The 2023 European Society for Medical Oncology (ESMO) annual meeting was held in Madrid, Spain, from 20 to 24 October, bringing together medical oncologists from all over the world. The congress provided a platform for presenting updates and results from numerous studies and clinical trials in the field of medical oncology. Here, we focus on this year’s highlights in the field of thoracic oncology.

In this article, we present data on immunotherapy-based therapy in the nonmetastatic setting, radiotherapy (RT) in non-small cell lung cancer (NSCLC), and bispecific T-cell engagers in small cell lung cancer (SCLC). In another article in this issue, we report about relevant data in all-stage NSCLC with special focus on targeted therapies, monoclonal antibodies, and antibody drug conjugates.

CheckMate 816

CheckMate 816 is a randomized, three-arm phase III trial in patients with resectable, stage IB (≥4 cm) -IIIA NSCLC without known EGFR or ALK alterations treated preoperatively with chemotherapy +/− nivolumab (nivo). The results for the primary endpoints, pathological complete response (pCR) and event-free survival (EFS), have previously been published [1] with a pCR rate of 24.0% versus 2.2%, an HR for disease progression or death (EFS) of 0.68 (95% confidence interval [CI], 0.49–0.93), and a numerically longer OS with a HR of 0.62 (99.34% CI: 0.36–1.05) in favor of the combination arm. Exploratory efficacy results for PD-L1 status were presented at ESMO 2023 [2]. In patients with tumor PD-L1 <1%, those receiving nivo-chemo had a pCR rate of 16.7% compared to 2.6% in patients in the chemo arm. However, EFS and OS were not significantly different with hazard ratios (HRs) of 0.87 (95% CI: 0.57–1.35) and 0.81 (0.48–1.36), respectively. In contrast, patients with tumor PD-L1 ≥1% had a pCR rate of 32.6% versus 2.2%, an EFS at 36 months of 72% versus 47% for nivo-chemo and chemo, respectively (HR: 0.46; 95% CI: 0.28–0.77). At 36 months, 85% versus 66% of patients were alive (HR for death, 0.37; 95% CI: 0.20–0.71). In patients with a PD-L1 expression of >1%, the combination is now approved by the EMA for stage II and IIIA/B (N2) patients. In addition, results from the third arm in the study, the nivo plus ipilimumab (ipi) arm, were presented for the first time [3]. During the first 9 months, EFS was worse with nivo-ipi compared to chemotherapy, mainly due to an excess of early disease progression. However, EFS at 36 months was 56% versus 44% favoring nivo-ipi (HR: 0.77; 95% CI: 0.51–1.15). For OS, this crossing of curves was less pronounced. At 36 months, 73% and 61% of patients were alive for nivo-ipi and chemo, respectively. HR for death was 0.73 (95% CI: 0.47–1.14). PCR and major pathological response (MPR) rates in the nivo-ipi and chemo arms were 20.4% versus 4.6% and 28.3% versus 14.8%, respectively. It will be of high interest to see the PD-L1 dependent EFS and pCR rates, as there is a high need to improve pCR rates in the subgroup of patients with PD-L1 negative tumors.

Keynote 671

Keynote 671, a randomized, double-blind, phase III trial in operable stage II-IIIB NSCLC patients with pembrolizumab + cisplatin-based chemotherapy or placebo + cisplatin-based chemotherapy followed by surgery and adjuvant pembrolizumab or placebo, presented updated results at the ESMO. Statistically significant positive results for the primary endpoints of l EFS and pCR were previously reported [4]. For the first time in a perioperative setting, a significant improvement in OS in favor of perioperative checkpoint inhibition was demonstrated in the ITT population. Median OS was not reached in the pembrolizumab arm (95% CI: not estimable) and 52.4 months in the placebo arm (95% CI: 45.7, not estimable) (HR: 0.72; 95% CI: 0.56, 0.93; p value, 0.0103). Benefit was observed in all subgroups [5]. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 44.9% and 37.3% of patients in the pembrolizumab and placebo arms, respectively. In conclusion, perioperative pembrolizumab is a new approach for operable patients with NSCLC (tumors ≥4 cm or node-positive), which was approved by the FDA on October 16, 2023, for all comers. Whether adjuvant pembrolizumab will be necessary for pCR patients and what strategies could be designed for non-pCR patients is an area of intense research.

Checkmate77T

Checkmate 77T is similar to CM816 with the difference that 4 cycles of chemo +/− nivolumab are administered (3 cycles in CM816) and nivolumab is also administered post-operatively (perioperative, CM816 was only preoperative). Results showed a significant improvement in EFS in the nivo+chemo/nivo arm compared to chemo+PBO/PBO (HR: 0.58; 97.36 CI: 0.42–0.81; p = 0.00025), along with improved pCR (25.3% vs. 4.7%) and MPR (35.4% vs. 12.1%) rates. Exploratory analyses revealed improved EFS in patients eligible for adjuvant therapy who received perioperative nivolumab versus chemo/PBO (HR: 0.45 [0.29–0.69]), regardless of pCR status. However, neoadjuvant nivo + chemo continued to provide benefit over chemotherapy alone in patients unable to receive adjuvant therapy (HR: 0.55; 0.37–0.83). The nivo+chemo/nivo arm had higher rates of treatment-related grade 3–4 AEs (32% vs. 25%). The study met its primary endpoint, showing a statistically significant improvement in EFS in favor of the nivo+chemo/nivo arm [6].

