Non-squamous Histology Research Articles

Real-world treatment patterns and clinical outcomes after introduction of immune checkpoint inhibitors: Results from a retrospective chart review of patients with advanced/metastatic non-small cell lung cancer in the EU5.

Real-world evidence is increasingly used to guide treatment and regulatory decisions for non-small cell lung cancer (NSCLC). Real-world treatment patterns and clinical outcomes among patients with advanced/metastatic NSCLC in France, Germany, Italy, Spain, and the UK (EU5) were assessed. This retrospective physician-completed patient chart review assessed treatment patterns (regimen, duration of treatment [DOT], time to discontinuation), and clinical outcomes (duration of response [DOR], progression-free survival [PFS], and overall survival [OS]) of patients with stage IIIB/C or IV NSCLC who received pembrolizumab-based first-line induction chemotherapy. Overall, 322 patients were included; at first-line maintenance (1LM), 92% had stage IV NSCLC, 68% had nonsquamous histology, and 89% had no central nervous system (CNS)/brain metastasis. The two most common 1LM regimens were pembrolizumab monotherapy (76% overall) and pembrolizumab + pemetrexed (21% overall). Docetaxel monotherapy was the most common second-line regimen in all countries except Germany (54% overall). For 1LM therapy, the overall median DOT and DOR were 5 and 10 months, respectively; PFS was 7 months and OS was 8 months. Germany had a longer duration of each outcome except for DOR which was longer in Spain. Clinical outcomes were generally poorer for patients with squamous histology and CNS/brain metastases. This study demonstrated differences in treatment patterns and clinical outcomes in NSCLC across the EU5 and patient subgroups. Improved survival was generally associated with response to first-line therapy, nonsquamous histology, and CNS/brain metastases absence. These real-world data provide valuable insights which may aid treatment decision-making and clinical trial design.

Surgically treated cervical cancer in a high-risk group in the era of the 2018 FIGO staging schema: a nationwide study

The 2018 International Federation of Gynecology and Obstetrics (FIGO) revision to the staging criteria for uterine cervical cancer adopted pathological staging for patients who underwent surgery. We investigated the correlation between clinicopathological factors and prognosis in patients with high-risk factors in accordance with the FIGO 2018 staging criteria by analyzing a real-world database of 6,192 patients who underwent radical hysterectomy at 116 institutions belonging to the Japan Gynecologic Oncology Group. A total of 1,392 patients were categorized into the high-risk group. Non-squamous cell carcinoma histology, regional lymph node metastasis, pT2 classification, and ovarian metastasis were identified as independent risk factors for mortality. Based on pathological findings, 313, 1003, and 76 patients were re-classified into FIGO 2018 stages IIB, IIIC1p, and IIIC2p, respectively. Patients with stage IIIC2p disease showed worse prognoses than those with stage IIB or IIIC1p disease. In patients with stage IIIC1p disease, overall survival was significantly better if their tumors were localized in the uterine cervix, except for single lymph node metastasis, with a 5-year overall survival rate of 91.8%. This study clarified the heterogeneity of the high-risk group and provided insights into the feasibility of upfront radical hysterectomy for a limited number of patients harboring high-risk factors.

Survival outcome and prognostic factors post inadvertent hysterectomy in carcinoma cervix treated with salvage chemo-radiation.

The standard of care for treating early invasive cervical cancer is radical hysterectomy or radiation alone while chemo-radiation is a definitive treatment for advanced disease. Occasionally, a simple hysterectomy is performed in the cancer cervix and these patients merit adjuvant treatment in view of the high chances of loco-regional recurrences. The aim of the study was to analyze the survival outcome of these patients treated with salvage chemo-radiotherapy and also to determine the prognostic factors affecting survival. The medical records of all patients with cervical cancer post simple hysterectomy outside and who received salvage treatment in our department between 2014 and 2020 were retrieved. The data regarding clinical, treatment details and survival were analyzed. A total of 198 patients were included. Median follow-up duration was 45.5months. Gross disease and lymphadenopathy were seen in 60% and 28% patients, respectively. The 5-year progression-free survival(PFS) and overall survival(OS) was 75% and 76%, respectively. Concurrent chemotherapy alone or in combination with induction chemotherapy using three-drug regimens showed better survival compared to those treated by radiation alone. On multivariate analysis, factors found to be adversely affecting OS and PFS were lymph node (LN) size of more than 2cm, non-squamous histology, overall treatment time(OTT) of more than 12weeks and use of non three-drug chemotherapy regimen. Subtotal hysterectomy results in a higher incidence of local recurrence of disease. Factors that impair the outcome in this sub-group of patients are gross lymphadenopathy, non-squamous histology and prolong OTT.

