1st Line Setting Research Articles

Abstract OT2-01-08: SEQUence of Endocrine therapy in advanced Luminal Breast cancer (SEQUEL-Breast): A phase 2 study on fulvestrant beyond progression in combination with alpelisib for PIK3CA-mutated, HR+ HER2- advanced breast cancer

Abstract Goal To investigate the efficacy of alpelisib added to fulvestrant beyond progression in patients with HR+ HER2- advanced breast cancer (ABC). Background The SOLAR-1 study (Andre et al, 2019) has shown that the addition of alpelisib, an alpha-specific PI3K-inhibitor to fulvestrant led to a PFS-benefit of 5.3 months in patients with PIK3CA-mutated HR+ HER2- ABC. In this study, patients were fulvestrant-naive, and only 6% of this population was previously treated with a CDK4/6 inhibitor (CDK4/6i). Nowadays, most patients have been treated with a CDK4/6i, either combined with an aromatase-inhibitor (AI) in 1st line, or with fulvestrant in the 1st or 2nd line setting. Results of the ongoing Dutch SONIA-trial (NCT03425838) will show whether the addition of CDK4/6i to an AI in 1st line is superior to the addition of CDK4/6i to fulvestrant in 2nd line. Patients who have progressed on a CDK4/6i in either line and fulvestrant may be treated with fulvestrant and alpelisib. However, the efficacy of fulvestrant beyond progression combined with alpelisib is unknown. Aim of this study The aim is to determine if treatment with fulvestrant beyond progression and alpelisib results in a clinically meaningful median PFS of ≥6 months. Primary endpoint: Progression-free survival (PFS). Secondary endpoints: ‘On treatment’ PFS Overall survival Objective Response Rate Clinical Benefit Rate Duration of response Safety Risk factors for alpelisib-induced hyperglycemia Quality of life Pharmacokinetics Prognostic value of ctDNA Mechanisms of resistance Trial design The SEQUEL-Breast trial is a nationwide Dutch investigator-initiated phase 2 trial. 25 centers are expected to participate in the SEQUEL-Breast. Clinicaltrials.gov identifier: NCT05392608 Intervention: fulvestrant beyond progression combined with alpelisib. Population Patients must be adults with HR+ HER2- ABC with an activating PIK3CA-mutation. Prior treatment with an AI and fulvestrant is mandatory, as well as prior treatment with a CDK4/6i in either line. Patients must have progressed on fulvestrant (+/- CDK4/6i), and fulvestrant must be the most recent line of therapy. Patients with ECOG performance score 0,1 or 2 are eligible, as well as those with controlled (HbA1C < 8.4%) diabetes mellitus type 2. Patients with uncontrolled diabetes, visceral crisis, symptomatic CNS metastases or clinically relevant heart disease are ineligible. Patients with diseases or previous surgery that might affect the bioavailability of alpelisib, those in need to use CYP3A4 inhibitors or BRCP inhibitors, as well as patients with any other conditions that would put them at particular risk when partaking in the study, are also ineligible. Accrual Start: June 2022 Accrual, June 27: 3 patients Target: 105 patients (minimum) to 130 patients (maximum) Estimated accrual time: 2-3 years Statistical considerations For sample size calculation, H1 (median PFS≥6 months) is weighed against H0 (median PFS≤4 months) in a one sample log rank test. α=0.05 β=0.1. 71 events are needed. We estimated that inclusion of 79 patients is required to reach 71 events, given an accrual time of 36 months and a minimum follow-up time of 6 months. To ensure that also PFS ‘on treatment’ has the desired accuracy, we accounted for 25% non-persistance due to toxicity, hence 105 patients. On top of these 105 patients, another 25 patients may be included, if they harbor rare PIK3CA mutations. Further information Corresponding author: sequel@nki.nl BOOG Study Center acts as sponsor for this trial. This trial is funded by Novartis. Citation Format: Cornelia AM Almekinders, Inge RHM Konings, Vincent van der Noort, Susan M van den Berg, Monique EMM Bos, Vincent O Dezentjé. SEQUence of Endocrine therapy in advanced Luminal Breast cancer (SEQUEL-Breast): A phase 2 study on fulvestrant beyond progression in combination with alpelisib for PIK3CA-mutated, HR+ HER2- advanced breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-08.