DUART-Study (LBA62)

DUART is a phase II multi-center study in patients with unresectable stage III NSCLC who are ineligible for chemotherapy and who receive standard-of-care RT alone as primary treatment followed by durvalumab 1,500 mg Q4W for up to 12 months [7]. An ECOG performance status of 0–2 was allowed. Patients received either a standard RT with 60 Gy +/− 10% (cohort A, n = 59) or a palliative RT with 40 to <54 Gy (cohort B, n = 43). The primary endpoint is the incidence of grade 3/4 possible TRAEs within 6 months of durvalumab initiation. All patients (n = 102) received ≥1 dose of durvalumab. Overall, 9.8% of grade 3/4 possible TRAEs were documented within 6 months of treatment (95% CI: 4.8–17.3), with 11.9% in cohort A and 7.0% in cohort B. Regarding efficacy, the ORR for all patients was 26.5% (18.2–36.1) with a median PFS of 8.0 months and a median OS of 15.9 months. In conclusion, these preliminary data from the DUART trial show that durvalumab after RT is safe and effective in patients who are ineligible for chemotherapy, providing a new treatment option for elderly and frail patients.

SACTION-1 Trial (LBA60)

One of the major challenges in neoadjuvant therapy is to develop strategies to increase the pCR rate. PCR rates typically range from 17 to 35% to more than 60%, depending on PD-L1 expression. One of the strategies could be to deliver RT only to the tumor in order to spare immunologically important lymph nodes. Therefore, the SACTION trial added stereotactic subablative RT with 3 × 8 Gy only to the primary tumor in combination with preoperative immunochemotherapy in resectable NSCLC. Forty-six patients with resectable stage II-III EGFR wild-type NSCLC were enrolled, subablative RT 8 Gy × 3 days was followed by platinum-based doublet chemotherapy plus immunotherapy with tislelizumab for 2 cycles [8]. The primary endpoint was MPR. The MPR rate was 76.1% (35/46), with pCR at 52.2% of the ITT population. Interestingly, lymph nodes were cleared at a high frequency (35/46, 76%) despite not being irradiated, suggesting a potential abscopal effect. This concept should be further evaluated especially in sub-populations that are known to have low pCR rates like PD-L1 negative patients.

DeLLphi-301

The phase II DeLLphi-301 trial evaluated the antitumor activity and safety of tarlatamab in previously treated (two or more prior lines) advanced SCLC patients. Tarlatamab is a bispecific T-cell engager immunotherapy that targets DLL-3 on SCLC and CD3 on T cells. The trial was conducted in 3 parts. In part 1 two dose levels (10 mg and 100 mg) were evaluated for efficacy and safety, leading to the dose expansion phase (part 2) and safety evaluation with reduced monitoring in cycle 1 (part 3) for the dose of tarlatamab selected in part 1. The antitumor activity of tarlatamab is assessed by the objective response rate (ORR) according to RECIST 1.1 (part 1 + 2). Objective response rates were 40% (97.5% CI: 29–52) in the 10 mg group and 32% (21–44) in the 100 mg group. Among responders, 59% had a duration of response (DOR) of at least 6 months. Median progression-free survival (PFS) was 4.9 months (95% CI: 2.9–6.7) in the 10 mg group and 3.9 months (2.6–4.4) in the 100 mg group. The most common adverse event, cytokine release syndrome, occurred primarily during cycle 1, was mostly grade 1–2 in severity and was generally manageable with supportive care. The shortened monitoring in part 3 did not alter the safety profile and discontinuation of tarlatamab due to TRAEs was low (3%) [9]. The 10 mg dose of tarlatamab administered intravenously every 2 weeks demonstrated antitumor activity with durable objective responses and a manageable safety profile, leading to its selection for further study in advanced SCLC patients.

The Thoracic Oncology Working Group of the AIO (Association of Internal Oncology) congress scholarship program sponsored five young physicians to attend the ESMO in Madrid in 2023. 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 2024 AIO Thoracic Oncology Scholarship will sponsor junior physicians to attend ESMO 2024 in Barcelona. For information on this year’s scholarships and the application process for junior physicians, please see the AIO website: https://www.aio-portal.de/.

