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Corresponding author: Medical Oncologist, Department of Oncology, University Hospital of Udine, Italy, P. Santa Maria della Misericordia 1, Udine, 33100, Italy. Tel secr: +390432554550.
Affiliations
Department of Oncology, University Hospital of Udine, Udine, ItalyDepartment of Radiation Oncology (Maastro Clinic), Maastricht University Medical Center, School for Oncology and Reproduction (GROW), Maastricht, the Netherlands
Department of Radiation Oncology (Maastro Clinic), Maastricht University Medical Center, School for Oncology and Reproduction (GROW), Maastricht, the Netherlands
Largest cohort of patients with stage III NSCLC and uncommon genomic alterations.
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Adjuvant durvalumab improved survival in patients with uncommon genomic alterations.
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Adjuvant durvalumab improved survival in patients with KRAS mutations.
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Molecular testing should be mandatory for patients with stage III NSCLC.
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Clinical trials should investigate the best adjuvant treatment in this setting.
Abstract
Adjuvant durvalumab is the standard of care for patients with stage III unresectable non-small cell lung cancer (NSCLC), without progression after concurrent chemo-radiation (CCRT). Patients with stage III NSCLC harbouring epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase rearrangements do not seem to benefit from durvalumab. Data are lacking about patients harbouring other driver genomic alterations (dGA). We performed a multicentre (N = 4, Netherlands and Italy) retrospective study including consecutive patients with unresectable stage III NSCLC and treated with CCRT—with or without adjuvant durvalumab—between 2016 and 2022. We enrolled 271 patients; 130 of which received adjuvant durvalumab. Sixty-six patients had dGA (41 KRAS mutations, 4 EGFR common mutations and 21 uncommon dGA). In the entire population, the median PFS was 24.9 months (95% CI 17.5–32.4) and 12.6 months (95% CI 9.0–16.1) with and without durvalumab (p = 0.001). In the dGA group (excluding common EGFR), mPFS was 12.3 months (95% CI 7.8–16.8) with and 7.6 (95% CI 3.4–11.9) without durvalumab (p = 0.038). For patients with KRAS mutations, mPFS was 12.3 months (95% CI 3.6–20.9) with and 7.2 months (95% CI 1.8–12.6) without durvalumab (p = 0.12). Among patients with uncommon dGA, mPFS was 12.9 months (95% CI 8.4–17.4) with and 7.6 months (95% CI 1.4–14) without durvalumab (p = 0.23). We have shown a meaningful survival benefit of adjuvant durvalumab in patients harbouring KRAS mutations and uncommon dGA. This is the largest stage III NSCLC cohort showing the efficacy of durvalumab in patients with uncommon dGA. Further prospective studies are needed to confirm our results.
]. In the PACIFIC trial, adjuvant durvalumab led to a median PFS (mPFS) of 16.9 versus 5.6 months (HR 0.55; 95% CI, 0.45 to 0.68) and a median OS (mOS) of 47.5 months versus 29.1 months (HR 0.72; 95% CI, 0.59 to 0.89) [
]. Testing for driver genomic alterations (dGA) was not mandatory in PACIFIC, but molecular testing for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements was performed in 73% of patients. Thirty-five (5%) and eight (1%) patients tested positive for EGFR mutations and ALK rearrangement, respectively [
Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis.
]. In the retrospective PACIFIC-R study (N = 1399, durvalumab expanded access program), the mPFS of patients with EGFR-mutated NSCLC (n = 46) was inferior to the mPFS of the total population (11.1 months versus 21.7 months) while mPFS for patients with Kirsten rat sarcoma (KRAS)-positive NSCLC was similar (24.2 months) [
Girard N, Bar J, Garrido P, et al. Treatment characteristics and real-world progression-free survival in patients with unresectable stage III NSCLC who received durvalumab after chemoradiotherapy: findings from the PACIFIC-R study. J Thorac Oncol. Published online October 2022:S1556086422018536. doi:10.1016/j.jtho.2022.10.003.
]. In the metastatic setting, immunotherapy seems to have different efficacy depending on the type of dGA (e.g. common versus uncommon EGFR mutations) [
]. In stage III NSCLC, data are lacking about the efficacy of adjuvant immunotherapy in patients harbouring other dGA, such as MET exon 14 skipping mutations, BRAF mutations and uncommon EGFR mutations. In 2022, a retrospective multicentre study (N = 323, n = 43 with NSCLC harbouring dGA) was published in the European Journal of Cancer [
]. Molecular profiling was available for 186 (57%) patients. This study suggested again a lack of benefit for EGFR (n = 6, mPFS 8.1 months, 95% CI 5.8-NR), ALK or BRAF V600-driven NSCLC (n = 8, mPFS 7.8 months, 95% CI 7.7-NR). However, subgroups were small and sometimes different dGA with potentially different responses to immunotherapy were grouped together (ALK and BRAF V600) [
]. We herein present the data about our cohort of patients with stage III NSCLC and dGA treated with adjuvant durvalumab.
