1st Line Treatment Research Articles

P2.09-32 Aumolertinib Plus Anlotinib as 1st-Line Treatment for EGFR Mutant Non-Small Cell Lung Cancer: A Phase II Trial (ALWAYS)

P2.09-32 Aumolertinib Plus Anlotinib as 1st-Line Treatment for EGFR Mutant Non-Small Cell Lung Cancer: A Phase II Trial (ALWAYS)

Differential gradients of immunotherapy vs targeted therapy efficacy according to the sun-exposure pattern of the site of occurrence of primary melanoma: a multicenter prospective cohort study (MelBase).

The tumor mutational burden (TMB) is high in melanomas owing to UV-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that survivals may depend on both the sun-exposure profile of the site of primary melanoma and the type of systemic treatment. Patients were screened from MelBase, a multicenter biobank dedicated to the prospective follow-up of stage III/IV melanoma. All patients with a known cutaneous primary melanoma who received a 1st-line systemic treatment by immunotherapy or targeted therapy were included (2013-2019). Outcomes were progression-free survival (PFS) and overall survival (OS). 973 patients received either anti PD-1(n=466), anti CTLA-4(n=143), a combination of both (n=118), or targeted therapies (n=246). Patients' characteristics at treatment initiation were: male (62%), median age of 62, AJCC stage IV (84%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 202 patients (G1: head neck), on intermittently sun-exposed skin in 699 patients (G2: trunk, arms, legs), and on sun-protected areas in 72 patients (G3: palms, soles). Median PFS was significantly higher in G1 under anti PD-1 treatment (8.7 months vs 3.3 and 3.4 months for G2 and G3, respectively) (p=0.011). PFS did not significantly differ in other groups. Similarly, median OS was significantly higher in G1 receiving 1st line anti PD-1 treatment (45.6 months vs 31.6 and 21.4 months for G2 and G3) (p=0.04), as opposed to 1st line targeted therapy (19.5 months vs 16.3 and 21.1 months for G1, G2 and G3 respectively). Our study confirms that immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas, but this finding needs to be confirmed by further research.

Sustained improved survival of patients with metastatic melanoma after the introduction of anti-PD-1-based therapies

BackgroundThe introduction of modern therapies improved the median survival of patients with metastatic melanoma (MM). Here, we determined the real-world impact of modern treatments on the long-term survival of MM. MethodsIn a population-based study, we extracted all cases of MM diagnosed in four non-consecutive years marked by major changes in available 1st line treatments (2012, 2014, 2016, and 2018) from the Danish MM Database. Patients were grouped into “trial-like” and “trial-excluded” based on common trial eligibility criteria. ResultsWe observed a sustained improved survival of “trial-like” patients diagnosed in 2016 or in 2018, compared to 2012 or 2014, but no major differences in 2018 versus 2016. In contrast, while survival of “trial-excluded” patients in 2016 was better compared to 2014 and 2012, survival in 2018 was improved over all previous years. We then developed a prognostic model based on multivariable stratified Cox regression, to predict the survival of newly diagnosed MM patients. Internal validation showed excellent discrimination and calibration, with a time-area-under-the-curve above 0.79 at multiple time horizons, for up to four years after diagnosis. ConclusionsThe introduction of modern treatments such as anti-PD-1 has led to a sustained, improved survival of real-world patients with MM, regardless of their eligibility for clinical trials. We provide an updateable prognostic model that can be used to improve patient information. Overall, these data highlight a positive population-based impact of modern treatments and can help health technology assessment agencies worldwide to evaluate the appropriateness of drug pricing based on known cost-benefit data.

Clinical outcomes of ALK+ non-small cell lung cancer in Denmark

Background Real-world clinical outcomes of anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) patients vary. This study aimed to investigate the treatment and clinical outcomes of all ALK+ NSCLC patients in Denmark in the period 2011–2018, regardless of disease stage. Materials and Methods A national pathology database with complete coverage was used to identify ALK+ NSCLC patients diagnosed between 2011 and 2018. Clinical data were obtained through retrospective chart reviews. Overall survival (OS) and duration of treatment (DOT) were analyzed using Kaplan-Meier methodologies. Results A total of 209 ALK+ NSCLC patients were included. The cohort had a slight overrepresentation of female patients (56.5%) with a mean age of 61.6 years. Most patients were adenocarcinoma cases (97%) and presented with an ECOG performance status of 0–1 (79%). Stage IIIb–IVb patients comprised 70% of the cohort. The use of ALK-tyrosine kinase inhibitors (TKIs) as first-line treatment increased over time, with the 1st generation ALK-TKI crizotinib being the predominant treatment in the 1st line. In 1st line treatment, 2nd generation ALK-TKIs had a median DOT more than twice the median DOT of crizotinib (25.1 and 9.1 months, respectively). The median OS for the entire cohort was 44.0 months. Patients with stage I–IIIA disease had a median OS that had not been reached, while those with stage IIIb–IVb disease had a median OS of 31.8 months. Patients with stage IIIb–IVb disease receiving an ALK-TKI as 1st line treatment had a median OS of 42.5 months with immature follow-up. Brain metastases at diagnosis or choice of 1st line treatment did not statistically significantly impact OS. Conclusion This study gives insights into the treatment and outcome of ALK+ NSCLC patients in Denmark and provides a real-world confirmation of the superior disease control provided by 2nd generation ALK-TKIs as compared to the 1st generation ALK-TKI crizotinib.

The Role of Radiation Therapy in the Management of Gray Zone Lymphoma.