Marcel Kemper: ESMO congress scholarship offered by the Association of Internal Oncology (AIO), including donations from Amgen, AstraZeneca, Daiichi Sankyo, Janssen-Cilag, Roche Pharma, Takeda Pharma, Novartis, Janssen-Cilag, and Takeda. ORCID: 0000-0001-8906-5297. Puyan Soltani Germy, Jingting Luan, and Miriam Blasi: ESMO congress scholarship offered by the AIO, including donations from Amgen, AstraZeneca, Daiichi Sankyo, Janssen-Cilag, Roche Pharma, and Takeda Pharma. Fabian Acker: ESMO congress scholarship offered by the AIO, including donations from Amgen, AstraZeneca, Daiichi Sankyo, Janssen-Cilag, Roche Pharma, Takeda Pharma, AstraZeneca, and IQVIA. ORCID: 0000-0002-6207-0237. Frank Griesinger: AbbVie, Amgen, Ariad, AstraZeneca, Beigene, BMS, Boehringer-Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Takeda, Tesaro/GSK, Siemens, and Sanofi. Amanda Tufman: Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Daiichi Sankyo, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda. Cornelia Kropf-Sanchen: Amgen, AstraZeneca, Artempi/Medtoday, Boehringer-Ingelheim, BMS, Celgene, Daiichi Sankyo, Eli Lilly, MSD, Novartis, onkowissen, Pfizer, Roche, Sanofi, Streamed Up, and Takeda. Tobias R Overbeck: AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen-Cilag, Merck, MSD, Novartis, Roche, Takeda, Tesaro/GSK, Lilly, and Roche. ORCID: 0000-0002-2579-0171. Annalen Bleckmann: Amgen, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen-Cilag, Merck, Mirati, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Sanofi, Servier, and Takeda.

The AIO scholarship 2023 was funded by an unrestricted grant by donations from Amgen, AstraZeneca, Daiichi Sankyo, Janssen-Cilag, Roche Pharma, and Takeda Pharma.

M.K., P.S.G., F.A., J.L., F.G., A.T., C.K.S., T.R.O., A.B., and M.B. 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

Marcel Kemper, Puyan Soltani Germy, Fabian Acker, Jingting Luan, Annalen Bleckmann, and Miriam Blasi contributed equally to this work.

1.
Forde
PM
,
Spicer
J
,
Girard
N
.
Neoadjuvant nivolumab (N) + platinum-doublet chemotherapy (C) for resectable NSCLC: 3-y update from CheckMate 816
. Presented at: 2023 European lung cancer congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 840.
2.
Pulla
MP
,
Forde
PM
,
Spicer
J
,
Wang
C
,
Lu
S
,
Mitsudomi
T
, et al
.
Neoadjuvant nivolumab (N) + chemotherapy (C) in the phase 3 CheckMate 816 study: 3-y results by tumor PD-L1 expression
. Presented at ESMO conference 2023, Madrid. Abstract LBA57.
3.
Awad
MM
,
Forde
PM
,
Girard
N
,
Spicer
JD
,
Wang
C
,
Lu
S
, et al
.
Neoadjuvant nivolumab (N) + ipilimumab (I) vs chemotherapy (C) in the phase 3 CheckMate 816 trial
. Presented at ESMO conference 2023, Madrid. Abstract 1261O.
4.
Wakelee
H
,
Liberman
M
,
Kato
T
,
Tsuboi
M
,
Lee
SH
,
Gao
S
, et al
.
Perioperative pembrolizumab for early-stage non-small-cell lung cancer
.
N Engl J Med
.
2023
;
389
(
6
):
491
503
.
5.
Spicer
JD
,
Gao
S
,
Liberman
M
,
Kato
T
,
Tsuboi
M
,
Lee
SH
, et al
.
Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC)
. Presented at ESMO conference 2023, Madrid. Abstract LBA56.
6.
Cascone
T
,
Awad
MM
,
Spicer
JD
,
He
J
,
Lu
S
,
Sepesi
B
, et al
.
CheckMate 77T: phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC
. Presented at ESMO 2023 conference, Madrid. Abstract LBA1.
7.
Filippi
AR
,
Dziadziuszko
R
,
García Campelo
MR
,
Paoli
JB
,
Sawyer
W
, et al
.
Durvalumab after radiotherapy (RT) in patients with unresectable stage III NSCLC ineligible for chemotherapy (CT): primary results from the DUART study
. Presented at ESMO conference 2023, Madrid. Abstract LBA62.
8.
Rui Zhao
Z
,
Liu
SL
,
Zhou
T
,
Li
ZC
,
Wu
JD
,
Xi
M
, et al
.
Stereotactic body radiation therapy with sequential immunochemotherapy as neoadjuvant therapy in resectable NSCLC
. Presented at ESMO conference 2023, Madrid. Abstract LBA60.
9.
Paz-Ares
L
,
Ahn
MJ
,
Felip
E
,
Handzhiev
S
,
Korantzis
I
,
Izumi
H
, et al
.
Tarlatamab for patients (pts) with previously treated small cell lung cancer (SCLC): primary analysis of the phase II DeLLphi-301 study
. Presented at ESMO conference 2023, Madrid. Abstract LBA92.