The European Society for Medical Oncology (ESMO) annual meeting took place in Paris in September 2022. The conference added a number of relevant study updates and novel treatment concepts. We report on highlights in the field of thoracic oncology. The topics cover oncogene-driven and immunotherapy-based therapeutic concepts in metastatic and non-metastatic NSCLC.

CodeBreaK 200

The CodeBreaK 200 phase III multicentre study on sotorasib versus docetaxel included 345 patients with KRAS G12C-mutant, unresectable or metastatic NSCLC who had previously been treated with both platinum-based chemotherapy (CT) and an immune checkpoint inhibitor [1]. The study met its primary endpoint, demonstrating a significantly improved progression-free survival with sotorasib versus docetaxel (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.51–0.86; p = 0.002) after a median follow-up of 17.7 months. Objective response rates (ORRs) were significantly improved with sotorasib versus docetaxel (28.1% vs. 13.2%; p < 0.001), albeit somewhat lower than the ORR of 37% reported in the CodeBreaK 100 phase I/II trial of sotorasib [2]. There was no difference in overall survival (OS; HR 1.01; 95% CI: 0.77–1.31; p = 0.54), possibly due to a high crossover and statistical considerations. No new safety signals on sotorasib were reported, and there were fewer severe adverse events in the sotorasib arm compared to docetaxel (10.7% vs. 22.5%). In summary, the CodeBreaK 200 study confirms sotorasib as the new standard of care in pretreated patients with KRAS G12C-mutant, advanced/metastatic NSCLC.

ELIOS

The ELIOS study attempted to establish a molecular profile of resistance mechanisms to osimertinib in first-line treatment by investigating paired tissue biopsies at baseline and at disease progression in metastatic EGFR-mutated NSCLC [3]. Of 154 enrolled patients, only 46 (39%) were evaluable for paired biopsies. Results were mostly consistent with previous studies [4, 5], with 5 patients (11%) showing acquired NKX2-1 amplification (encoding for thyroid transcription factor 1 [TTF-1]) upon progression as a potential new resistance mechanism of unknown function. This study demonstrates the low success rate of re-biopsy and the urgent need for more usage of liquid biopsy at acquired resistance.

INSIGHT2

The INSIGHT2 study is an international, single-arm, open-label phase 2 study that investigates the efficacy and safety of combination therapy of osimertinib with tepotinib, a selective oral MET inhibitor, in patients with locally advanced or metastatic EGFR-mutated NSCLC and acquired MET amplification (MET-amp) as resistance mechanism during first-line therapy with osimertinib [6]. MET-amp was assessed by FISH from tumor biopsy or NGS from liquid biopsy. MET-amp was detected in 153 (36%) of 425 screened patients (FISH, 133 patients, 33%; NGS, 47 patients, 11%). In the combination group (FISH, 70 patients; NGS, 27 patients), ORRs of 54.5% and 50%, respectively, were observed after a follow-up of 9 months, with good tolerability and no new safety concerns. At acquired resistance, targeting of the MET pathway alone by tepotinib monotherapy (12 pts) was ineffective with an ORR of only 8.3%. These results highlight the sub-clonal origin of acquired resistance alterations and the need for continued targeting of both the EGFR and MET pathway in this molecularly defined cohort.

ADAURA

The ADAURA study [7], investigating the efficacy and safety of adjuvant osimertinib versus observation in resected patients with stages IB–IIIA with a common EGFR mutation, was updated with all patients having completed the third year of adjuvant osimertinib. DFS continued to be significantly prolonged in stages IB–IIIA with a median of 65.8 versus 28.1 months (HR 0.27) in favor of osimertinib [8]. This benefit was independent of prior adjuvant CT. No new safety signals were observed with a median total duration of exposure to osimertinib of 35.8 months. Compared to data from 2020, a waning effect was seen in patients with stage II–III disease after 3 years, which potentially indicates that adjuvant TKI therapy may only postpone relapse, a phenomenon that has been described in other adjuvant TKI studies [9, 10]. Therefore, it will be of high interest to identify those patients in need of adjuvant TKI therapy, as has been done by Ahn et al. [11], who studied the impact of ctDNA positivity versus negativity after surgery in EGFR-mutated patients. A similar strategy is currently being tested in the PACE-Lung Study, where ctDNA monitoring is used for therapy stratification in metastatic EGFR-mutated NSCLC [12].