Gray zone lymphoma (GZL) is a relatively rare disease predominantly affecting young adults with purportedly poor outcomes with current treatment approaches. The role of radiation therapy (RT) in the management of GZL is not well established. This is the largest study to report on the outcomes of GZL patients treated with and without RT. A retrospective review of 30 patients with GZL treated across 3 institutions from 2009 to 2021 was performed. Event-free survival (EFS) was defined from initiation of frontline chemotherapy (CHT) to disease progression/relapse, initiation of salvage therapy, or death. Local control (LC) was defined from RT start date to in-field recurrence. The median age was 32 (range: 18-86) years, and 16 (53%) patients had early stage (I-II) disease. Bulky mediastinal disease was present in 63% of patients, and the median tumor diameter was 10 (range: 1.5-18) cm. Patients received ABVD (20%), RCHOP (33%), or REPOCH (47%) as frontline CHT. Among 25 patients with interim PET/CT scan, there were 6 rapid early responders and 14 slow early responders (SER), with 2-year EFS of 33% and 24%, respectively (p = 0.13). After the completion of CHT, 15 (50%) patients achieved complete response (CR) and 10 (33%) achieved partial response (PR), with 2-year EFS of 46% and 10%, respectively (p = 0.004). RT was given to 9 patients in CR (n = 3) or in PR (n = 6). The median RT dose was 36 (30.6-48.6) Gy, at 1.8-2 Gy/fraction. Those receiving RT had bulkier disease at diagnosis (p = 0.049) and lower rates of CR following CHT (p = 0.03). After RT, 3/6 (50%) PR patients converted to CR. At a median follow-up of 4 years, the 2-year EFS was 26% for all patients, 33% for RT and 23% for noRT (p = 0.44). Among patients who did not receive upfront RT and experienced progression (n = 17), 16 (94%) relapsed in pre-existing sites. The 5-year OS was 80% for all patients, 88% for RT and 78% for no RT (p = 0.63). Patients who achieved PR to CHT and received RT had better 2-year EFS (17% vs 0%, p = 0.007) compared to patients who did not receive RT. Similarly, patients with SER who received RT had superior 2-year EFS (33% vs 13%, p = 0.038). Patients with bulky mediastinal disease had a 2-year EFS of 43% with RT and 11% without RT (p = 0.08). After 1st line treatment, 22 (73%) patients relapsed and 18 were successfully salvaged with a sustained CR. The most common salvage regimen involved high dose CHT followed by hematopoietic cell transplantation (HCT) (n = 15). RT was given for 7 patients in the relapsed/refractory setting (consolidative peri-HCT n = 4; definitive salvage n = 3) and 5 (71%) achieved a sustained CR. Among the 16 patients who received RT in the upfront (n = 9) or salvage (n = 7) setting, 3 patients experienced in-field recurrence translating to 2-year LC of 79%. GZL patients have high risk of relapse and maximal upfront combined modality therapy should be considered. RT provides good local control and improves EFS particularly for SER, PR, and bulky mediastinal disease.

314. CLINICAL OUTCOME OF ICI COMBINATION THERAPY AS 1ST LINE TREATMENT FOR ESOPHAGEAL CANCER

Abstract Background The 1st line regimens including Immunocheckpoint Inhibitor (ICI) have lately been approved for unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC). However, evidence of these regimens in clinical practice remains limited. Methods A total of 67 unresectable advanced or recurrent ESCC patients who received FP (5-FU + CDDP) + Pembrolizumab/Nivolumab (FP + ICI group; n = 43) or Ipilimumab+Nivolumab (ICI + ICI group; n = 24) as the 1st line treatment from December 2017 to March 2023 at our hospital were evaluated. Results Patient characteristics(FP + ICI: ICI + ICI) were as follows; age = 69:74 year-old, male/female = 36/7:22/2, recurrent/unresectable = 17(40%)/26(60%):13(54%)/11(46%), number of administered courses = 4 [1–35]: 2 [1–17], follow up period = 9: 6 months. Best response rate was CR/PR/SD/PD = 6/22/9/6:4/9/6/5 cases, while response/disease control rates were 65:54% and 86:79%, respectively. Regarding survival analysis, median OS = 23 months:did not reach, and 1-year OS = 83.7:87.5%, median PFS = 8:5 months, 1-year PFS = 48.8:49.3%, and DOR (duration of response) = 4[2–38]:5[5–9] months. The most common treatment-related adverse events (CTCAE Grade 3 or higher) were neutropenia in 18 cases, followed by anorexia in 7 cases (FP + ICI group), and adrenal hypofunction in 2 cases and pruritus in 2 cases (ICI + ICI group). Conclusion Both 1st line regimens for unresectable advanced or recurrent esophageal squamous cell carcinoma seemed to be feasible and promising in clinical use.

Clinical observations of patients with metastatic castration-resistant prostate cancer living in the Tambov region

Treatment of patients with metastatic castration-resistant prostate cancer in clinical practice is a vital necessity and a challenging task since the causes of castration resistance are not fully understood. Adherence to treatment regimens in accordance with the National Clinical Guidelines allows to achieve an increase in both overall survival and progression-free survival, as well as to reduce the mortality rate in this category of patients. Administration of 1st-line treatment regimens stabilizes the disease in the majority of pancreatic cancer patients; in some cases, the disease becomes aggressive, distant metastases appear, most oſten in bones, lymph nodes, and internal organs, as demonstrated by three clinical observations presented in this article. The administration of enzalutamide (in 2 cases) and abiraterone acetate (in 1 case) at the stage of resistance to castration therapy allowed to obtain a complete “response” from visceral lesions, stabilise bone metastatic foci and increase the life expectancy of patients.

