
==== Front
ESMO Open
ESMO Open
ESMO Open
2059-7029
Elsevier

S2059-7029(24)01429-7
10.1016/j.esmoop.2024.103660
103660
Original Research
Chemotherapy and programmed cell death protein 1/programmed death-ligand 1 inhibitor combinations for tyrosine kinase inhibitor-resistant, epidermal growth factor receptor-mutated non-small-cell lung cancer: a meta-analysis
Piotrowska Z. zofia.piotrowska@mgh.harvard.edu
∗
Yeap B.Y.
Gainor J.F.
Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, USA
∗ Correspondence to: Dr Zofia Piotrowska, Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, 55 Fruit St, Yawkey 7B, Boston, MA 02114, USA. Tel: +1-617-724-4000 zofia.piotrowska@mgh.harvard.edu
20 8 2024
9 2024
20 8 2024
9 9 103660© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

The role of adding immune checkpoint inhibitors to chemotherapy in tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) remains unknown. We carried out a meta-analysis to comprehensively assess the role of chemoimmunotherapy combinations, with and without vascular endothelial growth factor (VEGF) inhibition, in TKI-resistant, EGFR-mutant NSCLC.

Materials and methods

We systemically searched PubMed/MEDLINE and the proceedings of key annual meetings between 2018 and 2024 to identify randomized studies that evaluated chemoimmunotherapy combinations and included patients with EGFR-mutant NSCLC. Six randomized, phase III trials (CheckMate-722, KEYNOTE-789, ORIENT-31, IMpower150, IMpower151, and ATTLAS) were included in the meta-analysis. To compare progression-free survival (PFS) and overall survival (OS) outcomes, we extracted hazard ratio (HR) and 95% confidence interval (CI) for PFS and OS for EGFR-mutant subgroups from each study. We used the fixed effects model with inverse variance weighting to estimate the overall effect sizes for PFS and OS for chemoimmunotherapy combinations (with and without VEGF inhibitors) versus control arms.

Results

A total of 1772 patients with EGFR-mutant NSCLC were included. Adding programmed death-ligand 1 [PD-(L)1] inhibitors to chemotherapy significantly improved PFS (HR 0.77, 95% CI 0.67-0.88, P = 0.0002). This effect was greater when both PD-(L)1 and VEGF inhibition were utilized (PFS: HR 0.62, 95% CI 0.52-0.73, P < 0.0001). The pooled OS HR was 0.86 (95% CI 0.75-1.00, P = 0.0429) with the chemotherapy + PD-(L)1 combinations and 0.98 (95% CI 0.79-1.22, P = 0.8463) with dual PD-(L)1/VEGF inhibition.

Conclusions

Despite modest improvements in PFS, most pronounced when both PD-(L)1 and VEGF inhibitors are added to chemotherapy, neither strategy led to clinically meaningful improvements in OS. Our results do not support the broad use of chemoimmunotherapy combinations in TKI-resistant, EGFR-mutant lung cancer. Novel immunotherapy approaches are urgently needed for oncogene-driven NSCLC.

Highlights

• We assessed chemoimmunotherapy combinations, with and without VEGF inhibition, in TKI-resistant, EGFR-mutant NSCLC.

• The meta-analysis included six randomized trials and 1772 patients with EGFR-mutant NSCLC.

• Adding PD-(L)1 inhibitors to chemotherapy improved PFS, particularly when both PD-(L)1 and VEGF inhibitors were used.

• Neither combination led to clinically significant improvement in OS when compared with chemotherapy.

• Our results do not support the broad use of chemoimmunotherapy in TKI-resistant, EGFR-mutant lung cancer.

• Novel approaches are needed to improve the efficacy of immunotherapy in EGFR-mutant NSCLC.