2. Material and methods
We performed a multicentre (N = 4, Netherlands and Italy) retrospective study including consecutive patients with FDG-PET and brain imaging staged, unresectable stage III NSCLC, treated with CCRT between 2016 and 2022. Clinical and molecular data were collected; genomic alterations were determined locally using validated techniques. Patients were evaluated for responses according to clinical practice: CT scans during durvalumab or first year of follow-up after CCRT were performed every 3–4 months and afterwards every 6 months. However, mPFS and mOS were defined as the time from the end of RT and the date of first progression or death, respectively. T-tests and chi-square analyses were used as appropriate. Survivals are described by Kaplan–Meier curves and compared with the log-rank test and Cox regression test as appropriate. Patients without event at the last day of follow-up were censored. Patients that progressed or died during CCRT were excluded from survival analyses, as were patients that participated in clinical trials after/during CCRT. Statistical analyses were performed on IBM® SPSS Statistics, version 22.
3. Results
A total of 271 patients with stage III disease who underwent concurrent chemo-radiotherapy were enrolled, of which 130 (48%) received adjuvant durvalumab. Reasons for not receiving durvalumab were unavailability of the drug at time of diagnosis (46%), toxicity after CCRT (12%), PDL-1<1% (8%), progressive disease (PD) (4%) and other causes (23%), such as auto-immune disease, patient's decision, classical EGFR mutation or clinical trial participation. Reasons were unknown in 7% of patients. Similar reasons were reported in the dGA subgroup. Patients' baseline characteristics are also reported in Table 1.
Table 1Baseline patients’ characteristics, reasons for not receiving durvalumab and median follow-up. Patients that progressed or died during CCRT or participated in clinical trials after/during CCRT are excluded.
In Italy, PDL-1>1% is required to prescribe durvalumab. Despite availability in some cases, it was chosen not to give durvalumab to patients with PDL-1>1%.
Abbreviations: dGA = driver genomic alteration; PS = performance status; PDL-1 = programmed death ligand-1; CCRT = concurrent chemo-radiotherapy; CI = confidence interval, FU = follow-up.
a In Italy, PDL-1>1% is required to prescribe durvalumab. Despite availability in some cases, it was chosen not to give durvalumab to patients with PDL-1>1%.
Among patients with dGA, the median age was 67.6 (39–78), 97% were current or former smokers, 86% had ECOG PS 0–1 and 33%, 54% and 13% had stage IIIA, IIIB or IIIC, respectively (TNM8), and 66% had a PDL-1 ≥1%. Overall, molecular profiling was performed in 117 (68%) patients with non-squamous NSCLC and dGA were present in 66 patients (55% of tested patients). Forty-one harboured KRAS mutations (18 KRAS G12C), four patients presented with EGFR common mutations (3 EGFR L858R mutation, 1 exon 19 deletion), and 21 patients presented with uncommon dGA (Fig. 1). One patient with a BRAF V600 mutation who progressed during CCRT, one patient with a KRAS G12C mutation who died during CCRT and two patients, one with BRAF V600E and one with KRAS G12C, receiving adjuvant immunotherapy within clinical trials were excluded from the analyses. Twenty-seven (44%) patients with dGA received adjuvant durvalumab, and the median duration of durvalumab treatment was 8.5 months (range 0.6–14.9 months); 10 patients (37%) completed 12 months of treatment. Two patients were still on durvalumab, three patients discontinued due to toxicity and 11 patients experienced disease progression during adjuvant durvalumab. Median FU (mFU) from the end of RT was 28.3 (95% CI 25.3–31.4) months in the whole cohort, 24.8 (95% CI: 16.8–32.8) and 34.4 (95% CI: 24.5–44.3) months in patients with dGA with and without durvalumab, respectively (p = 0.03). In the entire population, mPFS was 24.9 months (95% CI 17.5–32.4) with durvalumab and 12.6 months (95% CI 9.0–16.1) without durvalumab (HR 0.54, 95% CI 0.35–0.76, p = 0.001). mOS was not reached in the durvalumab arm and 27.5 months (95% CI 16.7–38.3) without durvalumab (HR 0.42, 95% CI 0.27–0.68 p < 0.001). In the dGA group (KRAS and uncommon dGA), mPFS was 12.3 months (95% CI 7.8–16.8) with durvalumab and 7.6 (95% CI 3.4–11.9) without durvalumab (HR 0.51, 95% CI 0.27–0.97, p = 0.038). mOS was not reached with and 14.9 months (95% CI 11.2–18.5) without durvalumab (HR 0.45, 95% CI 0.19–1.02, p = 0.05). For the subgroup of patients with a KRAS mutation, mPFS was 12.3 months (95% CI 3.6–20.9) with and 7.2 months (95% CI 1.8–12.6) without durvalumab (HR 0.54, 95% CI 0.25–1.18, p = 0.12). mOS was not reached with and 16.2 months (95% CI 12–20) without durvalumab (HR 0.33, 95% CI 0.18–1.01, p = 0.041). Among patients with uncommon dGA, mPFS was 12.9 months (95% CI 8.4–17.4) with and 7.6 months (95% CI 1.4–14) without durvalumab (HR 0.5, 95% CI 0.15–1.65, p = 0.23). Median OS was 21.3 months (95% CI 17.8–24.8) with and 14.9 months (95% CI 10.7–19) without durvalumab (HR 0.75, 95% CI 0.19–2.8, p = 0.67) (Fig. 1).