Abstract B022: Clinical outcomes in NF2-mutated RCC treated with contemporary immunotherapy regimens

Abstract Background: Neurofibromin-2 (NF2) encodes the cell scaffolding protein merlin, which is involved in the Hippo tumor suppressor pathway. Somatic loss of function NF2 alterations in renal cell carcinoma (RCC) are associated with poor prognosis and can also molecularly define a subset of unclassified renal cell carcinomas without a standard of care treatment. While immuno-oncology (IO) combination regimens such as ipilimumab/nivolumab (IO/IO) or PD-1 inhibitor with a VEGFR-targeted therapy (IO/VEGFR) are the standard of care for clear cell RCC, efficacy of IO-based regimens for NF2 mutated RCC remains unknown. We report the first comparison of clinical responses to IO/IO, IO/VEGFR, or other systemic therapies for NF2-mutated RCC. Methods: NF2-mutated RCC patients receiving systemic therapy at Memorial Sloan Kettering Cancer Center were retrospectively identified by screening of our targeted exome sequencing (MSK-IMPACT) database. Groups are defined by 1st line systemic therapy regimens: IO/IO, IO/VEGFR, and other (VEGFR-targeted monotherapy, IO monotherapy, everolimus/bevacizumab, and chemotherapy). PFS-2 is defined as time from start of 1st line to progression on next therapy, or death. ORR, PFS, and PFS-2 were measured by an independent RECIST radiologist (CD). PFS, PFS-2, and OS are estimated using the Kaplan-Meier method. Results: Histologic subtypes in the overall cohort were unclassified (N=25), clear cell (N=7), and papillary (N=3). ORR of IO containing regimens in any line of treatment (N=29) was 57% (95% CI 37, 75). In the 1st line setting, 8 patients received IO/IO, 12 received IO/VEGFR, and 15 received other regimens with an ORR of 38% (95% CI 9, 76), 75% (95% CI 43, 95), and 23% (95% CI 5, 54), respectively. Thirty-three patients were included for PFS and PFS-2 analysis and 34 for OS with a median duration of follow-up of 40 months. Median PFS is 11 months (95% CI 4, 19; 26 events), median PFS-2 is 14 months (95% CI 9, 25; 25 events) and median OS is 27 months (95% CI 13, 65; 21 events). PFS, PFS2, and OS did not differ by 1st line treatment group. Among patients who received any IO exposure in the 1st line versus patients who received non-IO-based therapy, there was no significant difference in median PFS (12 (95% CI 5, 22) vs 5 (95% CI 2,21) months, p=0.39), PFS2 (17 (95% CI 9, 28) vs 13 (95% CI 3, 25) months, p=0.49), or OS (27 (95% CI 13, 73) vs 26 (95% CI 4, NE), p=0.90). OS did not differ by tumor histologic subtype; however, sample size limits power to detect differences. Conclusion: In comparison to clear cell RCC, prognosis for patients with NF2-mutated RCC remains poor. IO-based therapy has activity in treating NF2-mutated RCC; patients may derive benefit even if first exposure to IO occurs ≥2nd treatment line. There was no significant difference in PFS, PFS2, or OS based on 1st line regimen for patients with NF2-mutated RCC. Further investigation of inhibitors specifically targeting downstream effectors of the Hippo pathway are warranted. Citation Format: Kelly N. Fitzgerald, Cihan Duzgol, Andrea Knezevic, Rachel Jacobi, Ritesh R. Kotecha, David H. Aggen, Maria I. Carlo, Neil J. Shah, Martin H. Voss, Darren R. Feldman, Robert J. Motzer, Chung-Han Lee. Clinical outcomes in NF2-mutated RCC treated with contemporary immunotherapy regimens [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B022.

Anlotinib Combined with Anti‐PD1 Potentiates Anti‐Tumor Immunity via Immunogenic Cell Death and Macrophage Reprogramming

AbstractThe combination therapy of targeted drugs and immune checkpoint inhibitors has shown prominent success. In addition to blocking mutated oncogene downstream signaling, the immunological mechanism(s) underlying the anti‐tumor effect of targeted‐immuno‐therapy is not clear. In this study, anlotinib, a novel pan‐targeted tyrosine kinase receptor inhibitor (pTKI), is combined with anti‐PD1 (αPD1) as a therapeutic regimen applying to an immunocompetent mouse tumor model. Anlotinib induces immunogenic cell death (ICD), elicits anti‐tumor inflammation and infiltration, and activation of DCs and CD8+ T cells, which are enhanced by αPD1. Furthermore, anlotinib reduces KC/MCP‐1 secretion by attenuating educational effect that cancer cells imposed on tumor‐associated macrophages (TAMs) and prevents their M2 polarization by inhibiting AKT/mTORC1 and Pparδ pathways. Importantly, anlotinib plus αPD1 prolongs median progression‐free survival time compared with standard chemotherapy plus pembrolizumab as the 1st line treatment in non‐small cell lung cancer (NSCLC) patients. Thus, anlotinib treatment elicits both innate and adaptive anti‐tumor immune responses while αPD1 enhances its potency. This study provides strong evidence that combination of targeted therapy and immunotherapy is a promising regimen for treating NSCLC.

The abscopal effect of immune-radiation therapy in recurrent and metastatic cervical cancer: a narrative review.