Key words

non-small-cell lung cancer
EGFR
immunotherapy
chemoimmunotherapy
meta-analysis
==== Body
pmcIntroduction

Activating mutations in the epidermal growth factor receptor (EGFR) define a distinct subset of non-small-cell lung cancer (NSCLC) that are sensitive to EGFR tyrosine kinase inhibitors (TKIs). For patients with advanced, EGFR-mutant NSCLC, third-generation EGFR inhibitors are the preferred first-line therapy but acquired resistance eventually develops.1 While tissue biopsies obtained after progression identify potentially targetable resistance mutations in a subset of patients,2,3 most patients lack these alterations and platinum-doublet chemotherapy remains the only approved next-line therapy for TKI-resistant, EGFR-mutant NSCLC.

Over the past decade, immune checkpoint inhibitors (ICIs) targeting programmed death-(ligand) 1 [PD-(L)1] have transformed the care of patients with NSCLC. Nonetheless, PD-(L)1 inhibitor monotherapy has limited benefit in cancers harboring EGFR mutations.4, 5, 6 In a meta-analysis of randomized studies examining ICIs after platinum-doublet chemotherapy among patients with EGFR-mutant NSCLC, single-agent PD-(L)1 inhibitors did not show a survival benefit compared with docetaxel.7 Recently, a series of pivotal studies demonstrated improvements in progression-free survival (PFS) and overall survival (OS) when PD-(L)1 inhibitors were added to chemotherapy, establishing this as a standard front-line therapy for oncogene driver-negative NSCLC.8, 9, 10, 11 Importantly, the majority of these trials included only a small number of patients with EGFR mutations or, more commonly, excluded them altogether. Therefore whether PD-(L)1 inhibitors should be added to platinum-doublet chemotherapy in EGFR-mutant NSCLC after progression on EGFR TKIs remains unknown.

Several landmark studies have now prospectively evaluated the role of adding PD-(L)1 inhibitors, alone or in combination with vascular endothelial growth factor (VEGF) inhibition, to platinum-doublet chemotherapy in EGFR-mutant NSCLC.12, 13, 14, 15, 16 To comprehensively evaluate the role of chemoimmunotherapy among patients with TKI-resistant, EGFR-mutant NSCLC, we conducted a systematic review and meta-analysis of clinical trials that prospectively evaluated the combination of platinum-based chemotherapy and PD-(L)1 inhibitors in this population.

Materials and methods

Search strategy and inclusion criteria

A systematic literature search of PubMed/MEDLINE was last performed on 8 April 2024 using the following terms: epidermal growth factor receptor OR EGFR AND lung cancer AND (PD-1 inhibitor OR PD-L1 inhibitor OR nivolumab OR pembrolizumab OR atezolizumab OR durvalumab OR sintilimab OR avelumab) AND chemotherapy. In addition, we manually searched abstracts from the proceedings of annual meetings of the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and the World Lung Cancer Conference (WCLC) from 2018-2024 to identify unpublished abstracts. We also manually reviewed the reference lists of eligible publications to identify other potential studies. We used the following inclusion criteria for the meta-analysis: (i) prospective, randomized trials evaluating chemoimmunotherapy combinations that enrolled patients with advanced NSCLC and included those with EGFR mutations, (ii) availability of hazard ratio (HR) and 95% confidence intervals (CIs) for PFS and OS rates for comparison between treatment arms, and (iii) abstracts/manuscripts available in English. Studies not meeting these criteria, particularly those that utilized PD-(L)1 inhibitor monotherapy, were not randomized, were focused on earlier stages of disease (i.e. non-metastatic NSCLC), did not include patients with EGFR-mutant NSCLC, or did not provide results for this patient subset, were excluded (additional reasons for study exclusion are summarized in Figure 1). Eligible studies were independently identified by two authors (JFG and ZP). Disagreements were resolved by discussion with all three authors. When multiple publications of the same study were available, the most recent publication was used, except in cases where the relevant data were provided only in an older publication. Similarly, for studies presented in both abstract and published form, data from the published manuscript were used. A systematic review protocol was not registered for this study.Figure 1 Flow diagram of inclusion/exclusion criteria and study selection for meta-analysis.EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; PD-(L)1, programmed death-(ligand) 1.