Fig. 1Progression-free survival of patients with KRAS and uncommon genomic alterations, patients with KRAS mutations only and patients with uncommon genomic alterations only. The cohort of patients with uncommon genomic alterations is detailed with patient by patient mPFS, disease status, along with PDL-1 expression levels.
Patients with a common EGFR mutation not treated with durvalumab (n = 3) had a mPFS of 9.1 months (95% CI 5.8–9.9), whereas the only patient treated with durvalumab had a PFS of 24.6 months. Of note, this patient was a current smoker (40 packs/year). In this subgroup, neither PFS formal comparison nor OS analyses could be performed due to the small number of cases and events.
4. Discussion
In the present study, we reported the outcomes of adjuvant durvalumab in patients with stage III NSCLC and driver oncogenic alterations (KRAS mutations and uncommon dGA), showing that durvalumab leads to a significant survival benefit in this setting. When we analysed the two subgroups of patients (KRAS mutated and uncommon dGA) separately, the survival benefit of durvalumab remains clinically meaningful in both subgroups. To the best of our knowledge, this is the largest stage III NSCLC cohort investigating and suggesting indeed efficacy of durvalumab in patients with uncommon dGA. Two retrospective studies (N = 37 and N = 36) investigated the efficacy of adjuvant durvalumab compared to CCRT alone in EGFR or HER-2-positive NSCLC showing no benefit for adjuvant durvalumab in these patients [
]. In stage IV NSCLC, recent retrospective series (N = 49 and N = 27) suggested that immunotherapy might have higher activity in patients with uncommon EGFR mutations versus common mutations, possibly due to higher levels of tumour infiltrating lymphocytes [
]. Thus, we divided our patients according to the type of EGFR mutation (common versus uncommon). Unlike Riudavets and colleagues, we included patients with BRAF mutations in the non-EGFR (common)/ALK group, as in contrast with EGFR and ALK, immunotherapy has shown activity in stage IV BRAF-mutated NSCLC [
Hendriks LE, Kerr K, Menis J, et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up†. Ann Oncol. Published online January 23, 2023. doi:10.1016/j.annonc.2022.12.009.
]. We included the patients with MET exon 14 mutations in the uncommon dGA for the same reason, as two retrospective series showed comparable immunotherapy efficacy for stage IV NSCLC, harbouring BRAF or MET exon 14 mutations [
]. The PFS of our patients with dGA is worse than the PFS reported from Riudavets et al. This may be due to more real-world patients included and maybe a different follow-up imaging schedule. Selection bias may also have contributed: patients who progressed to stage IV had higher probability to undergo molecular testing, thus overfilling our dGA cohort with patients at worse prognosis. However, even if this was the case, this does not affect our finding regarding the survival benefit of durvalumab. In our cohort, mPFS is in line with PACIFIC-R7. Two-year OS is slightly better than PACIFIC (74% versus 66%). This might be due to more accurate staging: 76% of our patients were staged with brain MRI (others brain CT) and 100% with PET-CT before CCRT, while in the PACIFIC trial, PET-CT staging was optional, and detailed information about staging methods is not available in the PACIFIC trial [
]. The retrospective nature of our study is an important limitation. Detection bias may have occurred due to the non-prespecified timing of CT scans. Moreover, the limited number of patients with dGA precluded multivariate analyses. Molecular tests were not performed/missing in 30% of patients with non-squamous NSCLC, 85% of which were diagnosed before 2021, probably due to a not yet recognised importance of molecular testing in this setting. In the ESMO guidelines for non-metastatic NSCLC (eUpdate 2021), EGFR testing is still the only mandatory molecular test; in 2022, ASCO guideline molecular testing is advised but not mandatory [
]. The PDL-1 data were missing in 33% of patients largely due to patients diagnosed before 2018 (18%) when durvalumab became available in the Netherlands and in Italy. Moreover, PDL-1 positivity is, in contrast with the EMA label, not mandatory to prescribe durvalumab in the Netherlands.