Despite human papillomavirus vaccination and screening, in about 5% of cases, cervical cancer (CC) is discovered at an initial metastatic stage. Moreover, nearly one-third of patients with locally advanced CC (LACC) will have a recurrence of their disease during follow-up. At the stage of recurrent or metastatic CC, there are very few treatment options. They are considered incurable with a very poor prognosis. For many years, the standard of care was the combination of platinum-based drug and paclitaxel with the possible addition of bevacizumab. The most recent years have seen the development of the use of immune checkpoint inhibitors (ICIs) (pembrolizumab, cemiplimab and others) in patients with CC. They have shown long term responses with improved overall survival of patients in 1st line (in addition to chemotherapy) or 2nd line (as monotherapy) treatment. Another emerging drug is tisotumab vedotin, an antibody-drug conjugate targeting tissue factor. Radiation therapy (RT) often has a limited palliative indication in metastatic cancers. However, it has been observed that RT can induce tumor shrinkage both in distant metastatic tumors beyond the radiation field and in primary irradiated tumors. This is a rarely observed phenomenon, called abscopal effect, which is thought to be related to the immune system and allows a tumor response throughout the body. It would be the activation of the immune system induced by the irradiation of cancer cells that would lead to a specific type of apoptosis, the immunogenic cell death. Today, there is a growing consensus that combining RT with ICIs may boost abscopal response or cure rates for various cancers. Here we will review the potential abscopal effect of immune-radiation therapy in metastatic cervical cancer.

Palbociclib (P) plus tamoxifen (TAM) ± goserelin in women with hormone receptor-positive (HR+)/HER2-negative (HER2−) advanced breast cancer (ABC): Primary results of NCCH1607/PATHWAY, an Asian international double-blind randomized phase 3 trial.

LBA1068 Background: In Asian countries, BC incidence rates are rising, with a higher proportion of pre/perimenopausal (pre/peri-M) patients (pts). Data on treatment options for pre/peri-M pts are limited. Adding P to endocrine therapy (ET), such as aromatase inhibitor or fulvestrant, has improved progression-free survival (PFS) in phase 3 studies. However, the efficacy and safety of P in combination with TAM are still unclear in pts with HR+/HER2− ABC regardless of M status. This combination was investigated in PATHWAY (NCT03423199): a double-blind randomized phase 3 trial conducted in Japan, Korea, Taiwan and Singapore. The study was conducted as a Clinical Research Collaboration with the National Cancer Center Hospital being the regulatory sponsor and Pfizer providing drug and financial support. Methods: Women with HR+/HER2− ABC were randomly assigned 1:1 to receive either P (125 mg once daily, days 1-21 of a 28-day cycle) or placebo in combination with TAM (20 mg once daily, continuously) as 1st or 2nd line treatment for ABC. Pre/peri-M women received concurrent ovarian function suppression with goserelin. Pts were stratified by 1st vs 2nd line ET and M status. The primary endpoint was PFS as assessed by investigators. Secondary endpoints include overall survival (OS), objective response, safety, and patient-reported outcomes. Results: A total of 184 pts were assigned to P + TAM (91 pts) and placebo + TAM (93 pts). At data cutoff date (Sep 15, 2022), 138 PFS events had occurred. Median follow-up was 40.9 months for censored pts. Median PFS was 24.4 months (95% CI: 13.1, 32.4) with P + TAM and 11.1 months (95% CI: 7.4, 14.6) with placebo + TAM (hazard ratio [HR]: 0.602 [95% CI: 0.428, 0.848], 1-sided p-value from stratified log rank test: 0.002). The HRs for PFS of the subgroups by stratification factors were as follows: for pts with 1st line ET (HR: 0.521 [95% CI: 0.332, 0.817]) or with 2nd line ET (HR: 0.707 [95% CI: 0.421, 1.189]), and for pre/peri-M pts (HR: 0.378 [95% CI: 0.192, 0.742]) or post-M pts (HR: 0.677 [95% CI: 0.456, 1.005]). While OS data were still immature, the primary analysis showed a 27% reduction in overall risk of death (median OS: not reached in both arms, HR: 0.73 [95% CI: 0.442, 1.207]). 93.4% of pts with P + TAM vs. 20.4% of pts with placebo + TAM had grade (G) ≥3 treatment-emergent adverse events (TEAEs). The most frequently observed G ≥3 TEAE was neutropenia (89.0% in P + TAM arm and 1.1% in placebo + TAM arm). There were no G5 TEAEs in either arm. Conclusions: The study achieved its primary endpoint, demonstrating a significant and clinically meaningful improvement in PFS for P + TAM compared with placebo + TAM for pts with HR+/HER2− ABC. Early OS data with P+TAM is encouraging. TEAEs were generally consistent with the known safety profile of P and ET. Clinical trial information: NCT03423199 .

BRENTUXIMAB VEDOTIN IN COMBINATION WITH CHEMOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED CD30‐POSITIVE PERIPHERAL T‐CELL LYMPHOMAS: REAL‐WORLD DATA