Characterization and survival benefit of drugs approved for advanced renal cell carcinoma.

633 Background: The treatment landscape of advanced renal cell carcinoma (RCC) drastically changed with the approval of tyrosine kinase inhibitors (TKIs). Since then, immunotherapy (IO) and now TKI plus IO combination therapies is considered standard-of-care. Despite multiple drug approvals, it remains unclear how much improvement in survival these therapies have provided. Methods: We reviewed the US Food and Drug Administration (FDA) website to evaluate all approvals for RCC from 2005 to 2022. We collected progression-free survival (PFS) and overall survival (OS) from the approval notification or from the corresponding clinical trial cited for drug approval. Results: Between 2005 and 2022, there were 16 drug (single or combination) approvals for advanced RCC. Most therapy approvals (93.75%) were granted through accelerated approval. Eight approvals were TKIs, 6 approvals were TKI plus IO combination therapies, and 1 approval each were for immunotherapy and a VEGF inhibitor. Average PFS benefit for 1st line approvals was 5.63 months (range 1.9-14.7) and average PFS benefit for 2nd or later line approvals was 2.95 months (range 0.2-9.1). Average OS benefit in the 1st line setting was 3.6 months and average OS benefit in the 2nd or later line setting was 5.4 months. Conclusions: Despite 16 drug (single or combination) approvals for advanced RCC since 2005, the improvements in average PFS and OS were modest. As OS data matures from recent TKI plus IO combination therapies, OS benefit may improve. Nonetheless, continued drug development is urgently warranted in advanced RCC. [Table: see text]

Multi-centre review of systemic anti-cancer prescribing patterns and treatment drop off rates in the United Kingdom 2018-2021.

689 Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved over recent years with several systemic anti-cancer therapies (SACT) licensed across different lines of treatment. There is ongoing discussion amongst oncology professionals about how best to optimise treatments in terms of sequencing to maximise the potential number of lines or to give the best treatments first. A previous south-west UK audit was completed in 2021 reviewing the drop off rates across 5 UK sites identifying that 69% of patients were able to receive second line therapy and 34% were able to receive third line therapy. Methods: In this study we conducted retrospective analysis of all patients who commenced treatment with SACT for mRCC between 1st January 2018 and 30th June 2021 in 18 centres across the 4 nations of the United Kingdom. All NHS reimbursed treatment options including the COVID interim treatment guideline options were included. Patients who received SACT as part of a clinical trial were also included. Patients who continued on their respective lines of treatment were censored. We also identified patients who had been on a period of active surveillance before staring SACT in this cohort. Results: 1549 patients (71% male: 29% female) were included. IMDC subgroup patients included 21.6% favourable, 52.3% intermediate, 25.1% poor and 1% unavailable. 9.1% of patients had been on active surveillance before starting SACT – defined as a period of longer than 3 months from mRCC diagnosis to starting SACT. Of those patients that started SACT 60.5% of eligible patients had 2nd line therapy, 25.3% had 3rd line, 7.2% received 4th line therapy and only 1% had 5th line therapy. In the 1st line setting 58.9% received single agent VEGF TKI, 24.5% received combination ipilimumab and nivolumab (IO-IO) immunotherapy, 14 % received IO/ VEGF TKI combination and 2.6% received other/trial treatment. The single agent VEGF TKI ratio for 1st line SACT declined year by year with rising IO-IO and IO/VEGF TKI combination ratios seen. In the second- and third-line settings cabozantinib (33.2% 2nd line and 44.4% 3rd line) and nivolumab (32.8% 2nd line and 22.6% 3rd line) were the most common options. Disease progression or death was the most common cause of SACT discontinuation amounting to 57.4%, 62.5% and 79% of SACT cessation in the 1st, 2nd and 3rd lines respectively. Treatment toxicity SACT discontinuation rates were 22.8%, 21.4% and 10.9% for 1st, 2nd and 3rd lines respectively. Conclusions: These results suggest that with more treatment options available, including combination/immunotherapy therapies, more patients are able to receive second- and third-line therapies. That said there remains significant drop off rates mostly driven by disease progression that would support the use of our most effective therapies in the upfront setting.