POSEIDON

The POSEIDON phase III multicentre study included 1,013 untreated patients with metastatic NSCLC, randomized 1:1:1 to receive either dual checkpoint inhibition with tremelimumab (T)/durvalumab (D) plus platinum-based CT or D plus CT versus CT alone [13]. In the ICI arms, D maintenance was implemented. Updated results after a median follow-up of 4 years confirmed the OS benefit with an HR of 0.75 (95% CI: 0.63–0.88) and a stable tail of the curve (3-year OS: 25% vs. 13.6% for T + D + CT vs. CT) [14]. In KRAS mt + NSCLC, a significant OS benefit was seen (HR 0.55, 95% CI: 0.36–0.85) in favor of T + D + CT, whereas a trend was seen in STK11 and KEAP mt + NSCLC [14]. In summary, this study confirms the efficacy of I/O-I/O + CT as a further option in the first-line setting. As of yet, there are no data which directly compare this treatment combination to other IO + CT options.

KEYNOTE 189/KEYNOTE 407

Five-year updates of KEYNOTE 189 and KEYNOTE 407 in non-squamous and squamous cell carcinoma, respectively, were updated at ESMO [15, 16], showing a stable benefit for patients irrespective of PD-L1 status, with the exception of PD-L1 <1% in squamous cell carcinoma which was not statistically significant. Thus, there is an urgent need to improve therapy strategies for PD-L1-negative patients, especially in squamous cell carcinomas.

IPSOS

The IPSOS study examined the efficacy of immunotherapy versus CT alone in elderly patients or patients with reduced performance status [17]. Patients with locally advanced/metastatic NSCLC without driver mutations ineligible for first-line platinum therapy were randomized 2:1 for immunotherapy with atezolizumab or monochemotherapy (vinorelbine or gemcitabine). 453 patients were randomized (302 atezolizumab; 151 CT). Median age was 75 years (range 33–94), 31% were ≥80 years, 83% had ECOG PS ≥2. Atezolizumab significantly improved OS versus CT only (median OS: atezolizumab vs. CT, 10.3 vs. 9.2 months, HR 0.78; 95% CI: 0.63, 0.97; p = 0.028) with a benefit in PD-L1 expression levels, PS, and histology. Benefit was also seen in 2-year OS rate, overall response rate, and duration of response. These data suggest a suitable alternative with atezolizumab for those patients ineligible for platinum-based therapy. EMA approval is pending.

EMPOWER-Lung 1

The EMPOWER-Lung 1 study was updated at ESMO with 3-year OS data showing a highly significant advantage for patients receiving cemiplimab versus CT (HR 0.57, p = 0.0001), although crossover in the observation arm to cemiplimab was more than 70% [18]. The second most interesting question asked in the trial was whether patients that had responded to cemiplimab and then acquired resistance to ICI single agent therapy would benefit from treatment beyond progression with cemiplimab and additional CT. This question is relevant as the current standard of care is combination CT alone and cessation of ICI therapy. ORR and progression-free survival in the subgroup of 64 patients receiving CT together with cemiplimab at the time of acquired resistance were as high as at start of therapy with cemiplimab alone; OS calculated from start of CTx-cemiplimab was 15 months. Unfortunately, no data were shown as to the clinical characteristics of the patients receiving CTx + cemiplimab and the outcome of those patients not receiving cemiplimab + CTx. Thus, this study asks for the first time a relevant question in the setting of acquired ICI resistance and investigates the concept of treatment beyond progression with ICI. Further studies in defined patient populations will be needed together with a translational program addressing mechanisms of acquired resistance in the future.

CheckMate 816

For CheckMate 816, a neoadjuvant trial in operable NSCLC stage UICC 7 IB–IIIA patients with nivolumab + CT or CT alone followed by surgery, updated results were presented [19]. Statistically significant positive results for the primary endpoints pathologic complete response (pCR) and event-free survival (EFS) were previously shown. A significant correlation of pCR with EFS (underlining pCR as a good predictor for EFS) and improved OS in favor of nivolumab + CT were demonstrated. In the LBA50 abstract, a post hoc analysis of pathologic features and efficacy outcomes was presented: improved EFS was observed with nivolumab + CT in patients node negative and node positive in favor of nivolumab + CT (median EFS: 31.6 m vs. 22.7 m; HR 0.69 and not reached in both arms; HR 0.74, respectively) and so were the pCR rates (19% vs. 1% in LN− and 40% vs. 6% in LN+) [20]. Both pCR in the primary tumor as well as in the lymph nodes had an impact on prognosis, with the worst prognosis in patients with residual tumor in both primary tumor and LN (2-year EFS rates: 92% [T + LN pCR], 76% [T pCR], and 49% [T and LN no pCR]). Quality of life was similar in both arms [21]. In conclusion, neoadjuvant nivolumab + CT is a new approach for operable patients with NSCLC waiting for approval by EMA expected in Q1 2023.

