Outcomes Analysis of Patients Receiving Local Ablative Therapy for Oligoprogressive Metastatic NSCLC Under First-Line Immunotherapy.

CONTEXT: Nonsmall Cell Lung Cancer (NSCLC) treatment relies on first-line immunotherapy as single agent or combined with chemotherapy. Oligoprogression may be observed in this setting. MATERIAL AND METHOD: We performed a European multicentric retrospective study on patients treated with first-line immunotherapy, who presented with oligoprogressive disease, treated with a local ablative treatment. RESULTS: A total of 61 patients were retrospectively included between 2018 and 2022. Twenty-four patients (39%) received immunotherapy as single agent, and 37 (61%) chemo-immunotherapy. First oligoprogression occurred more frequently in pre-existing metastatic sites (47% of patients). Median PFS1 (defined as time to first oligoprogression) was 11.5 months [IC95%: 10.0-12.3]. We observed that 37 patients (61%) progressed after first oligoprogression, and 20 (54%) from them presented second oligoprogression. Median OS for the whole cohort was 72.0 months [IC95%: 19.3-124.8], with positive correlation between OS and PFS1 (R=0.65, P < .0001). After loco-ablative treatment with radiotherapy, disease control rate was 89% with ablative radiotherapy: 88% with conventional radiotherapy, and 89% with stereotactic radiotherapy. CONCLUSION: Patients with oligoprogression under/after immunotherapy have better prognosis with a high risk of subsequent oligoprogression.

Clinical characteristic and survival outcomes of patients with advanced NSCLC according to KRAS mutational status in the French real-life ESME cohort.

PURPOSE: The RAS/MEK signaling pathway is essential in carcinogenesis and frequently altered in non-small-cell lung cancer (NSCLC), notably by KRAS mutations (KRASm) that affect 25%-30% of non-squamous NSCLC. This study aims to explore the impact of KRASm subtypes on disease phenotype and survival outcomes. PATIENTS AND METHODS: We conducted a retrospective analysis of the French Epidemiological Strategy and Medical Economics database for advanced or metastatic lung cancer from 2011 to 2021. Patient demographics, histology, KRASm status, treatment strategies, and outcomes were assessed. RESULTS: Of 10 177 assessable patients for KRAS status, 17.6% had KRAS p.G12C mutation, 22.6% had KRAS non-p.G12C mutation, and 59.8% were KRASwt. KRASm patients were more often smokers (96.3%) compared with KRASwt (85.8%). A higher proportion of programmed death-ligand 1 ≥50% was found for KRASm patients: 43.5% versus 38.0% (P < 0.01). KRASm correlated with poorer outcomes. First-line median progression-free survival was shorter in the KRASm than the KRASwt cohort: 4.0 months [95% confidence interval (CI) 3.7-4.3 months] versus 5.1 months (95% CI 4.8-5.3 months), P < 0.001. First-line overall survival was shorter for KRASm than KRASwt patients: 12.6 months (95% CI 11.6-13.6 months) versus 15.4 months (95% CI 14.6-16.2 months), P = 0.012. First-line chemoimmunotherapy offered better overall survival in KRAS p.G12C (48.8 months) compared with KRAS non-p.G12C (24.0 months) and KRASwt (22.5 months) patients. Second-line overall survival with immunotherapy was superior in the KRAS p.G12C subgroup: 12.6 months (95% CI 8.1-18.6 months) compared with 9.4 months (95% CI 8.0-11.4 months) for KRAS non-p.G12C and 9.6 months (8.4-11.0 months) for KRASwt patients. CONCLUSION: We highlighted distinct clinical profiles and survival outcomes according to KRASm subtypes. Notably KRAS p.G12C mutations may provide increased sensitivity to immunotherapy, suggesting potential therapeutic implications for sequencing or combination of therapies. Further research on the impact of emerging KRAS specific inhibitors are warranted in real-world cohorts.