Data analysis

For each trial, we extracted study and patient characteristics, HRs, and 95% CIs for PFS and OS for subgroups defined by EGFR mutation status. Data were extracted independently by one author (ZP) and verified by all authors. We used the fixed effects model with inverse variance weighting for pooling to estimate the overall effect sizes for PFS and OS. Interaction between PD-(L)1 and VEGF inhibitors was assessed to determine if the treatment effect depended on the use of anti-VEGF therapy. All hypothesis tests were two-sided and computed using the R package meta (R Foundation, Vienna, Austria).17 Publication bias was assessed by Egger’s test for funnel plot asymmetry, and heterogeneity between studies was based on the REML estimator.18,19

Results

Six randomized, phase III trials matched our search criteria and were included in the meta-analysis (Table 1 and Figure 1).12, 13, 14, 15, 16,20, 21, 22 Two trials evaluated platinum–pemetrexed in combination with a programmed cell death protein 1 (PD-1) inhibitor: CheckMate-722 utilized nivolumab, while KEYNOTE-789 utilized pembrolizumab. Four trials, ORIENT-31, IMpower150, IMpower151, and ATTLAS (KCSG-LU19-04), tested the addition of both PD-(L)1 and VEGF inhibitors to chemotherapy. In ORIENT-31, patients received cisplatin/pemetrexed alone (arm C), cisplatin/pemetrexed with the PD-1 inhibitor sintilimab (arm B), or cisplatin/pemetrexed in combination with both sintilimab and IBI305 (a bevacizumab biosimilar; arm A). IMpower150 treatment arms consisted of carboplatin, paclitaxel, and bevacizumab (BCP); carboplatin, paclitaxel, and atezolizumab (ACP); or all four drugs (ABCP), while IMpower151 treatment arms consisted of carboplatin, bevacizumab, and pemetrexed/paclitaxel (investigator’s choice) with either atezolizumab (arm A) or placebo (arm B). Finally, in the ATTLAS trial, the two treatment arms consisted of ABCP (carboplatin, paclitaxel, bevacizumab, and atezolizumab as in IMpower150) and a control arm of carboplatin or cisplatin with pemetrexed. Notably, the IMpower130 trial was identified in our search but ultimately excluded because the study reported the outcomes of the small cohort of patients with EGFR-mutant and ALK-positive NSCLC in aggregate only (i.e. the number of EGFR-mutant patients enrolled in the trial was not provided).10 The interaction effect between PD-(L)1 and VEGF inhibitors was borderline significant for PFS (P = 0.0614) in our meta-analysis, hence effect sizes were estimated separately according to the use of anti-VEGF therapy.Table 1 Summary of included trials and primary study outcomes

Study	Treatment arms	Patients with EGFR mutations, n	Median PFS, experimental versus control arm (months)	PFS HR (95% CI)	Median OS, experimental versus control arm (months)	OS HR (95% CI)	
Chemo + ICI	
CheckMate-72214	Chemo + nivolumab	144	5.6 versus 5.4	0.75 (0.56-1.00)	19.4 versus 15.9	0.82 (0.61-1.10)	
Chemo	150	
KEYNOTE-78913	Chemo + pembrolizumab	245	5.6 versus 5.5	0.80 (0.65-0.97)	15.9 versus 14.7	0.84 (0.69-1.02)	
Chemo + placebo	247	
ORIENT-3112,20	Chemo + sintilimab	158	5.5 versus 4.3	0.72 (0.55-0.94)	20.5 versus 19.2	0.97 (0.71-1.32)	
Chemo + placebo	160	
IMpower15021,22	Chemo + atezolizumab	45	6.9 versus 6.9	1.14 (0.73-1.78)	21.4 versus 20.3	1.16 (0.71-1.89)	
Chemo + bevacizumab	45	
Total (Chemo + ICI)		1194					
Chemo + ICI + VEGF	
ATTLAS15	Chemo + bevacizumab + atezolizumab	154	8.48 versus 5.62	0.62 (0.45-0.86)	20.63 versus 20.27	1.01 (0.69-1.46)	
Chemo	74	
ORIENT-3112,20	Chemo + IBI305 + sintilimab	158	7.2 versus 4.3	0.51 (0.39-0.67)	21.1 versus 19.2	0.98 (0.72-1.34)	
Chemo + placebo	160	
IMpower15021,22	Chemo + bevacizumab + atezolizumab	34	10.2 versus 6.9	0.61 (0.36-1.03)	26.1 versus 20.3	0.91 (0.53-1.59)	
Chemo + bevacizumab	45	
IMPower15116	Chemo + bevacizumab + atezolizumab	79	8.5 versus 8.3	0.86 (0.61-1.21)	NR	NR	
Chemo + bevacizumab + placebo	79	
Total (Chemo + ICI + VEGF)		783					
Total (All Patients)		1772					
Chemo, chemotherapy; CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; ICI, immune checkpoint inhibitor; NR, not reported; OS, overall survival; PFS, progression-free survival; VEGF, vascular endothelial growth factor.

