1.76 million deaths reported in 2018. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases., The mutations of epidermal growth factor receptor (EGFR) are implicated in 10%–20% of metastatic NSCLC cases in Western countries and 25%–40% cases in Asian countries, with the highest prevalence reported in non-smoking women of East-Asian descent.,, The incidence of EGFR mutations in Indian patients with metastatic NSCLC is comparable to those of other Asian countries (20%–35%), with a predominance of lung cancer cases in non-smoking females.,, Over the last decade, patients with metastatic EGFR mutated NSCLC were treated primarily through standard chemotherapy and tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and osimertinib. Programmed death (PD-1) inhibitors, programmed death-ligand (PD-L1) inhibitors, and a combination of PD-L1 and chemotherapy in the pharmaceutical armamentarium have provided survival gains in metastatic and locally advanced NSCLC., The ICIs, nivolumab, and pembrolizumab (which target PD-1 pathway), and atezolizumab (which target PD-L1 pathway) have demonstrated efficacy in patients with metastatic NSCLC without driver mutations with PD-L1 expression.,
The expression of PD-L1 is upregulated in patients with metastatic EGFR-mutated (EGFRm) NSCLC. The response rate in PD-L1-positive patients is higher with a longer time to progression when treated with TKIs compared with PD-L1-negative patients.,,, Despite this historic progress in the management of metastatic EGFRm NSCLC, a considerable proportion of patients fail to achieve optimal response. This review article explored the TKI-failed metastatic EGFRm NSCLC, summarized the clinical data available for use of ICIs in metastatic EGFRm NSCLC, and discussed further role of immunotherapy in patients with metastatic EGFRm NSCLC.
| » Impact of TKIs on Management of Metastatic EGFRm NSCLC|| |
TKIs have changed the course of therapy for patients with metastatic NSCLC with activating mutations of EGFR. Significant improvements were observed in the overall survival (OS) and progression-free survival (PFS) in several clinical trials [Table 1]. Although osimertinib is effective for treating patients who progressed on first- (gefitinib and erlotinib) or second-generation (afatinib) TKIs, harboring a T790M mutation, and as a first-line treatment option, disease progression eventually occurs. Furthermore, there are limited treatment options for patients with TKI-resistant metastatic disease with other mutations such as MET amplification, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), human epidermal growth factor receptor 2 (HER2), signal transducer and activator of transcription 3 (STAT3), CRK like proto-oncogene (CRKL), BRAF, and AXL., Thus, novel therapeutic strategies are being researched, which include combining different immunotherapy treatments, immunotherapy with chemotherapy, and targeted therapies, including TKIs.
| » Correlation of PD-L1 in EGFRm NSCLC and its Role as a Prognostic Marker|| |
Preclinical studies have shown an increase in PD-L1 expression with activating mutations of EGFR., Correlation between PD-L1 expression and EGFR has been evaluated in several clinical studies. The significant findings from these studies are summarized in [Table 2]. Initially, as per one of the studies, PD-L1 expression was found to have poor prognosis and survival in the wild-type EGFR but not in metastatic EGFRm patients treated with TKIs. PD-L1 expression was also found to be significantly associated with gender and smoking status. However, recent pooled analysis of the studies on the correlation of PD-L1 expression and EGFR mutations provides a contrasting perspective. Patients harboring EGFR mutations were less likely to have increased PD-L1 expression; PD-L1 expression was associated with wild-type EGFR.,, Similar results were found in a few other studies as well.,
|Table 2: Studies describing PD-L1 expression per EGFR mutation status in NSCLC patients|
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Current evidence in global and Indian patients with metastatic NSCLC demonstrate high level of heterogeneity in the PD-L1 expression in NSCLC and correlation of PD-L1 and EGFR mutations [Table 2]. Additionally, PD-L1 expression may also evolve and fluctuate during TKI treatment and may change post-progression. The rationale for these inconsistent results may be attributed to differences in the immunohistochemistry assays used for PD-L1 testing as well as other factors such as antibody clones and interpretive scoring. The expression may also change depending on the tissue samples being tested as well as the assay being used for testing. Another important factor responsible for this variation is different cutoff percentages considered for PD-L1 expression.