Palliative care integration and end-of-life care intensity for patients with NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) without oncogenic driver mutations is considered to have a poor prognosis, although recent therapeutic progress. This study aims to assess the real-life integration of palliative care (PC) and the intensity of end-of-life (EOL) care for this population. METHODS: This was an observational cohort study of decedent patients from metastatic NSCLC without oncogenic driver mutations over the period 01/2018 to 12/2022, treated in first line with immunotherapy +/- chemotherapy. We analysed PC integration and aggressiveness criteria of EOL care in the last month before death: systemic anti-cancer treatment administration, emergency room visits, intensive care unit admission, hospitalization, hospitalization duration > 14 days, and hospital death. RESULTS: Among 149 patients, 75 (50 %) met the PC team at least once, and the median time from the first encounter to death was 2.3 months. In the last month before death, at least one criterion of aggressive EOL care was present for 97 patients (70 %). For patients with PC use < 30 days and for patients with PC use < 90 days before death, there were significant changes: increase in the frequency of systemic anti-cancer treatment (respectively 51.1 % vs 20 %; p < 0.001 and 58.7 % vs 6.2 %; p < 0.001); decrease in hospitalization lasting > 14 days (respectively 30 % vs 7 %; p = 0.001 and 36 % vs 6.2 %; p = 0.018) and in death hospitalisation (respectively 66 % and 18 %; p < 0.001 and 58.7 % and 10.3 %; p < 0.001). After adjusting for the factors tested, patients with no PC or late PC use in the last month before death or in the last three month before death, the odds ratio (OR) remained significantly greater than 1 (respectively OR = 3.97 [1.70; 9.98]; p = 0.001 and OR = 23.1 [5.21-177.0], p < 0.0001). CONCLUSION: PC is still insufficiently integrated for patients with NSCL cancer. Cancer centres should monitor key indicators such as PC use and aggressiveness criteria of EOL care.

Evaluation of the relevance of the growth modulation index (GMI) from the FFCD 0307 randomized phase III trial comparing the sequence of two chemotherapeutic regimens.

BACKGROUND: Precision medicine trials disrupted the paradigm of randomized controlled trials in large populations. Patient selection may be based on molecular alterations rather than on primary tumor location. In small patient populations, the growth modulation index (GMI) has been developed to evaluate treatment efficacy by using each patient as its own control. The FFCD 0307 randomized phase III trial compared two sequences of chemotherapy in advanced gastric cancer, which represents a unique opportunity to evaluate the relevance of the GMI. PATIENTS AND METHODS: In the FFCD 0307 trial, patients with advanced gastric cancer were randomized between two chemotherapy sequences [ECX followed by FOLFIRI at disease progression (arm A) versus FOLFIRI followed by ECX (arm B)]. GMI was defined as the ratio of the progression-free survival on second treatment (PFS2) to the time to progression on first treatment (TTP1). Sequence benefit was defined as a GMI exceeding 1.3 (GMI-high). GMI was correlated with overall survival (OS). OS1 and OS2 were measured from first randomization and second-line failure to death. RESULTS: Four hundred and sixteen patients were randomized (209 in arm A, 207 in arm B). One hundred and seventy-five patients (42%) received the two sequences and were assessable for GMI (97 in arm A, 79 in arm B). The median GMI was higher in arm A than in arm B (0.62 versus 0.47, P = 0.04). Patients with a high GMI had a longer OS1 (median 14.9 versus 11.5 months, NS). Median OS2 was doubled in the GMI-high group (3.4 versus 1.6 months, NS). CONCLUSION: GMI analyses suggest that ECX followed by FOLFIRI might represent a better therapeutic strategy than FOLFIRI followed by ECX. High GMI was associated with prolonged survival.

Impact of the timing of tumor assessments on median progression-free survival in clinical trials in advanced cancer patients.

BACKGROUND: Survival-based surrogate endpoints such as progression-free survival (PFS) are commonly used in oncology clinical trials. The evaluation-time bias in the assessment of median disease progression in randomized trials has been suggested by several simulation studies, but never demonstrated in the clinic. We aimed to demonstrate the existence of potential evaluation-time bias by assessing the impact of the timing of tumor assessments on median PFS from control arms without any active treatment of randomized controlled trials involving advanced cancer patients. MATERIALS AND METHODS: A systematic literature search of English language publications from 1 January 2000 to 7 January 2021 was performed using MEDLINE (PubMed). Eligible trials for our meta-analysis included all randomized clinical trials evaluating anticancer drugs in adult patients with advanced cancers with a control arm without any anticancer drug consisting of best supportive care with or without a placebo. We performed a meta-regression analysis to analyze the correlation between the timing of the first tumor assessment and median PFS in patients randomized in the control arms without any active treatment. RESULTS: Of 3551 studies screened, 97 eligible trials were retrieved involving 36  747 patients, including 14  229 patients randomized into the control arms. A later first tumor assessment correlated with a prolonged median PFS (R2 = 0.44, P < 10-5). CONCLUSIONS: Our results confirm the existence of potential evaluation-time bias in clinical research that had been suggested by simulation studies. The timing of tumor assessments should be kept the same in precision medicine trials using the PFS ratio as an efficacy endpoint.