Allogeneic stem cell transplantation in patients with multiple myeloma-single center experience.

The standard of care in multiple myeloma (MM) consists of induction chemotherapy followed by autologous stem cell transplant (autoSCT), but this setting doesn't present curative potential. Despite advances in new, efficient, and targeted drugs, allogeneic transplant (aloSCT) remains the modality with curative potential in MM. With the knowledge of high mortality and morbidity related to the treatment in comparison to treatment with novel drugs, there is no consensus in the indication of aloSCT in MM, also the choice of ideal patients profiting from this method is difficult. Therefore, we performed a retrospective unicentric study of 36 unselected consecutive patients transplanted for MM in the University Hospital in Pilsen between the years 2000-2020 in order to define possible variables influencing survival. The median age of the patients was 52 years (38-63) and the distribution of MM subtypes was standard. The majority of the patients were transplanted in the relapse setting, 3 (8.3%) patients in the 1st line setting, and in 7 (19%) patients elective auto-alo tandem transplant was performed. 18 patients (60% of patients with available cytogenetics (CG) had high-risk disease. 12 (33.3%) patients were transplanted with chemoresistant disease (at least PR not reached). With a median follow-up of 85 months, we observed median overall survival (OS) of 30 months (range 10-60) and median progression-free survival (PFS) of 15 months (11-175). 1- and 5-year Kaplan Meier survival probabilities for OS were 55% and 30.5% respectively. During the follow-up, 27 (75%) patients died, 11 (35%) due to treatment-related mortality (TRM), and 16 patients (44%) due to a relapse. 9 (25%) patients were still alive, 3 (8.3%) of them with complete remission (CR), and 6 (16.7%) patients with relapse/progression. Altogether 21 (58%) of the patients relapsed/progressed with a median of 11 months (3-175). Incidence of clinically significant acute graft versus host disease (aGvHD gr. >II) was low (8.3%) and extensive chronic GvHD (cGvHD) developed in 4 patients (11.1%). Univariant analysis proved marginal statistical significance in disease status before aloSCT (chemosensitive × chemoresistant) for OS, favoring patients with the chemosensitive disease (HR 0.43, 95% CI 0.18-1.01, p=0.05), there was no significant impact of high-risk cytogenetics (CG) on survival. No other analyzed parameter was found to be significant. Our findings support the conclusion that aloSCT is able to overcome high-risk CG and that aloSCT still remains a valid treatment choice with acceptable toxicity in well-selected high-risk patients with curative potential, even though often with active disease, but not derogating the quality of life significantly.

CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors

BackgroundHigh-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs.Experimental designWe tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo.ResultsWe show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts.ConclusionOur findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

Abstract PR006: Initial results of a cohort of advanced pancreatic cancer patients in a phase 1b Study of NGM120, a first-in-class anti-GDNF Family Receptor Alpha Like (GFRAL) antibody