In general, metastatic EGFRm patients post TKI failure have a poor prognosis. This was demonstrated in a clinical study on gefitinib (IMPRESS) as well as in a retrospective analysis of 521 EGFR-TKI failed patients., A few studies have evaluated the prognosis of patients with PD-L1 expression in relation to EGFR mutations or wild-type EGFR. On treatment with TKIs, in EGFRm patients expressing PD-L1, median PFS was poor compared with those not expressing PD-L1 (9 months vs. 14 months; P = 0.016). In a meta-analysis, PD-L1 expression was not associated with OS (hazard ratio [HR] =0.90; 95% confidence interval [CI]: 0.42–1.38) or median PFS (HR = 1.03; 95% CI: 0.73–1.33) benefit in patients with metastatic EGFRm NSCLC receiving EGFR-TKIs. The effect of T790M mutations and PD-L1 expression in patients with TKI-resistant metastatic EGFRm NSCLC has been looked at as well., First, on evaluating TKI-resistant EGFR NSCLC prebiopsy samples, a high prevalence of PD-L1 positivity was found in T790M negative samples. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients. Second, the retrospective analysis of survival curves confirmed that PD-L1-/T790M + population had better survival and when treated with nivolumab after disease progression, median PFS difference was not improved in the T790M-negative patients (2.1 months) compared to T790M-positive patients (1.3 months; P = 0.099).,
To summarize, the PD-L1 is expressed more with wild-type EGFR and not with the mutated-EGFR tumors. T790M is less likely to be associated with higher levels of PD-L1 expression. No significant and better PFS and OS outcomes have been demonstrated with the use of ICIs in the TKI resistant EGFR T790M mutation. TKIs still provide the best outcomes in EGFRm tumors, irrespective of the PD-L1 expression. Moreover, the outcomes worsen as the PD-L1 expression increases in these mutated EGFR tumors.
| » Use of ICIs in Patients with Metastatic EGFRm NSCLC|| |
Clinical studies have confirmed longer survival duration in patients with metastatic NSCLC with PD-L1 expression compared to chemotherapy. However, in the Checkmate 057 study, there was a subgroup of patients (n = 82) with metastatic EGFRm NSCLC who did not achieve benefit in terms of median OS (HR 1.18 [95% CI: 0.69–2.00]) and median PFS (HR 1.46 [95% CI: 0.90–2.37]) with nivolumab treatment. Similarly, in the Keynote 010 study comparing pembrolizumab and docetaxel, 86 patients with metastatic EGFRm NSCLC did not show any significant median OS benefit (HR 0.88; 95% CI: 0.45–1.70). In a pivotal phase III trial on atezolizumab (OAK), 42 patients with metastatic EGFRm NSCLC did not have any survival benefit with PD-L1 antibody compared with docetaxel (HR 1.24 [95% CI: 0.71–2.18]). A phase II trial (NCT0287994) was conducted to evaluate the efficacy of pembrolizumab in EGFRm-TKI-naïve patients with metastatic NSCLC. However, the study was discontinued because of lack of efficacy. Two pooled analyses reported similar findings. There was no survival benefit in patients with metastatic EGFRm NSCLC compared to docetaxel therapy (HR = 1.05, [95% CI: 0.70–1.55]; P < 0.81 for the first analysis and HR 1.11 [95% CI: 0.80–1.53]; P = 0.54 for the second pooled analysis)., The hazard ratios of these meta-analyses are shown in Supplementary Data [Supplementary Table 1]. Furthermore, in a network meta-analysis of four studies, it was observed that patients with metastatic NSCLC and EGFR mutation previously treated with TKIs showed better OS when treated with docetaxel in comparison to ICIs. Thus, PD-1/PD-L1 inhibitors have failed to positively affect patients with metastatic EGFRm NSCLC. The key findings from these studies are presented in [Table 3].