Clinical and molecular features of long-term response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

We sought to identify features of patients with advanced non-small cell lung cancer (NSCLC) who achieve long-term response (LTR) to immune checkpoint inhibitors (ICIs), and how these might differ from features predictive of short-term response (STR). We performed a multicenter retrospective analysis of patients with advanced NSCLC treated with ICIs over ten years. LTR and STR were defined as response ≥ 24 months and response < 12 months, respectively. Tumor PD-L1 expression, mutational burden (TMB), next-generation sequencing, and whole exome sequencing data were analyzed to identify characteristics enriched in patients achieving LTR compared to STR and non-LTR. Among 3118 patients, 8% achieved LTR and 7% achieved STR, with 5-year overall survival of 81% and 18% among LTR and STR patients respectively. High TMB (≥ 50th percentile) enriched for LTR compared to STR (P = 0.001) and non-LTR (P < 0.001). Whereas PD-L1 ≥ 50% enriched for LTR compared to non-LTR (P < 0.001); PD-L1 ≥ 50% did not enrich for LTR compared to STR (P = 0.181). Non-squamous histology (P = 0.040) and increasing depth of response (median best overall response [BOR] -65% vs -46%, P < 0.001) also associated with LTR compared to STR; no individual genomic alterations were uniquely enriched among LTR patients. Among advanced NSCLC patients treated with ICIs, distinct features including high TMB, non-squamous histology, and depth of radiographic improvement distinguish patients poised to achieve long-term response compared to initial response followed by progression, whereas high PD-L1 does not.

Simultaneous integrated or sequential boost to clinically involved lymph nodes in patients with locally advanced cervical cancer treated with definitive chemoradiotherapy

ObjectiveThe optimal treatment of metastatic lymph nodes (LNs) in locally-advanced cervical cancer (LACC) is controversial. With the widespread use of modern radiotherapy (RT) techniques, it is become possible to perform dose escalation in clinically involved LNs. This study aimed to evaluate the oncologic outcomes of dose escalation to the involved LNs with the simultaneous-integrated (SIB) or sequential boost (SEB) techniques as a part of definitive chemoradiotherapy (CRT) for patients with LACC. MethodsThe data of 47 patients treated with definitive CRT with either a SIB or SEB technique to the metastatic LNs between 2015 and 2021 were retrospectively analyzed. All patients received 50.4 Gy/28 fractions of external-beam RT and 28 Gy/4 fractions of brachytherapy. ResultsThe number of boosted LNs was 146. The median size of the LNs was 2 cm (range, 1–5 cm). The median cumulative equivalent dose in 2-Gy fractions for the LNs was 64.2 Gy (range, 57.6–71.2 Gy). During the median 30 months of follow-up (range, 14–91 months), no boosted LNs recurred and the local control (LC) rate was 100%. The 2-year overall, disease-free, local recurrence-free, and distant metastasis-free survival rate was 83.1%, 70.5%, 77.5%, and 74.4%, respectively. In multivariate analysis, the non-squamous cell histology was the only negative independent prognostic factor for DFS and DMFS. Treatment was well tolerated without any serious acute toxicity. Serious late toxicity developed in three (6%) patients as ureteral stenosis, rectal bleeding and pelvic fracture in one patient each. ConclusionsRT dose escalation provides excellent LC for the clinically involved LNs, even for bulky ones, with a low toxicity profile. Routine LN dissection may not be necessary. However, randomized trials are needed to determine the optimal treatment approach.

Cemiplimab + Chemo Shows Clinical Benefit in Advanced NSCLC

Cemiplimab + Chemo Shows Clinical Benefit in Advanced NSCLC

PD-L1 expression as a unique negative predictive biomarker in advanced squamous NSCLC when treated with first-line chemotherapy.

e21140 Background: PD-L1 expression has been established as a positive predictive biomarker for immune checkpoint inhibition in advanced non-small cell lung cancer (NSCLC). We hypothesize that PD-L1 serves as a negative predictive biomarker of chemotherapy in squamous NSCLC in contrast to non-squamous NSCLC. Methods: Phase III randomized trials that investigated PD-L1 expression as a biomarker in advanced squamous NSCLC at first-line were identified and included through a systematic search of Embase and PubMed from inception until 24th September, 2022. To investigate the anti-thesis, trials that reported PD-L1 stratified KM plots in non-squamous NSCLC were evaluated too. Only trials that reported PD-L1 stratified KM curves of chemotherapy arms were included. A graphical reconstructive algorithm was used to retrieve survival data from reported Kaplan-Meier (KM) curves. Pooled survival analyses for progression-free and overall survival (PFS, OS) were conducted with Cox proportional hazard models with a shared-frailty term incorporated to account for inter-study differences. Results: Five phase III randomized trials (2 squamous NSCLC and 3 non-squamous NSCLC) reporting PD-L1 stratified KM plots of patients treated with first-line chemotherapy were included. In patients with squamous histology, PD-L1 expression negatively predicted for chemotherapy benefit – patients with higher PD-L1 expression were at a higher risk of tumour progression (PD-L1 ≥50% [n = 187] vs PD-L1 &lt; 1% [n = 247]: HR = 1.474, 95%-CI: 1.171-1.855, p &lt; 0.001; PD-L1 ≥50% [n = 187] vs PD-L1 1-49% [n = 239]: HR = 1.300, 95%-CI: 1.033-1.625, p = 0.025). Conversely, in patients with non-squamous histology, no significant differences in tumour progression was shown between PD-L1 subgroups (PD-L1 ≥50% [n = 137] vs PD-L1 &lt; 1% [n = 242]: HR = 1.238, 95%-CI: 0.919-1.667, p = 0.160; PD-L1 ≥50% [n = 137] vs PD-L1 1-49% [n = 199]: HR = 0.958, 95%-CI: 0.714 -1.285, p = 0.780). No significant difference in OS was found between PD-L1 subgroups dichotomized at 1% &amp; 50% among patients with squamous histology. In contrast, in patients with non-squamous histology, PD-L1 was a positive biomarker for chemotherapy benefit – patients with higher PD-L1 were at a lower risk of mortality (PD-L1 ≥50% [n = 40] vs PD-L1 &lt; 1% [n = 150]: HR = 0.523, 95%-CI: 0.316-0.865, p = 0.012). Conclusions: These findings suggest that PD-L1 expression is uniquely a negative predictor for tumour progression in advanced squamous NSCLC treated with first-line chemotherapy.