The CheckMate-722, KEYNOTE-789, and ORIENT-31 trials enrolled only patients with EGFR-mutant NSCLC. In the ATTLAS trial, patients with both EGFR and ALK-positive NSCLC were included, but the majority (215/228) of enrolled patients had an activating EGFR mutation; only 13 patients enrolled in ATTLAS had an ALK translocation and were included in the meta-analysis. The IMpower150 and 151 trials enrolled patients with and without known sensitizing EGFR mutations. In total, 1772 patients with EGFR-mutant NSCLC were included in the six studies (Table 1). Among them, 54% had an EGFR exon 19 deletion and 40% had EGFR L858R. Among those patients with data reported, baseline clinical and pathologic characteristics are summarized in Table 2. About 32% had a history of central nervous system metastases, and 41% had previously received a third-generation EGFR inhibitor; 65% of patients had no smoking history and 14% had tumor PD-L1 expression tumor proportion score ≥50% (Table 2). PD-L1 expression was not available/unevaluable in 49% of patients across all studies.Table 2 Patient characteristics

Study	Treatment arms	Patients with EGFR mutations, n	EGFR mutation, n (%)	History of prior third-generation EGFR, TKI, n (%)	History of brain metastases, n (%)	PD-L1, n (%)	Smoking status, n (%)	Race, n (%)	
Del19	L858R	Other	<1%	≥1%	≥50%	Unknown/unevaluable	Never	Current/former	Asian	White	Other	
Chemo + ICI	
CheckMate-72214	Chemo + nivolumab	144	80 (56)	54 (38)	10 (7)	32 (22)	51 (35)	54 (38)	72 (50)	30 (21)	17 (12)	88 (61)	56 (39)	136 (94)	7 (5)	1 (1)	
Chemo	150	82 (55)	58 (39)	10 (7)	36 (24)	51 (34)	60 (40)	76 (51)	39 (26)	14 (9)	94 (63)	56 (37)	139 (93)	11 (7)	0	
KEYNOTE-78913	Chemo + pembrolizumab	245	139 (57)	103 (42)	3 (1)	116 (47)	51 (21)	NR	NR	52 (21)	NR	161 (66)	84 (34)	150 (61)b	NR	NR	
Chemo + placebo	247	142 (58)	102 (41)	3 (1)	121 (49)	47 (19)	NR	NR	51 (21)	NR	164 (66)	83 (34)	150 (61)b	NR	NR	
ORIENT-3112,20	Chemo + sintilimab	158	85 (54)	62 (39)	11 (7)	54 (34)	58 (37)	11 (7)	5 (3)	5 (3)	142 (90)	109 (69)	49 (31)	158 (100)	0	0	
Chemo + placebo	160	88 (55)	61 (38)	11 (7)	59 (37)	59 (37)	6 (4)	7 (5)	4 (3)	147 (92)	114 (71)	46 (29)	160 (100)	0	0	
IMpower15021,22	Chemo + atezolizumab	45	20 (44)	13 (29)	12 (27)	NR	NR	23 (51)	22 (49)	4 (9)	0	29 (64)	16 (36)	20 (44)	25 (56)	0	