The safety of ICIs in patients with advanced NSCLC was also evaluated in these studies. The frequency of treatment-related adverse events was similar in patients with PD-L1 expression <1% and >1%. The most commonly reported adverse events reported in a frequency higher than that in the control group in these studies were rash, pruritus, thyroid disorders, nausea, increased liver enzymes, and diarrhea. The frequency of grade 3 and 4 adverse events was also similar between the chemotherapy and ICI groups.
| » Place of ICIs in Metastatic EGFRm NSCLC Management and Rationale for its Poor Efficacy|| |
Expression of PD-L1 is a biomarker to predict the response to anti-PD-1/PD-L1 agents and has been evaluated in several clinical studies. In a large phase I clinical study on nivolumab, 36% of patients with >5% PD-L1 expression had an objective response, while none of the PD-L1 negative patients had an objective response. PD-1/PD-L1 directed agents have demonstrated longer OS and PFS in patients with PD-L1 expressed tumors. The clinical efficacy of ICIs in metastatic NSCLC has been demonstrated in four pivotal clinical trials where improvement in OS and PFS as compared to chemotherapy was observed [Table 3].,,, Furthermore, the improvement in PFS and OS was related to the amount of PD-L1 expressed on the tumor cells. With nivolumab, patients expressing ≥5% PD-L1 showed improvement in PFS and OS, while in studies with pembrolizumab, favorable outcomes as significantly longer median PFS and median OS was seen in a patient population that had PD-L1 expression on ≥1% (locally advanced and advanced) as well as ≥50% (metastatic) of tumor cells.,, However, favorable outcomes were not observed in a subset of patients with metastatic EGFRm NSCLC. Though these analyses were done retrospectively with a limited patient population, these results do indicate the limited therapeutic role of PD-1/PD-L1 inhibitors in metastatic EGFRm NSCLC. The current standard of care treatment for metastatic EGFRm NSCLC post first-line TKI failure is third-generation TKIs (for T790M mutation-positive), and chemotherapy upon further failure. Several guidelines have recommended a similar line of therapies in EGFRm patients. The summary of these guidelines is presented in [Box 1].
The underlying mechanism for the decreased response of ICIs in metastatic EGFRm patients is not clearly understood. Several hypotheses have been proposed for this poor response and intense research is currently being undertaken to improve the response of ICIs in EGFRm patients. The most important factors determining the efficacy of ICIs are the tumor mutation burden (TMB) and PD-L1 expression.,, Nonsynonymous TMB has emerged as one of the predictive factors for the efficacy of ICIs in NSCLC. The most common EGFR-TKI sensitizing mutations are deletions in EGFR exon 19 and exon 21 L858R point mutations, which account for 90% of various types of activating EGFR mutations. Studies have confirmed that EGFR-mutated tumors, including those with T790M mutations, have low TMB compared to wild-type EGFR.,, Reason for low nonsynonymous TMB in EGFRm cells may be because of the molecular heterogeneity associated with EGFR mutations; another probable reason is smoking as a high TMB is observed with heavy smokers, while EGFR mutations are usually found in non-smoking populations., Higher TMB is associated with improved clinical outcomes, while low TMB is associated with poor response to ICIs., Thus, TMB can partially explain the lack of efficacy of ICIs in EGFRm patients. Theoretically, TMB may increase at the advanced stage of NSCLC after several lines of therapy, including chemotherapy, thereby making the tumor cells susceptible to ICIs. However, there is no clinical evidence still that supports this hypothesis.
The heterogeneity of PD-L1 expression in EGFRm patients is well known. The evidence on PD-L1 expression in patients with EGFRm is conflicting. A rationale for the lower efficacy of ICIs could be because of lower PD-L1 expression in the TKI-treated EGFRm cells compared with the wild-type cells. It has been proven that PD-L1 is a downstream target of the STAT3 pathway that is regulated by EGFR. Thus, EGFR-TKIs suppresses PD-L1 expression, leading to lesser efficacy of PD-1/PD-L1 inhibitors in these tumor types [Figure 1]. PD-L1 expression was found to be significantly correlated with ALK translocation and expression of MET, KRAS mutations, and ERBB2., However, some conflicting literature has also reported increased PD-L1 expression in EGFRm tumors, which is consistent with preclinical findings.,,, The Analysis of the Cancer Genome Atlas More Details and the GCLI cohort has also verified the inverse correlation between EGFR mutation and PD-L1 expression in tumors. The data on the frequency of PD-L1 expression in EGFRm NSCLC has been conflicting, with PD-L1 expression among EGFRm patients ranging from 11% to 72%. Thus, data on EGFR mutations affecting PD-L1 expression cannot explain the low response rate. Another possible mechanism could be the presence of an uninflamed tumor microenvironment in EGFRm NSCLC, which plays a role in developing immunosuppression and immune escape mechanism. EGFRm NSCLC is known to overexpress CD73, which may lead to reduced interferon-gamma (IFN-γ) signaling, and thus immunosuppression. Thus, EGFRm tumors could utilize other immune escape mechanisms to avoid immune attacks; thus, PD-L1/PD-1 inhibitors may not play an instrumental role in management of patients with EGFRm NSCLC. Thus, to overcome the immunosuppression in EGFRm tumors, novel therapeutic options are being investigated.