Abstract Background: Elevated circulating growth differentiation factor 15 (GDF15) and increased GDF15 expression in tumor tissues has been observed in patients with advanced pancreatic cancer (APC). These changes were correlated with poor survival. Effects of GDF15 on tumor progression, metastasis and immune escape may play a role. NGM120, a novel antibody to GFRAL that blocks the effects of GDF15, has resulted both in antitumor and anti-cachexia effects in experimental models. Here we report updated findings of the ongoing Phase 1b study with NGM120 in patients with APC. Methods: Metastatic pancreatic cancer patients with elevated serum GDF15 were treated with NGM120 (30 or 100 mg, s.c., q4wks) in a 1st line setting in combination with Gem/nab-paclitaxel. Primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetics, preliminary evidence of antitumor activity (RECIST) and anti-cachexia effects. Results: Eight patients received NGM120 in combination with Gem/nab-paclitaxel. Median age was 67 years, all patients had advanced disease. NGM120 was well tolerated with no dose-limiting toxicities. Most of the AEs or SAEs observed were Gem/nab-paclitaxel related and none of them attributed to NGM 120 treatment. As of data cut off on March 25, 2022, preliminary results include 3 patients with PR (extending >32 wks), 3 patients SD; 2 patients discontinued early (before first post-dose scan) due to toxicity attributed to Gem/nab-paclitaxel. Among the 6 evaluable patients, the disease control rate (DCR) is 100%, mPFS has not been reached, 12-month survival rate (12-month OS) is 83.3%. Over the course of the study, 5/6 of the patients gained or maintained their body weight (BW) and 5/6 of the patients gained or maintained their lean body mass (LBM) based on maximum change from baseline. Conclusions: NGM120 given in combination with Gem/nab-paclitaxel to patients with APC resulted in a 50% ORR (3 PR in 6 evaluable patients), 100% DCR, 83.3% 12-month OS and a “not reached” mPFS. Compared to historical Gem/nab-paclitaxel data, these findings are encouraging and support the potential role of NGM120 in the treatment of patients with APC. The positive effects on BW and LBM is also encouraging compared to the historical cachexia rate of 30% observed within 12 weeks of starting first-line chemotherapy in APC. A sign of NGM120 engages the GDF15-GFRAL pathway in managing body weight regulation. A Ph2a study is ongoing to further evaluate NGM120 in combination with Gem/nab-paclitaxel in the 1st line setting for the treatment of APC. Citation Format: Andrew Hendifar, Efrat Dotan, Benjamin Weinberg, Edward Kim, Peter Hosein, Jian Luo, Jiping Zha, Alex DePaoli, Vladimir Hanes, Cecilia Tranmuchowski, Kefei Zhou, Carol Tseng, Hsiao Lieu. Initial results of a cohort of advanced pancreatic cancer patients in a phase 1b Study of NGM120, a first-in-class anti-GDNF Family Receptor Alpha Like (GFRAL) antibody [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR006.

LBA16 Dalpiciclib plus letrozole or anastrozole as first-line treatment for HR+/HER2- advanced breast cancer (DAWNA-2): A phase III trial

Dalpiciclib (dalp), a novel CDK4/6 inhibitor, with fulvestrant improved PFS in patients (pts) with HR+/HER2- advanced breast cancer (ABC) progressing after endocrine therapy (ET) in the phase 3, DAWNA-1 trial (Nature Medicine 2021). Here we assessed dalp with ET in the 1st-line setting. DAWNA-2 was a randomized, multicenter, double-blind, phase 3 trial done in 42 centers in China. Pts with untreated HR+/HER2- locally recurrent or metastatic BC, and any menopausal status were randomized 2:1 to receive dalp (150 mg, po, qd, d1-21, q4w) or placebo + letrozole (2.5 mg, po, qd) or anastrozole (1 mg, po, qd). The primary endpoint was PFS per investigator (INV). A prespecified interim analysis was done after 186 (70.5% of total expected) PFS events occurred (Jun 1, 2022), and the corresponding superiority boundary was 1-sided P <0.0076. 456 pts were randomized to dalp + letrozole/anastrozole (N=303) or placebo+ letrozole/anastrozole (N=153). With a median follow-up of 21.7 and 21.4 mo respectively, PFS per INV was significantly improved in the dalp group vs the placebo group (median, 30.6 mo [95% CI 30.6-NR] vs 18.2 mo [16.5-22.5]; HR 0.51 [95% CI 0.38-0.69], 1-sided P <0.0001). PFS benefit with dalp was evident regardless of menopausal status (Table 1). ORR and DoR per INV also favored the dalp group (Table 1). The most frequent grade ≥3 AEs in the dalp group was neutropenia (85.8% [grade 3/4, 64.6%/21.2%] vs 0 in the placebo group) and leukopenia (66.6% [grade 3/4, 65.9%/0.7%] vs 0). SAEs occurred in 11.9% in the dalp group and 6.5% in the placebo group; 4.0% and 2.0% discontinued any treatment due to AEs respectively.Table: LBA16Efficacy summaryDalp group (N=303)Placebo group (N=153)PFSOverall populationMedian (95% CI), mo30.6 (30.6-NR)18.2 (16.5-22.5)HR (95% CI)∗, P†0.51 (0.38-0.69), P <0.0001Pre/peri-menopausal womenMedian (95% CI), moNR (27.7-NR)16.6 (12.9-27.7)HR (95% CI)‡0.53 (0.33-0.85)Postmenopausal womenMedian (95% CI), mo30.6 (24.9-NR)19.4 (16.6-24.6)HR (95% CI)‡0.52 (0.36-0.75)ORR, % (95% CI)57.4 (51.6-63.1)47.7 (39.6-55.9)Median DoR (95% CI), moNR (26.9-NR)15.0 (12.9-20.3)∗ StratifiedCox proportional hazards model.† 1-sided stratified Log-rank test. ‡ Unstratified Cox proportional hazards model. NR=not reached. Open table in a new tab ∗ StratifiedCox proportional hazards model.† 1-sided stratified Log-rank test. ‡ Unstratified Cox proportional hazards model. NR=not reached. Adding dalp to letrozole/anastrozole significantly prolonged PFS in HR+/HER2- ABC, with manageable toxicities. Dalp is the 4th CDK4/6 inhibitor showing survival benefit with letrozole or anastrozole in untreated HR+/HER2- ABC, or with fulvestrant in pretreated HR+/HER2- ABC, in addition to palbociclib, ribociclib and abemaciclib.