Clinical and molecular features of long-term response to anti-PD-(L)1 therapy in patients with advanced non-small cell lung cancer.

9107 Background: PD-(L)1 blockade can generate long-term responses in subsets of patients (pts) with advanced non-small cell lung cancer (NSCLC), but the clinical and molecular features of long-term responders (LTR) are not well established. Whereas features predictive of initial response have been rigorously explored, long-term follow up in large cohorts is required to identify features distinguishing LTR from short-term responders (STR). Methods: We analyzed pts with advanced NSCLC treated with anti-PD-(L)1 therapy at three institutions (MSK, DFCI, MDACC) between 2011 and 2022; responses were assessed by RECIST. LTR was defined as partial response (PR) or complete response (CR) ≥ 24 months; STR was defined as PR/CR &lt; 12 months followed by progressive disease (PD). PD-L1 IHC, tumor mutational burden (TMB), next generation sequencing (NGS), and whole exome sequencing (WES) results from subsets of pts were analyzed. High TMB was defined by harmonized TMB z-score ≥ 0 (≥ median TMB in each cohort: ≥ 7.9 for MSK, ≥ 10.5 for DFCI). Results: Among 3240 pts overall (MSK = 1536, DFCI = 1238, MDACC = 466), LTR was achieved in 267 (8.2%, 95% CI 7.3 to 9.2%) and STR was achieved in 213 (6.6%, 95% CI 5.7 to 7.5%), with similar rates from each site. 5-year overall survival (OS) was 83% among LTR and 20% among STR. In univariate analyses, non-squamous histology (non-SQ: odds ratio [OR] 2.13, p = 0.005), peripheral blood derived neutrophil to lymphocyte ratio (dNLR) &lt; 3.0 (OR 2.15, p &lt; 0.001), and high TMB (OR 2.25, p = 0.001) were associated with LTR compared to STR; high PD-L1 (PD-L1 ≥ 50%: OR 1.19, p = 0.494) was not. In multivariate analyses, non-SQ histology (OR 2.56, p = 0.047) and high TMB (OR 2.73, p = 0.001) remained independently associated with LTR over STR. Among LTR compared to patients with best response of PD, dNLR &lt; 3.0 (OR 1.72, p = 0.030), high PD-L1 (OR 5.23, p &lt; 0.001), and high TMB (OR 2.55, p = 0.001) associated with LTR. LTR showed deeper radiographic responses compared to STR (best response of -50% or greater: OR 3.88, p &lt; 0.01). Among 1798 pts with NGS, pathogenic ARID1A alterations were numerically higher among LTR compared to STR, but this was not significant when accounting for multiple hypothesis testing (14% vs 2%, p = 0.022, q = 0.196). Among 73 pts with available WES, both clonal (p = 0.037) and subclonal TMB (p = 0.010) were significantly higher among LTR compared to STR. Conclusions: We report outcomes from &gt; 10 years of advanced NSCLC pts treated with anti-PD(L)1 therapy in a large multicenter cohort, with ongoing response at 2 years associated with &gt; 80% 5-year OS. High TMB was a strong independent predictor of LTR over STR. Non-squamous histology, low dNLR, and depth of response also correlate with LTR, while no individual genomic alterations clearly distinguish LTR. These features may assist in identifying pts more likely to derive durable benefit from anti-PD(L)1 therapy without treatment intensification.

Patient characteristics, treatment patterns, and clinical outcomes among patients with de novo advanced or metastatic (stage IIIB–IV) non-small cell lung cancer in a real-world setting.