|Figure 1: EGFR-TKI modulation of PD-L1 expression on tumor cells AKT = Protein kinase B, AP-1 = activator protein-1 transcription factor, CD8 + T cell = cytotoxic T lymphocytes, EGFR = epidermal growth factor receptor, ERK = extracellular signal–regulated kinases, NFκB = nuclear factor kappa-light-chain-enhancer of activated B cells, PD-L1 = programed death ligand-1, PD-1 = programed death receptor-1, PI3K = phosphatidylinositol 3-kinase, STAT3 = signal transducer and activator of transcription 3, TKI = tyrosine kinase inhibitor|
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In a recent study, IMpower150 evaluated a combination of ICI, anti-vascular endothelial growth factor (VEGF), and chemotherapy in patients with progressed NSCLC. The hypothesis for this combination was built on the proposed synergistic effect of these drugs. This international, open-label, randomized, phase 3 study compared the efficacy of combining atezolizumab with bevacizumab plus carboplatin plus placitaxel (ABCP; n = 400) vs. atezolizumab plus carboplatin plus placitaxel (ACP; n = 402) vs. bevacizumab plus carboplatin plus placitaxel (BCP; n = 400). The study included a subgroup of 124 patients with sensitizing EGFR mutations. Improved median OS with ABCP vs. BCP was observed in patients with sensitizing EGFR mutations (OS not estimable [NE] with ABCP [26 of 400] vs. 17.5 months [95% CI: 11.7–NE] with BCP [32 of 400]; HR 0.31 [95% CI: 0.11–0.83]). No OS benefit was seen with ACP (21.4 months) vs. BCP in patients with sensitizing EGFR mutations. While the results from this study are promising in terms of improved PFS and OS, the analysis has been done in a small subgroup with antecedent limitations Nevertheless, this study has provided a different approach to strategize the course of therapy in patients with EGFR activating mutations. Based on these findings, several combinations of ICIs and EGFR-TKIs are being evaluated for third-line therapy after failure of TKIs in patients with advanced EGFRm NSCLC. The available results of some of these studies are elaborated in [Table 3].
| » Future of Immunotherapy in Patients with Metastatic EGFRm|| |
First-line treatment with EGFR-TKIs increases the median PFS in patients with metastatic EGFRm NSCLC compared to chemotherapy. However, post-progression with TKIs, there is a dearth of treatment strategies. Osimertinib, as a second-line treatment for T790M resistance, increases the median PFS by approximately 10 months, but after failure of osimertinib, chemotherapy seems to be the only viable option currently, which has a dismal median OS of 5–6 months. Similarly, as a first-line treatment, osimertinib has shown a significant increase in median OS (38.6 months), but post failure of osimertinib, the options are limited. Use of PD-1/PD-L1 monotherapy as second- or third-line treatment after failure of TKIs also did not have any favorable outcome.,, Thus, several combination treatments of TKIs and ICIs are now being researched to increase the survival in TKI-resistant metastatic EGFRm NSCLC [Figure 2]. The rationale of these combinations is based on the creation of a favorable tumor microenvironment to elicit an appropriate immune response. Moreover, TKIs are known to have a moderate duration of response but higher response rate, while ICIs have durable disease control but a lower response rate. Thus, combining these factors to a favorable therapeutic effect may result in a better prognosis in patients with metastatic EGFRm NSCLC. However, one of the major concerns in designing and executing these studies is the toxicity profiles of the individual drugs. Interstitial lung disease is one of the common adverse events with ICIs. In the TATTON study (NCT02143466), the incidence of interstitial lung disease was higher in the combination group of osimertinib and durvalumab compared to the individual drugs. Thus, well-designed early phase studies to determine the optimal dose, schedule, and sequence of EGFR-TKIs with ICIs can result in understanding the overlapping adverse events and finding ways to mitigate them.