1028P BIOLUMA: A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in lung cancer and to evaluate biomarkers predictive for response – results from the NSCLC cohort

In NSCLC, combining blockade of PD-1 and CTLA-4 is more effective than monotherapy but is accompanied by an increase in toxicity. Thus, it is of great interest to identify patients who benefit from adding the CTLA-4 inihibitor to the anti-PD-1 therapy in case of progression. We present data from the NSCLC cohort of the BIOLUMA trial, which evaluates efficacy and safety of nivolumab and ipilimumab in lung cancer and includes a translational program to identify potential biomarkers predictive of response and resistance. BIOLUMA is an investigator-initiated, multicentre, phase II trial in 2nd line patients with non-squamous NSCLC. Patients are treated with nivolumab 240 mg until disease progression (part A) and subsequently with a combination therapy of nivolumab 3 mg/kg q2w and ipilimumab 1mg/kg q6w (part B). Primary endpoint is overall response rate of the combination treatment. Analysis of sequential tumor biopsies and PBMCs were performed at different timepoints. In total, 27 patients were enrolled. Two patients dropped out due to changes of tumor histology after central pathological assessment. Thirteen patients were transferred to treatment part B (combination therapy nivolumab plus ipilimumab) and were available for primary endpoint analysis. In 4 of these patients (30.8%) the addition of ipilimumab induced a tumor response: three patients with primary nivolumab refractory disease experienced partial response (2 confirmed by RECIST). One patient had an unconfirmed SD after addition of ipilimumab. PD occured in 9 out of 13 patients. The cohort was terminated early due to a high dropout rate of 52% from treatment part A to B, mainly attributed to rapid disease progression and immune-mediated adverse event while on nivolumab treatment. In nivolumab refractory NSCLC patients, addition of ipilimumab shows promising anti-tumor activity. The results give an important signal for further trials in 1st line setting for overcoming resistance to anti-PD-1 monotherapy by sequentially adding a second checkpoint inhibitor and hereby moving potential toxicity and chemotherapy to later treatment lines.

P2.09-03 A Radiomics Approach Using Baseline CT Can Predict Response to 1st-Line Pembrolizumab in Advanced NSCLC with High PD-L1

Clinical trials showed both pembrolizumab alone (KN024), and pembrolizumab/platinum doublet chemotherapy (PDC) (KN189/407) are superior to PDC in 1st-line setting for advanced NSCLC without EGFR/ALK aberration. In PDL1≥50% subset across 3 trials, objective response rate (ORR) with pembrolizumab in KN024 was 45%, compared to 60% with pembrolizumab/PDP in KN189/407 with comparable 12 months overall survival (OS). Recent 5-year survival data from KN024 showed 32% of patients were alive at 5 years, most of whom were “responders”.