Background: Based on the results of ECHELON-2 trial, Brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin and prednisone (CHP) has been approved by EMA for the treatment of newly diagnosed systemic anaplastic large cell lymphoma (ALCL) and become the standard of care for this patient population. In Czech Republic, BV plus CHP is approved as 1st line treatment for CD30-positive peripheral T-cell lymphomas (PTCL), including non-ALCL PTCL since 8/2020. The aim of this analysis is to provide real world data with this combination. Methods: Using the prospective observational NiHiL project (NCT03199066), we identified patients (pts) ≥ 18 years of age with histologically confirmed CD30+ PTCL (diagnosed between August 2020 to October 2022), who received BV in combination with chemotherapy as 1st line treatment. Results: A total of 63 pts were recruited; 31 (49%) had ALCL (12 ALK+, 19 ALK-) and 32 (51%) had non-ALCL PTCL (16 with PTCL NOS, 14 with AITL, and 2 with EATL). Median age was 60 years (range; 19-82). Most pts showed adverse clinical features at lymphoma diagnosis, including Ann Arbor stage III-IV (n = 46; 73%) or elevated LDH (n = 34; 54%). Of note, 18 (29%) pts had ECOG performance status ≥ 2 (incl. 6 pts ECOG 3 and 1 pt ECOG 4). By IPI, 16 (25%), 18 (29%), 12 (19%), and 17 (27%) pts belonged to low, low-intermediate, high-intermediate, and high-risk groups, respectively. The most common chemotherapy backbone was CHP administered in 45 (71%) pts, followed by CHP + etoposide administered in 13 (21%) pts. Five (8%) pts received attenuated regimen. Nine (14%) pts underwent pre-planned consolidative autologous stem cell transplant. Sixty (95%) pts received G-CSF prophylaxis. The most common grade ≥3 adverse events were neutropenia (49%), anaemia (30%), febrile neutropenia (19%), thrombocytopenia (19%), and infections (18%). Neuropathy (all grades) occurred in 21 pts (33%); grade 3 neuropathy in 3 pts (5%). Grade 5 AE occurred in 2 (3%) pts, sepsis in both cases. Out of 63 there were 56 (89%) pts evaluable for response (PET/CT) at the time of database lock. The overall objective response rate (ORR) was 80% with 63% complete response (CR). The ORR/CR rates in ALCL (n = 26) versus non-ALCL (n = 30) pts were 89%/73% versus 73%/53%, respectively. The median follow-up of surviving pts is 16.6 months (range; 4.3- 31.3). The overall 18-months PFS and OS probability were 61.8% and 73.7%, respectively (Figure 1). By lymphoma subtype, the 18-months PFS and OS probability were 77.6% and 83.5% in ALCL and 50.3% and 65.9% in non-ALCL, respectively (Figure 1). Evaluation of the relationship between % of CD30+ neoplastic cells and clinical outcome is ongoing. The research was funded by: The study is supported by the Cooperation Program, research area “Oncology and Haematology” and NU20-03-00253 and NU22-03-00370. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Combination Therapies Conflicts of interests pertinent to the abstract A. Sykorova Other remuneration: ROCHE, GILEAD, TAKEDA H. Mocikova Consultant or advisory role Takeda, Roche, Astra Zeneca, Janssen, Abbvie D. Belada Other remuneration: Roche, Gilead Sciences M. Trneny Consultant or advisory role Takeda Honoraria: Takeda

Osemitamab in combination with capecitabine and oxaliplatin (CAPOX) as a first line treatment of advanced G/GEJ cancer: Updated data of cohort C from a phase I/IIa, multi-center study (TranStar102/TST001-1002).

4046 Background: Adding a claudin18.2 antibody to a chemotherapy is a clinically validated approach for patients with high CLDN18.2 expressing tumors. TST001 is a best in class differentiated antibody whose improved CLDN18.2 affinity and enhanced antibody-dependent cellular cytotoxicity, leads to anti-tumor activity in low to medium CLDN18.2 expressors gastric cancer cells. Pre-clinical studies also showed that TST001 has stronger tumor regression effects than the IMAB362-analog at the same dose. Methods: The efficacy and safety of osemitamab with CAPOX as 1st line treatment with G/GEJ cancer was explored in a dose escalation and expansion phase 1/2 study in China (Cohort C, NCT04495296). Positive claudin18.2 expression (membranous staining ≥1+ intensity in≥10% of tumor cells) as assessed centrally using the LDT assay was required in the expansion phase only. Results: As of Dec 31, 2022, 64 patients were dosed with osemitamab in combination with CAPOX, 15 patients received osemitamab at doses ranging from 1 to 8 mg/kg Q3W in the dose escalation and 49 patients at 6 mg/kg in the dose expansion. The median follow up was 151 days. Patient characteristics were typical of 1st line G/GEJ cancer, with relatively higher percentage of peritoneal disease (48.4%). Nausea (65.4%), vomiting (46.2%) and hypoalbuminemia (65.4%) were the most common adverse events related to TST001 at dose of 6mg/kg in 52 patients (3 patients in dose escalation and 49 patients in dose expansion), most of them were grade 1 or 2 (only one patient experienced grade 3 nausea and vomiting, and one experienced grade 3 hypoalbuminemia). In the expansion cohort, 40 of the 45 patients with measurable lesions had at least one post-treatment tumor assessment. 27 achieved partial response (PR) of which 21 were confirmed. There was no obvious trend in improved efficacy with higher level of CLDN18.2 expression based on overall response rate (ORR). Progression free survival (PFS) and duration of response (DOR) were still immature. Conclusions: TST001 in combination with CAPOX as first-line treatment for the patients with G/GEJ cancer is safe and encouraging anti-tumor activities have been observed regardless of the CLDN18.2 expression levels above 1+ intensity in >=10% tumor cells per central LDT assay. Updated ORR, mPFS and mDOR will be presented at the time of the congress. Clinical trial information: NCT04495296 .