|Figure 2: Ongoing studies on the combination of EGFR-TKIs and ICIs in NSCLC|
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Several other immunomodulatory agents are also being evaluated for their role in advanced NSCLC. One such target is indoleamine 2,3-dioxygenase (IDO). IDO is a key regulator of immune tolerance that acts by affecting the T cell response. Two phase III studies are evaluating first-line epacadostat (selective IDO inhibitor) plus pembrolizumab with or without platinum-based chemotherapy in patients with advanced NSCLC., LY-55716 with pembrolizumab is another combination that is being evaluated with pembrolizumab. LY-55716 is a small molecule agonist of the retinoic acid receptor-related orphan receptor, which increases the activity of PD-1/PD-L1 inhibitors, augments the number and activation of tumor-infiltrating lymphocytes, and diminishes immune suppression. Another target identified is CD73; CD73 expression was found to be increased by tenfold in EGFRm NSCLC, which along with reduced expression of the IFNγ mRNA signature has been linked to an immune suppressive environment in EGFRm NSCLC. A trial is currently underway evaluating an anti-CD73 molecule (oleclumab, MEDI9447) in combination with osimertinib in EGFRm NSCLC (NCT03381274)
| » Conclusion|| |
In crux, though ICIs have changed the course of therapy with improved survival in metastatic NSCLC, patients with EGFRm do not benefit from PD-1/PD-L1 monotherapy in initial lines of therapy. The mechanism of action of EGFR-TKIs, the signaling pathways they are associated with, and the uninflamed microenvironment in EGFRm NSCLC play an important role in unfavorable survival outcomes in these patients when treated with ICI therapy. Thus, post TKI failure, the prognosis of metastatic EGFRm NSCLC patients remains poor. To overcome this, several newer treatment modalities, including a combination of ICI, anti-VEGF, and chemotherapy, are being studied. The option of combining PD-L1/PD-1 inhibitors and EGFR-TKIs is also currently investigated for treating TKI-failed patients. Preliminary data suggest that these combinations may open a new approach to overcome the treatment obstacle of EGFR-TKI failure in patients with NSCLC.
- Evidence on the correlation between PD-L1 expression and EGFR mutations is not conclusive
- PD-L1/PD-1 monotherapy has shown limited efficacy in metastatic EGFRm NSCLC
- Platinum chemotherapy is the only option available post TKI failure
- IMpower150 subgroup analysis provides a signal for OS in TKI-resistant metastatic NSCLC
- Several newer combination approaches are being investigated in EGFRm progressed patients.
List of abbreviations
CI confidence interval
CRKL CRK like proto-oncogene
EGFR Epidermal growth factor receptor
EGFRm EGFR mutant
HER2 human epidermal growth factor receptor 2
HR hazard ratio
ICI immune checkpoint inhibitor
NSCLC non-small cell lung cancer
OS overall survival
PD-1 programmed cell death-1
PD-L1 programmed death-ligand 1
PFS progression-free survival
PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
STAT3 signal transducer and activator of transcription 3
TKI tyrosine kinase inhibitors
TMB tumor mutation burden
VEGF vascular endothelial growth factor
| » Acknowledgments|| |
The authors would like to thank AstraZeneca Pharma India Ltd. for the development of this manuscript in collaboration with Ms. Prajakta Nachane M. Pharm. from Covance Scientific Services and Solutions Pvt. in accordance with the GPP3 guidelines (http://www. ismpp.org/gpp3).
Financial support and sponsorship
AstraZeneca Pharma India Ltd.
Conflicts of interest
J K Akshay is an employee of AstraZeneca Pharma India Ltd
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]