Survival benefit with checkpoint inhibitors versus chemotherapy is modified by brain metastases in patients with recurrent small cell lung cancer.

Introduction: Small cell lung cancer (SCLC) is a rapidly growing malignancy with early distant metastases. Up to 70% will develop brain metastases, and the poor prognosis of these patients has not changed considerably. The potential of checkpoint inhibitors (CPI) in treating recurrent (r/r) SCLC and their effect on brain metastases remain unclear. Methods: In this retrospective multicenter study, we analyzed r/r SCLC patients receiving second or further-line CPI versus chemotherapy between 2010 and 2020. We applied multivariable-adjusted Cox regression analysis to test for differences in 1-year mortality and real-world progression. We then used interaction analysis to evaluate whether brain metastases (BM) and/or cranial radiotherapy (CRT) modified the effect of CPI versus chemotherapy on overall survival. Results: Among 285 patients, 99 (35%) received CPI and 186 (65%) patients received chemotherapy. Most patients (93%) in the CPI group received nivolumab/ipilimumab. Chemotherapy patients were entirely CPI-naïve and only one CPI patient had received atezolizumab for first-line treatment. CPI was associated with a lower risk of 1-year mortality (adjusted Hazard Ratio [HRadj] 0.59, 95% CI 0.42 to 0.82, p=0.002). This benefit was modified by BM and CRT, indicating a pronounced effect in patients without BM (with CRT: HRadj 0.34, p=0.003; no CRT: HRadj 0.50, p=0.05), while there was no effect in patients with BM who received CRT (HRadj 0.85, p=0.59). Conclusion: CPI was associated with a lower risk of 1-year mortality compared to chemotherapy. However, the effect on OS was significantly modified by intracranial disease and radiotherapy, suggesting the benefit was driven by patients without BM.

Study Design and Rationale for the PACE-LUNG Trial: A Multicenter, Single-Arm, Phase II Clinical Trial Evaluating the Efficacy of Additional Chemotherapy for Patients with EGFRm NSCLC with the Continued Presence of Plasma ctDNA EGFRm at Week 3 After Start of Osimertinib First-Line Treatment.

BACKGROUND: Tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) like the third-generation TKI osimertinib have substantially improved the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, there is a subset of patients that do not benefit from these therapies in terms of response rate or progression-free-survival (PFS). It has been shown that persistence of EGFR mutations in circulating tumor DNA (ctDNA) at weeks 3 and 6 after start of osimertinib predicts shorter PFS. These patients may benefit from additional chemotherapy. While combination therapies with older TKI have been demonstrated effective in improving outcome, they are associated with a significant increase in toxicity. PATIENTS AND METHODS: PACE-LUNG is a multicenter, single-arm, investigator initiated, phase II trial conducted with the German national Network Genomic Medicine (nNGM). Patients with stage IIIB or IV NSCLC and exon 19 deletion or p.L858R EGFR mutation not amenable to curative treatment with persisting ctDNA after 3 to 4 weeks of first-line osimertinib monotherapy will receive additional chemotherapy (4 cycles of either cisplatin/pemetrexed or carboplatin/pemetrexed). Afterwards, osimertinib will be continued as standard of care until disease progression or intolerable toxicity. The primary endpoint is PFS. Secondary endpoints include overall survival, response rate, safety, and quality of life. Concomitant translational research will be performed to identify patterns of mutational evolution in ctDNA upon disease progression or ctDNA persistence. Enrollment started in December 2021. DISCUSSION: The PACE-LUNG trial is designed to evaluate the efficacy and safety of a biomarker-driven strategy for therapy escalation in patients at high risk for early treatment failure. This approach aims not only to improve treatment outcomes, but also to limit the anticipated additional toxicity to high-risk patients. TRIAL REGISTRATION NUMBER: 2019-004757-88 (EudraCT).

Structural basis for interaction of the ribosome with the switch regions of GTP-bound elongation factors.

Elongation factor G (EF-G) catalyzes tRNA translocation on the ribosome. Here a cryo-EM reconstruction of the 70S*EF-G ribosomal complex at 7.3 A resolution and the crystal structure of EF-G-2*GTP, an EF-G homolog, at 2.2 A resolution are presented. EF-G-2*GTP is structurally distinct from previous EF-G structures, and in the context of the cryo-EM structure, the conformational changes are associated with ribosome binding and activation of the GTP binding pocket. The P loop and switch II approach A2660-A2662 in helix 95 of the 23S rRNA, indicating an important role for these conserved bases. Furthermore, the ordering of the functionally important switch I and II regions, which interact with the bound GTP, is dependent on interactions with the ribosome in the ratcheted conformation. Therefore, a network of interaction with the ribosome establishes the active GTP conformation of EF-G and thus facilitates GTP hydrolysis and tRNA translocation.