Chemo + bevacizumab	45	23 (51)	9 (20)	13 (29)	NR	NR	29 (64)	16 (36)	5 (11)	0	20 (44)	25 (56)	18 (40)	25 (56)	2 (4)	
Chemo + ICI + VEGF	
ATTLAS15	Chemo + bevacizumab + atezolizumab	154	70 (48)	75 (51)	2 (1)	63 (41)	67 (44)	55 (60)	37 (40)	15 (16)	62 (40)	97 (63)	57 (37)	NR	NR	NR	
Chemo	74	42 (62)	25 (37)	1 (2)	29 (39)	31 (42)	24 (49)	25 (51)	8 (16)	25 (51)	46 (62)	28 (38)	NR	NR	NR	
ORIENT-3112,20	Chemo + IBI305 + sintilimab	158	80 (51)	70 (44)	8 (5)	62 (39.2)	59 (37)	4 (3)	6 (4)	3 (2)	148 (94)	111 (70)	47 (30)	158 (100)	0	0	
Chemo + placebo	160	88 (55)	61 (38)	11 (7)	59 (37)	59 (37)	6 (4)	7 (5)	4 (3)	147 (92)	114 (71)	46 (29)	160 (100)	0	0	
IMpower15021,22	Chemo + bevacizumab + atezolizumab	34	15 (44)	11 (32)	8 (24)	NR	NR	20 (59)	14 (41)	4 (12)	0	20 (59)	14 (41)	12 (35)	21 (62)	1 (3)	
Chemo + bevacizumab	45	23 (51)	9 (20)	13 (29)	NR	NR	29 (64)	16 (36)	5 (11)	0	20 (44)	25 (56)	18 (40)	25 (56)	2 (4)	
IMPower15116	Chemo + bevacizumab + atezolizumab	79	50 (63)	26 (33)	3	56 (70)	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	
Chemo + bevacizumab + placebo	79	46 (58)	31 (39)	2	48 (61)	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	
Totala, all patients, n (%)		1772	962 (54)	700 (40)	97 (5)	676 (41)a	474 (32)a	286 (25)a	280 (25)a	220 (14)a	555 (49)a	1053 (65)a	561 (35)a	1101 (68)a	89 (8)a	4 (<1)a	
Chemo, chemotherapy; Del19, exon 19 deletion; EGFR, epidermal growth factor receptor; ICI, immune checkpoint inhibitor; NR, not reported; PD-L1, programmed death-ligand 1; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

a Where indicated, percentages are calculated among patients with available data for each category. Data for central nervous system metastases and treatment history (use of prior third-generation EGFR TKI) were not reported in the IMpower150 and IMpower151 studies (16% of the overall patient population). In KEYNOTE-789 (28% of the overall study population), PD-L1 data were reported only for the percent of patients with PD-L1 ≥50%; further breakdown by PD-L1 status was not provided. Breakdown by PD-L1 status is also missing from the IMpower151 trial (158 patients 9% of the overall cohort).

b In KEYNOTE-789, patients reported as ‘enrolled in East Asia’ are included in the ‘Asian’ category; further details of breakdown by race were not provided. Breakdown by race is not provided in the IMpower151 and ATTLAS studies.