e21032 Background: In the past decade, therapies targeting EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET variants , and PD-L1 expression were approved and recommended for use in advanced non-small cell lung cancer (aNSCLC). This study describes real-world patient characteristics, biomarker testing, treatment patterns, and clinical outcomes in patients with de novo stage IIIB–IV aNSCLC in the United States. Methods: This is a retrospective cohort study of patients with aNSCLC using TEMPUS oncology data. Patients were included if they were diagnosed with stage IIIB, IIIC, or IV NSCLC (index date) as their primary NSCLC diagnosis between 1/1/2012 and 12/31/2020, and were &gt;18 years of age at index. Patients with an advanced diagnosis within 90-days of their primary diagnosis were defined as having de novo aNSCLC. Patient demographics and clinical characteristics including biomarker testing for EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET alterations, and/or PD-L1 expression, as well as treatment patterns, were described. Median progression-free survival (PFS) and median overall survival (OS) were stratified by stage at diagnosis (IIIB/IIIC vs IV) and evaluated by Kaplan–Meier analysis. Results: A total of 7,624 patients met the study criteria. 12.5% (n = 955) were diagnosed at stage IIIB/IIIC versus 87.5% (n = 6,669) diagnosed at stage IV. Of the de novo patients with aNSCLC, 47.6% (n = 3,632) were female, median age (IQR) was 65.3 years (58.1–72.4), 67.4% (n = 5,136) were White, and 62.7% (n = 4,781) had evidence of biomarker testing. Biomarker testing was significantly more common among patients diagnosed at stage IV (64.9%, n = 4,325) than stage IIIB/IIIC (47.7%, n = 456; p &lt; 0.001). At index, 10.3% (n = 785) of patients had evidence of brain metastasis, 49.2% (n = 3,749) were current or former smokers, and 66.7% (n = 5,086) had non-squamous histology. 69.1% (n = 5,269) received first-line treatment with chemotherapy (58.5%, n = 3,083), chemotherapy + immune checkpoint inhibitor (ICI) (20.8%, n = 1,096), ICI monotherapy (9.5%, n = 503), tyrosine kinase inhibitors (10.4%, n = 548), or other treatments (0.7%, n = 39). Among patients with de novo aNSCLC overall at stage IIIB/IIIC and stage IV, median PFS was 5.0 months (mos) (95% CI: 4.8, 5.3), 7.2 mos (95% CI: 6.3, 8.1), and 4.8 mos (95% CI: 4.6, 4.9; p &lt; 0.0001), respectively; median OS was 13.9 mos (95% CI: 13.3, 14.5), 19.4 mos (95% CI: 16.8, 22.0), and 13.2 mos (95% CI: 12.6, 13.8; p &lt; 0.0001), respectively. Conclusions: Among patients with de novo aNSCLC, those diagnosed at stage IIIB/IIIC had significantly longer median PFS and OS than those diagnosed at stage IV. Many real-world patients with aNSCLC were not tested for biomarkers for which there are now approved targeted therapies. Earlier diagnosis and increased biomarker testing may improve clinical outcomes in real-world patients with aNSCLC.

The incidence and risk factors predictive of bone metastases at initial diagnosis of malignancy.

e18816 Background: Bone metastases are associated with increased morbidity and decreased quality of life in patients with solid tumors. We report here the incidence and predictive factors for bone metastases at initial diagnosis in a large population-based dataset. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients 18 years-old or older and with solid cancers of all stages diagnosed from 2010 to 2019. We calculated the incidence and predictive factors for bone metastases according to demographic and tumor characteristics. Results: Among the 1,132,154 patients identified, 1,075,069 (94.96%) had known bone metastasis status and were eligible for the study. Bone metastases were detected in 55,903 (4.9%) patients. Among patients with bone metastases, the most common primary tumors were lung (44.4%), prostate (19.3%), breast (12.4%), kidney (4.0%), colorectal (2.24%) and pancreas (2.23%). The percentage of bone metastases in patients with non-small cell lung cancer (NSCLC), prostate adenocarcinoma, infiltrating ductal carcinoma of the breast (IDC), and colorectal adenocarcinoma (CRC) was 18.04% (18,123 out of 100,447), 5.92% (9,071 out of 153,325), 2.9% (4,490 out of 154,626), and 1.17% (1,043 out of 89,510) respectively. In addition to T and N stage, independent risk factors by multivariable analysis for bone metastases included female sex and non-squamous histology in NSCLC, black race, hormonal and HER2 status in breast cancer, Gleason score and PSA in prostate cancer, male sex, black race, rectal location, liver metastases and lung metastases in CRC. In univariate analysis, the strongest predictors for bone metastases were N2/3 (28.3%) and T3/4 (24.9%) in NSCLC, T3/4 (15.8%), N2/3 (10.6%), N1 (5.9%) and HER2 positive (4.9%) in IDC, N1 (38.1%), Gleason score 9/10 (22.8%), PSA 98 or higher (19.5%) and PSA 20-97 (16.8%) in prostate cancer, and rectal or rectosigmoid location (1.43% vs 1.05% in colon cancer, p &lt; 0.001) in CRC. Conclusions: Approximately 5% of patients with solid tumors have bone metastases at presentation. In addition to T and N stage, there are several risk factors for bone metastases according to the primary tumor site.

Real world assessment of clinical benefit with consolidation durvalumab following chemoradiotherapy in stage III unresectable non-small cell lung cancer.

e18853 Background: The phase III PACIFIC trial compared the efficacy of consolidation durvalumab to placebo in newly diagnosed, unresectable stage III non-small cell lung cancer (NSCLC) who had not progressed after chemoradiotherapy (CRT). With a median follow-up of 34.2 months, the median progression free survival (PFS) was 16.9 months (13.0-23.9) compared to 5.6 months (4.6-7.7) for placebo (HR = 0.55, 95% CI,0.45-0.68). We report a real-world study that utilizes surrogate endpoints to assess duration of clinical benefit with consolidation durvalumab. Methods: OncoHealth, a digital health company, conducted a retrospective observational real-world study to assess time to treatment failure in patients with unresectable Stage III NSCLC who received consolidation durvalumab after completion of CRT between June 2018-June 2021. Data sources included electronic medical records (EMR) submitted with prior authorization (PA) requests to OncoHealth and medical claims data. With a data cut-off of 12/22/2022, real-world Time to Progression (rwTTP), and real-world Time to Next Treatment (rwTTNT) were evaluated to assess time to treatment failure. All end points were measured from durvalumab administration dates, rwTTP spanned until earliest date of clinician-assessed progression, and rwTTNT spanned until initiation of subsequent treatment. Results: Total of 281 patients with unresectable Stage III NSCLC who received durvalumab after completion of definitive CRT were identified. Median age was 71 years (range: 53 to 88), 57% male, 53% former smokers, 47% Stage IIIA, 52% non-squamous histology and 98% received concomitant platinum-based chemotherapy prior to durvalumab. Median time between completing CRT and initiating durvalumab was 41 days. With a cutoff date of 12/22/2022, and a median follow up of 28.4 months, 34% (n = 95) experienced disease progression. Sites of progression included lung, lymph nodes, adrenal, liver, bone and brain. The median rwTTP was 10.6 months (range: 2.0-38.1 months) and median rwTTNT was 12.4 months (range: 2.5-39.6 months). Conclusions: In this real-world study, the patient and disease characteristics available in EMR were comparable to those reported in the PACIFIC trial. The rwTTP and rwTTNT reported here suggest treatment failure occurred within one year of exposure to durvalumab and subsequent line of treatment was initiated shortly thereafter. Variables such as co-morbidities, performance status, treatment compliance, change of payers and barriers to treatment in real world will be further explored.