IMPOWER010

The IMpower010 study investigated the impact of adjuvant atezolizumab after surgery for stages IB–IIIA (UICC 7) and after cisplatin-containing adjuvant CT. Based on the DFS results, atezolizumab has been approved by EMA for the adjuvant treatment in patients with PD-L1 expression of ≥50% and exclusion of EGFR and ALK alterations. At WCLC, OS results of a preplanned interim analysis were presented [22]. OS was highly statistically improved in the relevant PD-L1 ≥50% TC subgroup (HR 0.43; 95% CI: 0.24–0.78). Thus, OS data confirmed the indication of atezolizumab in the PD-L1 ≥50% EGFR & ALK WT population after surgery and adjuvant platinum-based CT.

INCREASE

The INREASE trial asked the question whether resectable and borderline resectable NSCLC (cT3-4 N0-2 M0) would be resectable after induction therapy with 2 cycles of platinum-based CT and dual I/O (ipilimumab/nivolumab) and concurrent radiotherapy (50–60 Gy) [23]. 24 of 27 enrolled patients were operated; 15 had pCR (55%) and 19 had MPR (70%), with pCR observed in all PD-L1 subgroups. Radiologic PR did not correlate with pCR and MPR (PR: 15%, SD: 81%, and PD: 4%). Treatment was feasible and toxicity was manageable with 18 (64%) grade 3/4 in total and only 5 (19%) grade 3/4 immune-related adverse events (one grade 3/4 pneumonitis). Neither delay in surgery due to neoadjuvant treatment nor treatment-related deaths were observed. Further evaluation of this strategy is warranted, especially with regard to borderline operable patients and in comparison to definitive radiochemotherapy and maintenance immunotherapy.

The abstracts presented provide the rationale for current and upcoming diagnostic and therapeutic approaches in non-small cell lung cancer. The ESMO Congress is a good opportunity to present and discuss these innovations.

The Thoracic Oncology Working Group of the AIO (Association of Internal Oncology) congress scholarship program sponsored three young physicians to attend the ESMO in Paris in 2022. The aim of the program is to enable young doctors and medical doctoral students to attend congresses and exchange ideas with expert mentors. The scholarship recipients co-authored this manuscript. We acknowledge the German AIO thoracic oncology steering board (Leitgruppe Thorakale Onkologie) for their support. The 2023 AIO Thoracic Oncology Scholarship will sponsor junior physicians to attend ESMO 2023 in Madrid. For information on next year’s scholarships and the application process for junior physicians, please see the AIO website: https://www.aio-portal.de/.

Friederike C. Althoff and Maximilian Rost: none; ESMO congress scholarship offered by the Association of Internal oncology (AIO), including donations from Amgen, Takeda Pharma, and AstraZeneca. Toki A. Bolt: Roche; ESMO congress scholarship offered by the Association of Internal oncology (AIO), including donations from Amgen, Takeda Pharma, and AstraZeneca. Akin Atmaca: BMS, MSD, Roche, Takeda, Pfizer, Novartis, AstraZeneca, Sanofi, Amgen, and BioNTech; Annalen Bleckmann: Alexion, Gilead, Novartis, BMS, Bayer, Servier, Roche, AstraZeneca, Takeda, Merck, BeiGene, MSD, Lilly, Janssen-Cilag, BeiGene, Takeda, Boehringer-Ingelheim, Pfizer, and Amgen; Frank Griesinger: ASTRA, Boehringer, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Siemens, Tesaro/GSK, Amgen, Sanofi, Daiichi-Sankyo, and Beigene; and Amanda Tufman: Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Celgene, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda, Tesaro/GSK. Tobias R. Overbeck: AstraZeneca, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen-Cilag, Merck, MSD, Novartis, Roche, Takeda, Tesaro/GSK, Lilly, and Roche.

The AIO scholarship 2022 was funded by an unrestricted grant by donations from Amgen, Takeda Pharma, and AstraZeneca.

Friederike C. Althoff, Toki A. Bolt, Maximilian Rost, Akin Atmaca, Annalen Bleckmann, Frank Griesinger, Amanda Tufman, and Tobias R. Overbeck fully contributed to the conception and design of the work, drafted the work, revised it critically, gave final approval of the version to be published, and gave agreement to be accountable for all aspects of the work.

Additional Information

Friederike C. Althoff, Toki A. Bolt, and Maximilian Rost contributed equally to this work.

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