To determine the effect of adding PD-(L)1 inhibitors (without anti-VEGF therapy) to chemotherapy in EGFR-mutant NSCLC, we performed a meta-analysis of CheckMate-722, KEYNOTE-789, and the chemotherapy and sintilimab arm of ORIENT-31, each of which compared the chemoimmunotherapy combination with a control arm of chemotherapy alone. Treatment with a chemotherapy–PD-(L)1 combination resulted in a significant improvement in PFS compared with chemotherapy alone (PFS: HR 0.77, 95% CI 0.67-0.88, P = 0.0002, bias P = 0.3317, heterogeneity P = 0.8162; Figure 2A). The pooled HR for OS was 0.86 (95% CI 0.75-1.00, P = 0.0429, bias P = 0.6487, heterogeneity P = 0.6927; Figure 2B). The impact of patient subgroups, including by PD-L1 expression status, could not be evaluated due to heterogeneity in reporting across studies and incomplete data availability (Table 2). Of note, IMpower150 was excluded from this initial analysis because the control arm used a combination of chemotherapy with bevacizumab. However, the inclusion of IMpower150 resulted in similar outcomes (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2024.103660).Figure 2 Forest plots of meta-analysis results. (A) Forest plot of hazard ratios comparing progression-free survival among patients who received chemotherapy with a PD-(L)1 inhibitor versus chemotherapy alone (top), or chemotherapy with a PD-(L)1 and VEGF inhibitor versus chemotherapy alone (bottom). (B) Forest plot of hazard ratios comparing overall survival among patients who received chemotherapy with a PD-(L)1 inhibitor versus chemotherapy alone (top), or chemotherapy with a PD-(L)1 and VEGF inhibitor versus chemotherapy (bottom). Note that IMpower151 is not included in the overall survival analysis as overall survival outcomes were not provided for the EGFR-mutant patient subgroup. For each trial, individual hazard ratios are represented by squares, with the horizontal line indicating the 95% confidence interval (CI). The diamonds represent the estimated overall effect based on the meta-analysis. EGFR, epidermal growth factor receptor; HR, hazard ratio; ICI, immunotherapy; PD-(L)1, programmed death-(ligand) 1; VEGF, vascular endothelial growth factor.

We next analyzed clinical outcomes among EGFR-mutant patients receiving dual PD-(L)1/VEGF inhibition with chemotherapy. This analysis included four studies: ORIENT-31, IMpower150, IMpower151, and ATTLAS. Importantly, two studies (ORIENT-31 and ATTLAS) included control arms of chemotherapy with or without a placebo alone, while two studies (IMpower150 and IMpower151) included control arms of chemotherapy plus bevacizumab with or without a placebo. For the purposes of this meta-analysis, all four studies were included. Across 783 patients with EGFR-mutant NSCLC, the addition of anti-PD-(L)1 and anti-VEGF therapy to chemotherapy resulted in a 38% reduction in the risk of disease progression (PFS HR 0.62, 95% CI 0.52-0.73, P < 0.0001, bias P = 0.6501, heterogeneity P = 0.1379; Figure 2A). However, there was no difference in OS between the four-drug regimens and the control arms (HR 0.98, 95% CI 0.79-1.22, P = 0.8463, bias P = 0.4848, heterogeneity P = 0.9538; Figure 2B).

Discussion

For patients with EGFR-mutant NSCLC who progress on first-line osimertinib, platinum-doublet chemotherapy remains the only approved post-TKI treatment regimen. The role of adding ICIs to chemotherapy in this population has, until recently, been unknown. In this meta-analysis, we observed a modest improvement in PFS when chemotherapy is combined with PD-(L)1 inhibitors. Notably, we observed a more pronounced improvement in PFS when dual PD-(L)1 and VEGF inhibition is added to chemotherapy, suggesting that the addition of anti-VEGF therapy may enhance the activity of chemoimmunotherapy in EGFR-mutant NSCLC. VEGF has been shown to mediate immunosuppression in NSCLC, an effect that may be particularly relevant in EGFR-mutant cancers, where EGFR activation has been shown to drive VEGF expression via upregulation of HIF-1alpha.23 Despite improvements in PFS with the combinations of chemotherapy and PD-(L)1 inhibition with or without VEGF inhibition, neither combination led to clinically significant improvements in OS in this meta-analysis. Thus these data suggest that, for most patients with EGFR-mutant NSCLC who progress on first-line osimertinib, platinum-doublet chemotherapy without immunotherapy should remain the current standard of care.