STAR-121: A phase 3, randomized study of domvanalimab (DOM) and zimberelimab (ZIM) in combination with chemotherapy vs pembrolizumab (pembro) and chemotherapy in patients with untreated metastatic non-small cell lung cancer (mNSCLC) with no actionable gene alterations.

TPS9141 Background: Although immune checkpoint inhibitors have improved clinical outcomes in mNSCLC, the majority of patients will experience progression and shorter survival. Thus, an urgent need exists for more effective treatment options in mNSCLC. DOM is an anti-TIGIT IgG1, Fc-silent monoclonal antibody designed to inhibit the interaction between TIGIT and its ligand, CD155, thereby reducing immunosuppression of T cells and natural killer cells and promoting antitumor activity. ZIM is an anti–PD-1 IgG4 monoclonal antibody with demonstrated antitumor activity in vivo and preliminary clinical activity in multiple tumor types. Preliminary studies have shown that dual blockade of TIGIT and PD-(L)1 increases antitumor activity relative to PD-(L)1 inhibition. In ARC-7, a randomized phase 2 study in PD-L1–high, first-line NSCLC, DOM and ZIM in combination recently demonstrated a higher objective response rate (ORR) and longer median progression-free survival (PFS) than ZIM monotherapy. We hypothesize that DOM and ZIM in combination with chemotherapy will improve clinical outcomes in patients with untreated mNSCLC without EGFR or ALK aberrations regardless of PD-L1 expression. Methods: STAR-121 is a phase 3, global, open-label, randomized study to evaluate the safety and efficacy of DOM and ZIM plus chemotherapy vs pembro plus chemotherapy as first-line therapy for patients with mNSCLC with no EGFR or ALK aberrations or other known actionable gene alterations. Approximately 720 patients will be randomized into 3 groups (A, B, or C) in a 4:4:1 ratio and stratified by baseline PD-L1 tumor proportion score ( &lt; 50% vs ≥50%), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Eligible patients are aged ≥18 with untreated mNSCLC with no EGFR or ALK aberrations. Group A will receive DOM 1200 mg + ZIM 360 mg + platinum-doublet chemotherapy (PT), group B will receive pembro 200 mg + PT, and group C will receive ZIM 360 mg + PT. DOM, ZIM, and pembro will be administered until disease progression (PD) as assessed by blinded independent central review (BICR) per RECIST 1.1 or intolerable toxicity or for up to 35 doses. Study treatment will be administered IV every 3 weeks. PT will be chosen by investigators based on tumor histology and administered for the first 4 cycles, after which, pemetrexed can be continued for patients with nonsquamous histology until PD or intolerable toxicities. The primary endpoints are PFS by BICR and overall survival. Key secondary endpoints are ORR and duration of response by BICR, safety, and quality of life. This study is currently enrolling globally. Clinical trial information: NCT05502237 .

Class II and class III BRAF mutations in patients with advanced non-small cell lung cancer (NSCLC): Clinical characteristics, mutation patterns, and survival outcomes.

e21204 Background: Class II and class III BRAF mutations (i. e., non-V600X) in NSCLC differ from V600E in terms of dimerization and KRAS-dependency. Whereas V600X is effectively targetable by combined BRAF- and MEK-inhibition, no specific targeted approach for non-V600X exists, and a comprehensive description of the patient group is lacking. This retrospective cohort analysis presents clinical and genomic characteristics of a large cohort of patients with advanced BRAF nonV600X mutant lung cancer. Methods: Molecular data of 1411 lung cancer patients staged IIIb/IV and harboring BRAF mutations were linked to hospital registry data in the NGM (Network Genomic Medicine) database. Biospecimens were analyzed using next-generation sequencing (NGS). Results: 721 patients with BRAF non-V600X mutations were identified, of whom 10.5% had been diagnosed with squamous cell carcinoma (SCC) and 89.5% had non-squamous histology. Median age at diagnosis was 66 years (range: 34-81) and the cohort comprised 409 (56.7%) men and 312 (43.3%) women. 301 (41.8%) of the BRAF non-V600X alterations detected in this cohort are “activators” in the MAPK pathway (class II, including G469A/V/R, G464A/E/L/V, K601E/N, L597Q/R/V), while 310 (43.0%) function as “amplifiers” (class III, including mutants such as D594A/G/H/N, G466A/E/V, G469E, N581I/S/T in this cohort). While 21.5 % (155; SCC: 12.3%; non-SCC: 22.9%) of patients did not have any co-occurring mutations (55.6% of SCC and 37.1% of non-SCC patients respectively), TP53 was the most frequent co-mutation, detected in 56.6% (SCC: 74.0%; non-SCC: 53.8%) of patients. 16.4% (118) exhibited a KRAS co-mutation (SCC: 4; non-SCC: 109). A preliminary survival analysis suggests no significant difference in overall survival between these broad classes (HR 0.92, 95%-CI 0.62, 1.36). Conclusions: The study highlights the heterogeneity of patients with BRAF class II and class III regarding histology and co-mutational status, with both classes equally frequent. A more granular investigation of non-V600X alterations and their associated clinical outcomes under different treatment approaches is ongoing.