Clinical pathways utilization and characteristics of non-adherence at Sidney Kimmel Cancer Center.

e13505 Background: Clinical pathways are utilized by many oncology practices with goal to deliver high quality, consistent care across health systems. In pathway tools, evidence-based treatments are recommended using the following hierarchy 1) efficacy, 2) adverse events, 3) cost. Previous research has shown that increasing adherence to pathways delivers evidenced based care at reduced cost. However, this comes at the expense of increased “clicks” and inefficiencies in workflow. We hypothesized that at a large academic center with subspecialty oncologists that lack of adherence to pathway utilization did not result in decrease adherence to evidence-based medicine. Methods: At our institution’s main academic hub, all breast, genitourinary (GU), and gastrointestinal (GI) chemotherapy encounters ordered from July 2020 through June 2021 were identified. A subset of these encounters, those ordered without use of Elsevier’s ClinPath, “pathway-independent,” were identified. Chart review was performed to identify clinical characteristics, ordering physicians, and line of treatment. Treatment choice was compared to ClinPath pathways to determine if treatment was “on-pathway” or “off-pathway.” Treatment was also compared to NCCN guidelines, to determine if aligns with standard of care. Results: 1,111 breast, GU, and GI total chemotherapy ordering encounters were identified. Only 103 (9.3%) were pathway-independent orders. 41 were hepatobiliary orders, which do not have a ClinPath pathway at our institution, leaving 62 pathway-independent orders despite a pathway available. 87% of the pathway-independent encounters were on-pathway, just not utilizing the ClinPath tool, and 91.9% align with standard of care. Only 8 of the 62 (12.9%) pathway-independent encounters were off-pathway. Of these 8 encounters, 4 (50%) were GI and 4 (50%) GU chemotherapy. 5 were 1st line treatment, 2 were 2nd line, and 1 was 3rd line. 3 of 8 off-pathway encounters were in accordance with NCCN guidelines. There were justifications for 2 of the 8 off-pathway treatments: prohibitive hepatic dysfunction and patient preference to continue treatment ordered by outside institution. The remainder were by physician preference. Conclusions: At our academic institution, there was high utilization of ClinPath when ordering GI, GU, and breast chemotherapy, with 94.4% total encounters utilizing ClinPath. The vast majority of chemotherapy ordered at our center, even when ordered without ClinPath, aligns with standard of care. While the number of pathway-independent decisions was very small in this sample, it suggests that the clinical pathway tool may not influence clinical decision making as much as suggested in other studies, but likely adds administrative burden to physicians who practice in highly subspecialized areas.

Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2+) pathogenic variants: SWOG S2001.

TPS4198 Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Several clinical studies in solid tumors have shown preliminary efficacy with the combination of PARP plus immune checkpoint inhibitors. Based upon these data, SWOG S2001 aims to further improve the PFS of gBRCA1/2+ mPDA pts. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in December 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 pathogenic variants identified with standard of care germline genetic testing and progression-free after receiving at least 16 weeks of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to compare PFS in mPDA pts treated with olaparib + pembrolizumab versus olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha=0.10, this design requires enrolling 88 pts for a total of 78 eligible and evaluable pts. As of February 2023, 26 participants have been accrued. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Clinical trial information: NCT04548752 .

Association between intra-tumoral microbiome and clinical benefit (CB) from immunotherapy (IO) in patients with metastatic renal cell carcinoma (mRCC).

4561 Background: Specific bacteria and microbial diversity in the gut may drive response to IO in patients (pts) with mRCC (Routy et al Science 2018; Salgia et al Eur Urol 2020). Despite the evidence of bacterial proliferation in RCC tumors (Heidler et al Urol Int 2020), the impact of the intra-tumoral microbiome in RCC has been poorly delineated. Here, we explored its association to CB in mRCC pts receiving IO-based regimens. Methods: We identified pts with mRCC and available RNA sequencing (RNA-seq) data from tumor tissue collected prior to start of IO.Intra-tumoral microbiome analysis was performed on formalin-fixed paraffin-embedded samples. Following quality and adapter trimming, RNA-seq reads were mapped to a human genome to filter host reads using the STAR alignment tool. Taxonomic classification was performed using Kraken2 and Bracken. Following removal of common contaminants, the relative abundances among all non-human species were calculated. Microbial diversity was assessed using the Shannon index and statistical analysis performed using a t-test. Relative microbial abundance was compared between tumors from pts with or without CB from 1st line IO treatment using the Kruskal-Wallis test. P-values less than 0.05 were considered significant. Results: A total of 96 pts (71:25, M:F) with mRCC were included in this analysis. Of these, 85 (89%) had clear cell histology and 68 (71%) were IMDC intermediate/poor risk. The median age at the time of tissue sampling was 62.7 yrs old and most of the samples analyzed (57%) were collected from the primary site. IO, alone or in combination, was received as 1st line treatment in 57 pts (59%), with the most common regimen being nivolumab/ipilimumab (47%). CB from 1st line IO was observed in 39 (68%) pts. Tumors from pts achieving CB from 1st line IO had elevated microbial diversity compared to tumors from pts without CB (p=0.01). Tumor samples from these pts also had a significantly higher relative abundance of several bacterial genera compared to tumors from pts without CB. These included Pasteurella, Escherichia, and Cloacibacterium (p<0.05). No significant differences in bacterial diversity were observed between CB and no-CB pts receiving IO as 2nd line or beyond. Conclusions: This is the largest study exploring the association between the intra-tumoral microbiome of mRCC and CB from IO. In line with gut microbiome studies, an increased intra-tumoral Shannon diversity index was also associated with CB to IO in our 1st line cohort, further suggesting that bacterial diversity could be a driver of response. Additionally, several genera associated with CB are particularly relevant. For instance, members of the Pasteurella genus have been implicated in the activation of c-myc, a proto-oncogene that has been shown to induce PD-L1 expression.