Across the trials included in this meta-analysis, predictive biomarkers to identify EGFR-mutant NSCLCs most likely to benefit from immunotherapy remained elusive. While patients with PD-L1 ≥50% treated with chemotherapy and nivolumab had the longest median PFS in the CheckMate-722 study, the results did not reach statistical significance. Similarly, the observed PFS benefit of the ABCP treatment arm was greatest among patients with PD-L1 ≥50% in the ATTLAS trial, but the findings are limited by small patient numbers. Furthermore, no significant difference was observed between treatment arms among patients with PD-L1 ≥50% enrolled in IMpower151. In KEYNOTE-789, PFS results were not reported by PD-L1 status, but there was no difference in OS by PD-L1 status (<1% or ≥1%). The ORIENT-31 and IMpower150 studies did not report results by PD-L1 status. Historically, PD-L1 expression has not been associated with immunotherapy response in this population, and there is little evidence to support the use of PD-L1 status to select patients with EGFR-mutant NSCLC for chemoimmunotherapy combinations. Similarly, subgroup analyses of these studies failed to identify clinical characteristics that could be used to select patients; when tested, neither the type of EGFR mutation, treatment history, nor the presence of brain metastases have been associated with clinical outcomes on chemoimmunotherapy.

Our study has several important limitations. First, we did not have access to individual patient-level data, and thus were unable to carry out a meta-analysis of clinical outcomes among such subgroups of interest due to the heterogeneity of how subgroups were defined in each trial and variable data reported. For example, there was significant heterogeneity among the racial/ethnic and geographic composition of the patients enrolled in the included trials; ORIENT-31, IMpower151, and ATTLAS enrolled patients exclusively in Asia and >90% of those enrolled in Checkmate 722 were Asian, while other studies including KEYNOTE-789 enrolled a more global population. The impact of these factors on the effectiveness of chemoimmunotherapy could not be evaluated in this meta-analysis.

In addition, our findings regarding the role of anti-VEGF and anti-PD-(L)1 combination are limited by the different control arms used across the four studies that evaluated this approach. Two of the trials, ORIENT-31 and ATTLAS, used a chemotherapy control arm without bevacizumab, while the control arms of both IMpower150 and 151 trials included chemotherapy and bevacizumab, potentially impacting the outcomes of these trials and of the meta-analysis. OS outcomes should be interpreted with caution as this measure is likely to be impacted by the subsequent treatments received by patients, which are not reported in the individual trials and thus cannot be accounted for in this meta-analysis. Finally, our conclusions about EGFR-mutant NSCLC may be limited by the 13 patients with ALK-positive disease enrolled in the ATTLAS study (who were not excluded from the meta-analysis because results from the study were not broken down by genotype subgroup), but given the similarities between immunotherapy outcomes in EGFR- and ALK-positive NSCLC,4 we do not expect this small population to have a major impact on our findings.

While our meta-analysis focused only on efficacy, it should be noted that the use of checkpoint inhibitors in EGFR-mutant lung cancers also raises important safety considerations. Currently, the role of continuing osimertinib with second-line chemotherapy remains an open question and the subject of an ongoing phase III trial (COMPEL; NCT04765059), but the combination is commonly employed in clinical practice, particularly for patients whose central nervous system disease remains controlled on osimertinib despite systemic disease progression.24 Importantly, this approach cannot be safely deployed for patients whose treatment will include a PD-(L)1 inhibitor. The combination of durvalumab and osimertinib led to unexpectedly high rates of pneumonitis (35%) in the TATTON trial,25 and recent data suggest that treatment-related toxicities including pneumonitis are also more common when patients receive an EGFR TKI following a PD-(L)1 inhibitor.26

Moving forward, novel approaches beyond PD-(L)1 inhibitors will likely be required to generate more effective antitumor immune responses in EGFR-mutant NSCLC, with multiple strategies being investigated. For example, a recent study demonstrated upregulation of the CD73/adenosine pathway in EGFR-mutant NSCLC,27 and a phase Ib/II study of the anti-CD73 antibody oleclumab and osimertinib showed an objective response rate of 25% at the first dose level tested.28 Adaptive cell therapies are also being studied in NSCLC and have thus shown anecdotal reports of benefit in EGFR-mutant NSCLC. In a recent trial of autologous TIL therapy with nivolumab, the most durable benefit was observed in a patient with an EGFR exon 19 deletion whose disease was refractory to nivolumab.29 Further efforts to identify novel targets for immunotherapy use in EGFR-mutant NSCLC will be needed.