Prevalence of pathogenic germline variants in a cohort of patients with early onset non-small cell lung cancer (EOLUNG).

10630 Background: Patients with early onset lung cancer might be more likely to carry pathogenic (or likely-pathogenic) germline variants (PGV) in genes associated with cancer predisposition. However, germline testing is not recommended in this population. We designed this study to determine the prevalence of PGVs in patients with early onset lung cancer. Methods: This prospective, multicenter cohort study assessed PGV in patients younger than 51 years diagnosed with non-small cell lung cancer (NSCLC) in 3 sites at the Catalan Institute of Oncology between June 2018 to May 2022. Genomic DNA was sequenced using a custom-designed NGS panel covering 164 cancer-predisposing genes and results were discussed in a multidisciplinary tumor board. Results: 138 patients were included. Median age was 45.5 (28-50) years; 49% were females; 79% were ever-smokers with a median packs-year of 24 and median age of tobacco initiation of 16 years old. Most patients had non-squamous histology (88%) and had stage IV (62%) at diagnosis. Somatic oncogenic drivers were found in 74 patients (54%): EGFR 27 (20%); ALK 22 (16%); KRAS 20 (14%); RET 3 (2%); ROS1 1 (1%); BRAF V600E 1 (1%). Only 4% had past personal history of cancer and 50% had family history of cancer in a first-degree relative, being lung and breast cancer the most common tumors. Overall, 20 patients (14%) carried PGVs involving 12 genes associated with cancer predisposition: PARK2 (n=4); SBDS (n=3); NBN (n=2); ATM (n=2); TSC1 (n=2) and BLM, FANCA, MCPH1, PMS2, POLH, SDHA, RECQL4 (n=1, each). Four patients (3%) fulfilled criteria to be referred to genetic counseling clinic. There were no significant differences in clinical and molecular characteristics among patients with PGVs compared to their counterparts (Table). Conclusions: In this prospective cohort, 14% of patients with early onset NSCLC harbored germline PGVs. As clinicopathological and genomic features were not associated with PGVs, germline testing might be considered in addition to comprehensive genomic characterization of tumor tissue in young patients with NSCLC. However, only a minority of PGVs were deemed clinically actionable.[Table: see text]

Final results from a phase II trial of CIMAvax-EGF and nivolumab as second-line (2L) therapy after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC).

9135 Background: CIMAvax-EGF (C-E) is a recombinant anti-human epidermal growth factor (EGF) depleting immunotherapy which has previously shown increased survival as maintenance after platinum-based chemotherapy in patients (pts) with advanced NSCLC. The primary objective of this single-arm phase II trial was to evaluate the 12-month overall survival (OS) in pts receiving C-E in combination with Nivolumab(N) as 2L therapy for advanced NSCLC. Methods: Pts with previously treated, immunotherapy-naive advanced NSCLC received 2.4 mg C-E IM every 2 weeks(w) for 4 doses (loading phase) in combination with N 240mg IV every 2 w, then continued monthly maintenance C-E combined with N 240mg IV every 2 w. Enrollment to this arm was terminated before estimated sample size was met due to poor accrual as immunotherapy became incorporated into 1st line therapy. We present OS and progression-free survival (PFS) data [determined using a Kaplan-Meier test with 90% confidence intervals (CI)] of pts who were able to complete the loading phase per protocol (PP). Results: 21 out of 23 enrolled pts were included in the PP analysis. Among the 21 pts, 17 (81.0%) had non-squamous(nsq) histology, 12 (57.1%) were KRAS wildtype (9.5% unknown status), 13 (61.9%) had PD-L1 tumor proportion score 0%. 43% pts (n=3) with known KRAS mutation (n=7) had co-mutated STK11. Disease control rate was 47.6% (n=10) defined as pts who had stable disease or partial response as best response per RECIST v1.1. The 21 PP pts had a 29% 3-year(yr) OS rate (90% CI 14, 45; intention-to-treat [ITT] population in 23 pts with 26% 3-yr OS rate, 90% CI 13, 42). Median(m) OS for PP pts was 11.9 months, 90% CI 8.0 – 23.9 months (ITT mOS 10.4 months, 90% CI 6.8-13.6). Pts with squamous histology had a better 3-yr OS rate compared to those with nsq histology [50% (90% CI 10, 81) vs 24% (90% CI 9, 41), respectively]. Pts with PD-L1 expression ≥1% had higher 3-yr OS [38% (90% CI 12, 63)] and 3-year PFS [38% (90% CI 12, 63)] compared to pts with no PD-L1 expression (3-yr OS 23% [90% CI 8, 44] and 3-yr PFS 8% [90% CI 1, 25]). mOS, 1-yr and 3-yr OS for EGFR/ALK/KRAS wildtype pts was higher [31.7 months (90% CI 5.9, NR), 67% (90% CI 4, 84), 50% (90% CI 24,71), respectively) compared to KRAS mutated NSCLC [10.1 months (90% CI 6.5, 12.1), 29% (90% CI 6, 56), 0% (90% CI 1, 41), respectively]. Conclusions: NSCLC pts who were able to complete the PP combination of C-E plus N at the minimum had numerically better OS compared to historical study cohorts with N as 2L monotherapy. Among pts who completed PP treatment, pts with KRAS wildtype NSCLC had the longest mOS observed. C-E is currently being investigated in combination with pembrolizumab as maintenance therapy after completing 1L chemoimmunotherapy for NSCLC with PD-L1 &lt; 50% and as 1L therapy in combination with pembrolizumab for EGFR/ALK wildtype NSCLC and PD-L1 ≥ 50%. Clinical trial information: NCT02955290 .