Outcomes for immuno-chemotherapy based treatment in patients with poorly differentiated extrapulmonary neuroendocrine carcinoma.

e14619 Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) represents a rare collection of neuroendocrine cancers characterized with a poor prognosis and modest treatment benefit similar to small cell lung carcinoma (SCLC). Platinum-based chemotherapy (cisplatin or carboplatin) and etoposide is the preferred 1st line therapy for patients (pts) with metastatic EP-NEC who are not eligible for curative surgery (Frizziero et al. 2019). Studies in pts with advanced SCLC have shown improved progression free survival (PFS) and overall survival (OS) with the addition of atezolizumab, an anti-PD-L1 monoclonal antibody, to induction chemotherapy (4 cycles) versus chemotherapy alone (Horn et al. 2018). Prospective trials investigating immune checkpoint inhibitors such as atezolizumab plus chemotherapy have yet to be published in EP-NEC. Methods: We retrospectively reviewed all registered pts at the Gastrointestinal Medical Oncology Clinic at Banner-University of Arizona Cancer Center who received at least 1 dose of atezolizumab from 1/2017 through 3/2022 (UAIRB00001593). Criteria for pt selection for analysis was based on the following: pts diagnosed with grade III, Ki 67>20%, poorly differentiated, metastatic EP-NEC and treated with ≥ 1 dose of atezolizumab plus chemotherapy as 1st line treatment. Results: Ten pts received atezolizumab based therapy during this timeframe. 6 pts met criteria for analysis and 4 pts were excluded for alternative diagnoses. 4 pts were female, 2 pts were male, and the average age at diagnosis was 63.8 years. The median number of chemotherapy cycles was 7.0 [4-17]. The median number of atezolizumab doses was 7.5 [6-28]. The median PFS was 7 months (95% CI 5-*). The median overall survival (mOS) was 13 months (95% CI 8-*). The mOS since starting atezolizumab was 12 months (95% CI 8-*). [*Upper bound of 95% CI cannot be determined.] Five pts (83%) demonstrated a partial response per RECISTv1.1. All pt tumors were MMR-proficient/MSI-stable and PD-L1 expression was negative in 3 pts (PD-L1 status unavailable for 3 pts). No hospitalizations related to immunotherapy or chemotherapy were observed. The most common adverse events included nausea, diarrhea and fatigue. One immune-mediated adverse event of thyroid dysfunction was observed and successfully medically managed. Conclusions: Our experience with atezolizumab plus chemotherapy for 1st line EP-NEC pts demonstrated efficacy via high response rate and survival rates above historical experience. Continuing chemotherapy beyond the induction phase until maximum clinical response demonstrated tolerability with manageable side effects. Although the scope is limited due to sample size, this data supports further investigation of this combination. There is an ongoing large, randomized, prospective trial investigating this regimen in frontline, metastatic EP-NEC pts ( NCT05058651 ).

CtDNA-based genomic landscape analysis to evaluate molecular brake and gatekeeper mutations in FGFR2 alterations.

3049 Background: FGFR2 and FGFR3 (FGFR2/3) gene alterations are oncogenic drivers found across various cancer types and have been successful targets of drug development. Several FGFR inhibitors (FGFRi) are approved for clinical use, and most are ATP-competitive, reversible inhibitors (1st-gen). Efficacy of the 1st-gen FGFRi can be limited by acquired resistance mutations in the FGFR kinase domain, typically molecular brake or gatekeeper mutations, which disrupt compounds binding through conformational changes or through direct steric hindrance, respectively. Irreversible (covalent) FGFRi, such as futibatinib, are in development to overcome kinase domain resistance mutations. However, preclinical evidence indicates that some of the known resistance mutations (eg. V564L) remain insensitive to futibatinib. Methods: To assess the landscape of FGFR-driven cancers and to better understand the prevalence of molecular brake and gatekeeper mutations, we analyzed the distribution of FGFR2/3 alterations in a large clinical genomic research database. This ctDNA-based genomic database was selected for the analysis given that liquid biopsy is a fit-for-purpose method to detect acquired resistance mutations. Results: We identified over 2,100 patients with FGFR2/3 alterations. Non-small cell lung cancer (NSCLC), breast, bladder, and cholangiocarcinoma (CCA) had the highest number of patients with FGFR2/3 alterations. 36% of all FGFR2 alterations across all cancer indications consisted of molecular brake or gatekeeper mutations. This finding was most enriched in CCA and breast cancer where 51% and 57%, respectively, of FGFR2 alterations were molecular brake or gatekeeper mutations. In breast cancer patients, molecular brake mutations were common and represent activating mutations in FGFRi-naïve patients. A small number of FGFR3 gene fusions were detected in CCA patients who had significantly shorter time on 1st-line treatment and trended toward shorter overall survival when compared to patients with FGFR2 fusions. We also identified CCA patients with FGFR2 fusions and one or more concurrent FGFR2 SNVs; primarily those in the kinase domain and associated with FGFRi resistance. Most of these putative cases of acquired resistance were polyclonal, with 2 or more (up to 8) FGFR2 SNVs coexisting with the fusion. Bladder cancer and NSCLC had the highest numbers of FGFR3 alterations. FGFR2/3 alterations were typically found without other driver mutations in CCA, bladder, and NSCLC patients. However, in breast there was a large overlap between FGFR2/3 alterations and other drivers. Conclusions: Herein, we identify a cohort of patients with FGFR2/3 molecular brake and gatekeeper mutations that may benefit from next-generation FGFR2/3-targeted therapies designed to inhibit a broad spectrum of both primary and secondary resistance mutations.

Long-term effectiveness and treatment sequences in patients with extensive stage small cell lung cancer receiving atezolizumab plus chemotherapy: Results of the IFCT-1905 CLINATEZO real-world study.