5. Conclusions
Despite its limitations, we believe that our study sheds more light on the management of patients with unresectable NSCLC and uncommon dGA. We believe that molecular testing should be mandatory for all patients with unresectable stage III non-squamous NSCLC, and that clinical trials should evaluate the efficacy of durvalumab or targeted therapy in those with a targetable driver alteration (e.g. NCT05170204 and NCT03521154). Alternatively, prospective multicentre collaborations should evaluate the best adjuvant treatment for patients with unresectable stage III NSCLC and uncommon genomic alterations.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Authors’ contributions
Francesco Cortiula: data curation, formal analysis, investigation and writing - original draft.
Dirk De Ruysscher: conceptualisation, supervision and writing - review & editing.
Michelle Steens: data curation.
Robin Wijsman: investigation.
Anthonie van der Wekken: writing - review & editing.
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
FC: Lilly, Travel expenses, Institutional; AstraZeneca, Local PI, Institutional.
DDR: AstraZeneca, Research Grant, Institutional; AstraZeneca, Steering Committee Member, Institutional, AstraZeneca, Coordinating PI, Institutional, BeiGene, Funding, Institutional, BMS, Research Grant, Institutional, BMS, Coordinating PI, Institutional, Olink, Funding, No financial interest.
Philips Health, Steering Committee Member, Institutional, Varian, Research Grant, Institutional.
MS: No conflict of interest to declare.
RW: No conflict of interest to declare.
AvdW: Received research grants from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche and Takeda outside the current work. Was involved in advisory boards of AstraZeneca, Janssen, Lilly, Roche and Takeda and was speaker in educational meetings sponsored by AstraZeneca, BMS, Lilly, Pfizer and Roche. Involved in clinical studies for AstraZeneca, Amgen, Blueprint medicine, Nuvalent, Novartis, Merck, Pfizer, Roche and Takeda. Payments from Dutch Guidelines for NSCLC. All finances received by the UMCG. Non-financial: Board Member Dutch Oncology Group (NVALT), Member of Patient Panel of Longkanker Nederland and Member of Patient Advisory Panel of ROS1ders.
MA: No conflict of interest to declare.
LH: Amgen, Advisory Board, Institutional; AstraZeneca, Other, Personal, Mentorship with key opinion leaders funded by AstraZeneca; AstraZeneca, Invited Speaker, Institutional for educational webinar; Bayer, Invited Speaker, Institutional; Educational webinar/interview, Benecke, Invited Speaker, Personal, payment for post ASCO/ESMO/WCLC presentations, educational committee member; BMS, Advisory Board, Institutional; Boehringer Ingelheim, Advisory Board, Institutional; high5oncology, Invited Speaker, Institutional, payment for post ESMO/ASCO discussion; Janssen, Advisory Board, Institutional; Janssen, Other, Institutional, Educational webinar.
Takeda, Other, Institutional, podcast on brain metastases; VJOncology, Invited Speaker, Personal, payment for post ASCO round table discussion; Dutch guidelines NSCLC, brain metastases and leptomeningeal metastases, Other, Personal, member of the committee that revised these guidelines; Abbvie, Local PI, Institutional; AstraZeneca, Local PI, Institutional; AstraZeneca, Research Grant, Institutional; Blueprint Medicines, Local PI, Institutional; Boehringer Ingelheim, Research Grant, Institutional; Gilead, Local PI, Institutional; GSK, Local PI, Institutional; Merck, Research Grant, Institutional, donation for health care improvement project; Merck Serono, Local PI, Institutional; Mirati, Local PI, Institutional, MSD, Local PI, Institutional; Novartis, Local PI, Institutional; Pfizer, Research Grant, Institutional, funding for healthcare improvement project; Roche, Local PI, Institutional; Roche, Research Grant, Institutional; Takeda, Local PI, Institutional, Research Grant, Institutional.
Non-financial interests: EORTC, chair metastatic NSCLC for lung cancer group, NVALT, secretary NVALT studies foundation.
Acknowledgements
None.
References
Amin M.B.
Edge S.
Greene F.
et al.
AJCC cancer staging manual.
8th ed. Springer International Publishing: American Joint Commission on Cancer,
2017
Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis.
Girard N, Bar J, Garrido P, et al. Treatment characteristics and real-world progression-free survival in patients with unresectable stage III NSCLC who received durvalumab after chemoradiotherapy: findings from the PACIFIC-R study. J Thorac Oncol. Published online October 2022:S1556086422018536. doi:10.1016/j.jtho.2022.10.003.
Hendriks LE, Kerr K, Menis J, et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up†. Ann Oncol. Published online January 23, 2023. doi:10.1016/j.annonc.2022.12.009.
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