Phase II results of ivonescimab (AK112/ SMT112), a novel PD-1/VEGF bispecific, in combination with chemotherapy for first line treatment of advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGA) in EGFR/ALK.

9087 Background: Since the initial approval of bevacizumab (bev) with chemo in NSCLC, the subsequent focus of bev use in combination with PD1 therapy for first line metastatic disease has largely focused on non-squamous (non-SCC) histology. Ivonescimab is a novel anti-PD-1/VEGF bispecific antibody. The bispecific approach to these targets has the potential to recalibrate the malignant immuno-architecture in favor of a more immune-responsive and anti-tumor microenvironment. Cooperative VEGF binding with the bispecific has been shown to elevate affinity of ivonescimab to PD-1 by more than 10-fold. Ivonescimab has a mean T1/2 of 6-7 days while bev T1/2 is 20 days. Therefore, we aimed to assess the efficacy and safety of ivonescimab combined with chemotherapy for first line advanced or metastatic NSCLC in patients (pts) with squamous (SCC) or non-SCC NSCLC. Methods: An open-label, multi-center phase II study evaluating the efficacy and safety of ivonescimab combined with chemotherapy in pts with advanced or metastatic NSCLC. Pts were enrolled into 3 cohorts based on prior therapy and presence of AGA. Data from pts with prior therapy for advanced or metastatic disease were presented in ASCO 2022 and here we report additional pts and longer-term data from pts with NSCLC without AGA receiving first line therapy for advanced/metastatic disease. Pts were treated with 10 or 20 mg/kg ivonescimab once every 3wks combined with carboplatin and pemetrexed (non-SCC) or carboplatin and paclitaxel (SCC). The primary endpoint was ORR per RECIST by investigator. Results: 135 pts with advanced or metastatic NSCLC received ivonescimab plus chemotherapy including 63 with SCC and 72 with non-SCC. Median age was 61 yrs (. 78% male, 3% and 97% pts had ECOG PS 0 and 1, respectively, and 20% pts had baseline brain metastasis. Median follow-up was 11.5 mo. Pts with SCC experienced a 75% ORR with median DOR 15.4 mo, 95% DCR, the 9-mo PFS and OS rate was 67% and 93%, respectively. Pts with non-SCC experienced a 55% ORR, DOR was not reached, 100% DCR, the 9-mo PFS rate and OS rate was 61% and 81%, respectively. The most common treatment related adverse events (TRAEs)≥ 10% were epistaxis, proteinuria, rash, amylase increased, anemia, ALT increased, infusion related reaction, AST increased, pruritus, decreased appetite, and WBC decreased. Grade ≥3 TRAEs occurred in 28.1% TRAE leading to discontinuation occurred in 6.7% of pts. Conclusions: Ivonescimab, plus chemotherapy has shown promising anti-tumor activity in pts with advanced/metastatic NSCLC without AGA and can be administered safely in combination with platinum doublet chemotherapy to patients with SCC and non-SCC histology. Clinical trial information: NCT04736823 .

Retreatment with nivolumab and ipilimumab with or without chemotherapy in patients with metastatic non-small cell lung cancer after progression on immune checkpoint inhibitor therapy.