8583 Background: Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer with a tendency towards early recurrence and limited survival. Standard-of-care in 1st-line treatment is platinum-etoposide chemotherapy plus anti-PD-L1 immune checkpoint inhibitor atezolizumab or durvalumab, based on landmark, randomized, phase 3 clinical trials. Methods: IFCT 1905-CLINATEZO is a nationwide, non-interventional, retrospective chart review study of patients (pts) with extensive-stage SCLC who received atezolizumab + chemotherapy as part of the French early access program between May 2019 and January 2020 (1402 pts). Inclusions were exhaustive per participating centers (65/307). Data collection run from February to November 2021. Key objectives were to assess effectiveness and safety of atezolizumab + chemotherapy and analyze subsequent treatment sequences. Results: The population analyzed included 518 out of the 1402 pts. There were 66% male and mean age was 65.7 years (range: 36.7-88.0); 89% had a performance status (PS) 0/1 and 27% brain metastases. Almost all the pts (96%) were smokers, with a median number of pack-years of 40. Fifty-five pts (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7 (range: [1-48] ) for a median duration of 4.9 months (95% CI 4.5-5.1). Twenty-seven pts (5%) were under ongoing treatment at date of last news. Atezolizumab was continued beyond disease progression in 122 pts (24%) for a median duration of 1.9 months (95% CI 1.4-2.3). Best objective response was complete and partial response in 19 (3.9%) and 378 pts (77.1%) respectively; stable disease was observed in 50 pts (10.2%). After a median follow-up of 30.8 months (95% CI: [29.9-31.5]), median overall survival (OS), 12- and 24-months OS rates were 11.3 months (95% CI: [10.1-12.4]), 46.7% (95% CI 42.3-50.9) and 21.2% (95% CI 17.7-24.8) respectively. Median real world-progression free survival (based on date of the first source evidence for progression referenced by the treating physician), 6- and 12-months rates were 5.2 months (95% CI 5.0-5.4), 37.5% (95% CI 33.3-41.7) and 15.2% (95% CI 12.2-18.6) respectively. For the pts with PS 0/1, median OS was 12.2 months (95% CI 11.0-13.5). For the 55 pts with previous treatment, median OS was 14.9 months (95% CI 10.1-21.5). A total of 326 (66.4%) pts received subsequent treatment. Conclusions: IFCT 1905-CLINATEZO study shows the reproducibility, in a real-life setting, of the key survival outcomes of IMpower-133, that may be attributed to the selection of pts fit for this regimen, the adoption of pragmatic approaches for the management of pts receiving atezolizumab, that includes concurrent radiotherapy and treatment beyond progression, and the high proportion of pts treated with 2nd-line therapies, mostly based on chemotherapy.

Nivolumab treatment of NSCLC patients in clinical practice in Greater Poland: Long term survival analysis.

e21178 Background: Immunotherapy has changes the landscape of advanced NSCLC therapy. Clinical trilas showed promising results but real world evidences are the definitive confirmation. This study evaluates distant outcomes and toxicity of treatment with nivolumab in patients with NSCLC in daily clinical practice. Methods: Study included 84 pts. with adv. NSCLC, receiving nivolumab (NIVO) in the early access programme (EAP) at the Greater Poland Centre of Pulmonology and Thoracic Surgery in Poznań in 2016-19: 57 men and 27 women; aged between 26 and 88 years (mean 63); majority with ECOG PS 1; 40 pts. with squamous and 44 with non-squamous NSCLC; 86.9% stage IV. Responses were assessed according to RECIST 1.1 criteria and toxicity according CTCAE v.4. OS and PFS were analyzed in relation to selected demographic and clinical parameters. Type of response as well as incidence, nature, time of occurrence and severity of adverse events (AEs) were assessed. Neutrophil-lymphocyte ratio (NLR) in relation to OS, PFS and immunotherapy-related AEs were also analyzed. Results: Partial remission (PR)/disease stabilization (SD) or disease progression (PD) were observed in 61% and in 39% of patients, respectively. The best responses were obtained in patients > 70 years, with stage IIIB, receiving nivolumab in 1st-line treatment. The 1, 2, 3, 4, 5 and 6-year OS rates were 42,9%, 23,8%, 20,2%, 17,86%, 11,9% and 10,7% respectively. After 4, 5 and 6 years 5,95%, 5,95% and 4,76% patients remains on treatment respectively. The median OS was 9.6 months. The 1, 2 and 3-year PFS rates were 19%, 15.5%, and 11.9%, respectively. The median PFS was 4,7 months. Age, sex, stage, and treatment line appeared to be factors significantly affecting OS and PFS. The objective response rate (ORR) and disease control rate (DCR) also correlated with OS and PFS. Treatment-related AEs occurred in 66,7% of patients, primarily grade 1-2; 44% of AEs occurred in the first 3 months of treatment. Discontinuation rate due to AEs was 20.2%, and treatment-related toxic effects caused fatalities in 11,9% of patients. The AEs risk was higher in patients receiving NIVO in ≥4 treatment line. High baseline NLR was associated with shorter OS and PFS. There was also a correlation between baseline and final NLR values, occurrence of grade 1-2 AEs, and grade 3-5 AEs. Conclusions: Majority of patients with advanced NSCLC treated with NIVO achieved PR or SD. The long-term outcomes are satisfactory with 3-year OS rate > 20% and 3-year PFS rate of 1.9%. Female sex, age > 60 years, lower stage, treatment with NIVO in 1-line and PR/SD achieving were predictors of improved long-term outcomes. NIVO has acceptable toxicity profile, mostly with mild-to-moderate AEs and low discontinuation rate. Most AEs occur in the first 3 months of therapy, mainly in patients treated in later lines. NLR could be potential predictor of both response and toxicity; however, studies with larger cohorts are necessary.