For patients who experience disease progression after osimertinib, comprehensive evaluation including repeat tissue biopsy (or circulating tumor DNA evaluation if tissue cannot be safely obtained) should be performed to identify potentially targetable resistance mechanisms.30,31 For example, for patients with acquired mesenchymal–epithelial transition (MET) amplification, combined MET and EGFR inhibition has shown promising clinical activity,32,33 while those with transformation to small-cell or squamous histology should receive histology-specific chemotherapy. For patients without identified resistance mechanisms, carboplatin/pemetrexed chemotherapy remains the standard of care, but novel approaches such as chemotherapy plus amivantamab, which improved PFS compared with chemotherapy alone in the phase III MARIPOSA-2 trial,34 and the HER3 antibody–drug conjugate patritumab deruxtecan, which showed promising activity in the post-TKI, postchemotherapy setting,35 are expected to gain regulatory approval in the near future.

In conclusion, the results of this meta-analysis suggest that adding PD-1 pathway blockade, either alone or in combination with VEGF inhibition, to platinum-doublet chemotherapy in TKI-resistant, EGFR-mutant NSCLC resulted in statistically significant improvements in PFS, but neither strategy produced clinically meaningful improvements in OS. As establishing an OS benefit has long been the gold standard to modify clinical practice, these results suggest that PD-(L)1 inhibitors should not be routinely incorporated into the care of patients with EGFR-mutant NSCLC following disease progression on frontline TKIs. Moving forward, emphasis should be placed on expanded biomarker analysis of EGFR-mutant tumors to identify rare subgroups that may be driving the observed PFS benefit with chemotherapy–PD-(L)1 combinations, ideally using biospecimens collected as part of the aforementioned phase III studies. In parallel, novel immunotherapy approaches aimed at converting immunologically ‘cold’ tumor microenvironments, as is typical of EGFR-mutant lung cancers,4 into inflamed tumor microenvironments are desperately needed, as such approaches may extend the reach of cancer immunotherapies to EGFR-mutant lung cancer, as well as other oncogene-driven subtypes of NSCLC.

Supplementary data

Supplementary Figure S1

Funding

This work was supported by the 10.13039/100000002 National Institutes of Health (grant number NIH R01 CA137008) to ZP and BYY and the LUNGstrong and Targeting a Cure Funds (no grant number) at 10.13039/100005294 Massachusetts General Hospital .

Disclosure

ZP has served as a compensated consultant or received honoraria from Black Diamond Therapeutics, Boehringer Ingelheim, Merck, Bayer, AstraZeneca, Janssen, Takeda, Blueprint Medicines, Daiichi Sankyo, Cullinan, and C4 therapeutics; research grants (to institution) from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GSK, Cullinan, Daiichi Sankyo, AbbVie, Janssen, and Blueprint Medicines; travel support from Janssen and AstraZeneca; and serves on a data safety monitoring committee for Genentech/Roche, all outside the submitted work. JFG has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech/Roche, Takeda, Loxo/Lilly, Blueprint Medicine, Gilead, Moderna, AstraZeneca, Mariana Therapeutics, Mirati, Jounce, Merus Pharmaceuticals, Nuvalent, Pfizer, Novocure, AI Proteins, Novartis, Merck, iTeos, Karyopharm, and Silverback Therapeutics; research support from Novartis, Genentech/Roche, and Takeda; institutional research support from Bristol-Myers Squibb, AstraZeneca, Palleon, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; serves on the scientific advisory board and has equity in AI Proteins; and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals (all outside of the submitted work). BYY has declared no conflicts of interest.
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