e21192 Background: The advent of immune checkpoint inhibitor (ICI) has revolutionized the therapeutic arsenal for metastatic non-small cell lung cancer. However, better therapeutic options after a progression on frontline ICIs are urgently needed and remain to be defined. ICI retreatment (rt) may constitute a rational therapeutic alternative in these patients. However prospective studies evaluating such opportunity are still lacking. Methods: We retrospectively collected data from 30 metastatic NSCLC patients (pts) having progressed on ICI (anti-PD-1, anti-PD-L1 or anti-PD-1/anti-CTLA4 combined or not with histologydriven chemotherapy) who were retreated by double-agent ICI (ipilimumab and nivolumab) combined or not with histology-driven ChT in order to evaluate rt overall survival (OS) and rt progression-free-survival (PFS). The rt PFS was calculated from rt ICI initiation to death, last follow-up or disease progression. An assessment of correlation between certain clinical variables like sex, age, smoking history and others; and survival variables was performed. Results: The median age of the 30 pts included in the analysis was 64 years (63% of pts were &lt; 70 years old and 37% ≥ 70 years old) and 53% (n = 16) of the pts were male. Most suffered from a non-sq NSCLC (73%), with bone mets (66%), and were current or former smokers (90%). Median OS and median PFS in the whole group were 9 months (m) [95% confidence interval (CI): 5.7 - 14] and 2.5 m [95% CI: 2 - 4.6] respectively. Retreatment PFS was higher in pts having received dual ICI combined with ChT than dual ICI only [95% CI: 4.3 (3.7 – 6) versus 2.1 (1.5 – 2.9) m; hazard ratio (HR): 0.51 (0.24 – 1.10); p – value (p) = 0.085]. Retreatment OS and PFS were numerically higher in pts having received single- or double- ICI as prior therapy compared to ICI plus ChT [9.6 (6.4 – not reached) m versus 8.4 (3.7 – 13.5) m; HR: 0.53 (0.22 – 1.29), p = 0.15], and [4.2 (2.2 – not reached) m versus 2.4 (2 – 4.5 m); HR: 0.56 (0.25 – 1.24); p = 0.14), respectively], regardless of the rt. When we assessed the correlation between prior therapy and rt, we found the association of ChT to dual-ICI after prior single- or dual-ICI as first line treatment leads to a significantly higher PFS [4.5 (4 – NR) m versus 2.5 (1.6 – NR) m] compared to pts having received first ChT plus ICI then dual-ICI alone as second line treatment [HR 0.35 (95% CI: 0.13 – 0.93); p: 0.03]. The trend in OS benefit probably also favored ChT with dual-ICI as rt after prior single- or dual-ICI (HR 0.55; p = 0.23). Binary variables such as sex, histology, PD-L1 expression, smoking history, therapeutic discontinuation interval (TDI), baseline derived neutrophil-to-lymphocyte ratio dNLR) and baseline absolute lymphocyte counts (ALC) influenced positively the PFS in pts receiving dual ICI combined with ChT [ sex HR: 0.28; non-squamous histology HR: 0.26; PDL1 expression HR:0.22; former smoker HR: 0.23; never-smoker HR: 0.40; TDI less than 30 days HR: 0.09; high (≥ 3) dNLR HR: 0.22; and low (&lt;1000) ALC HR: 0.37]. Conclusions: Patients previously treated by ICI could be retreated by ICI combined with histology-driven chemotherapy in an individual approach, under certain circumstances, which are yet to be formally evaluated and determined.

Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer.

To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non-Small Cell Lung Cancer.

ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC); however, limited characterization has been pursued. Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets. A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATM-mutant (ATMMUT) NSCLC was significantly associated with female sex (P = 0.02), ever smoking status (P < 0.001), non-squamous histology (P = 0.004), and higher tumor mutational burden (DFCI, P < 0.0001; MSK, P < 0.0001) compared with ATM-wild-type (ATMWT) cases. Among 3,687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q < 0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs. 28.6%; P < 0.0001) compared with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) and chemo-immunotherapy (N = 951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy. Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.

Overall survival in patients with advanced non-small cell lung cancer with KRAS G12C mutation with or without STK11 and/or KEAP1 mutations in a real-world setting

BackgroundKRAS mutations occur frequently in advanced non-small cell lung cancer (aNSCLC); the G12C mutation is the most prevalent. Alterations in STK11 or KEAP1 commonly co-occur with KRAS mutations in aNSCLC. Using real-world data, we assessed the effect of KRAS G12C mutation with or without STK11 and/or KEAP1 mutations on overall survival (OS) in patients with aNSCLC receiving cancer immunotherapy (CIT), chemotherapy, or both in first line (1L) and second line (2L).MethodsPatients diagnosed with aNSCLC between January 2011 and March 2020 in a clinico-genomic database were included. Cox proportional hazards models adjusted for left truncation, baseline demographics and clinical characteristics were used to analyze the effect of STK11 and/or KEAP1 co-mutational status on OS in patients with KRAS wild-type (WT) or G12C mutation.ResultsOf 2715 patients with aNSCLC without other actionable driver mutations, 1344 (49.5%) had KRAS WT cancer, and 454 (16.7%) had KRAS G12C–positive cancer. At 1L treatment start, significantly more patients with KRAS G12C–positive cancer were female, smokers, and had non-squamous histology, a higher prevalence of metastasis and programmed death-ligand 1 positivity than those with KRAS WT cancer. Median OS was comparable between patients with KRAS G12C–positive and KRAS WT cancer when receiving chemotherapy or combination CIT and chemotherapy in the 1L or 2L. Median OS was numerically longer in patients with KRAS G12C vs KRAS WT cancer treated with 1L CIT (30.2 vs 10.6 months, respectively) or 2L CIT (11.3 vs 7.6 months, respectively). Co-mutation of STK11 and KEAP1 was associated with significantly shorter OS in patients receiving any type of 1L therapy, regardless of KRAS G12C mutational status.ConclusionsThis real-world study showed that patients with KRAS G12C–positive or KRAS WT cancer have similar OS in the 1L or 2L when treated with chemotherapy or combination CIT and chemotherapy. In contrast to aNSCLC patients with EGFR or ALK driver mutations, patients with KRAS G12C–positive cancer may benefit from CIT monotherapy. Co-mutation of STK11 and KEAP1 was associated with significantly shorter survival, independent of KRAS G12C mutational status, reflecting the poor prognosis and high unmet need in this patient population.