EP08.01-075 Combination of Baseline Disease and Smoking Pack-Years Can Guide The 1st-line Treatment Decision in Advanced NSCLC with High PD-L1 Expression

KN024 showed pembrolizumab improved survival compared to platinum doublet chemotherapy (PDC) in 1st-line setting for advanced NSCLC with PDL1≥50%. KN189/KN407 demonstrated pembrolizumab/PDC in advanced NSCLC achieved superior 12-month survival compared with PDC. In patients with PDL1≥50% cross 3 trials, objective response rate with pembrolizumab in KN024 was 45% compared to 60% with pembrolizumab/PDP in KN189/407. The clinical question is: can we distinguish this 45% of patients who are best treated with pembrolizumab alone, and who need additional PDC? Currently, there are no biomarkers or clinicopathological features to distinguish this population.

The prognostic value of chemotherapy or endocrine therapy choice according to circulating tumor cell count in HR+HER2- metastatic breast cancer: a retrospective study.

BackgroundCirculating tumor cell (CTC) count have prognostic role for metastatic breast cancer (MBC). No clear biomarkers can guide selection of chemotherapy (CT) or endocrine therapy (ET) in 1st-line setting of hormone-receptor positive and human epidermal growth factor receptor 2 negative (HR+HER2−) MBC. The present study investigated the prognostic role CT or ET according to the CTC count in HR+HER2− MBC.MethodsWe consecutively collected the data of 53 HR+HER2− MBC patients who received 1st-line CT or ET, who had CTC count detected by our peptide-based nanomagnetic CTC isolation system (Pep@MNPs) from January 2014 to December 2015. The clinicopathological characteristics according the CTC count and 1st-line ET vs. CT were compared. Follow-up was conducted every 6 months. The primary endpoint was progression-free survival (PFS) and overall survival (OS). A Cox regression analysis was conducted to determine the prognostic roles of CTC and 1st-line therapy of ET vs. CT for PFS and OS.ResultsThe median CTC count of the 53 patients was 2 (range, 0–18). The clinicopathological characteristics of the patients in the CTC count <2 group and the CTC count ≥2 group were similar. The patients with a CTC count <2 had a significantly longer PFS than those with a CTC count ≥2 (P=0.005, hazard ratio =4.138, 12.1 vs. 7.1 months). The patients who received CT had a significantly longer PFS than those who received ET (P=0.041, hazard ratio =2.721, 9.9 vs. 7.2 months). In the CTC count ≥2 group, the patients who received CT had a significantly longer PFS than those who received ET (P=0.048, hazard ratio =2.475, 8.7 vs. 6.3 months). In the CTC count <2 group, there was no significant difference in PFS between the CT and ET groups (P=0.071). Additionally, the CTC count had no significant effect on OS (P=0.116, hazard ratio =2.391, 54.2 vs. 34.2 months).ConclusionsThe present study showed that CTC count determined by the Pep@MNP system confirmed the prognostic value in the HR+HER2− MBC patients. And it might be helpful in choosing a 1st-line treatment of CT or ET for HR+HER2− MBC patients.

Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1st- and 2nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.

Outcomes of single-agent PD-(L)-1 versus combination with chemotherapy in patients with PD-L1-high (≥ 50%) lung cancer.

9052 Background: Single agent PD-(L)-1 blockade (IO) and PD-(L)-1 blockade combined with chemotherapy (ChemoIO) are both standard first-line treatments for patients with PD-L1-high (≥ 50%) metastatic non-small cell lung cancer (NSCLC). These regimens have not been compared prospectively, so comparative effectiveness is unclear. It is also unknown if clinical and molecular tumor characteristics differentially associate with benefit to IO vs ChemoIO in patients with NSCLC with high PD-L1 tumor expression. Methods: All patients with metastatic NSCLC treated with IO or ChemoIO at two institutions (Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute) were reviewed. Patients with EGFR or ALK alterations, PD-L1 expression &lt; 50%, treated with IO or ChemoIO in &gt; 1st line setting were excluded. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were compared between the IO vs ChemoIO groups and association with clinical, pathologic, and molecular features was examined. To account for NGS panel differences, tumor mutational burden (TMB) values were harmonized using a z-score conversion as previously described (Vokes et al, 2019). Results: Of 639 patients with stage IV EGFR/ ALK wild-type NSCLC and PD-L1 ≥50% treated in the 1st line setting, 504 received IO and 135 received ChemoIO. Baseline ECOG performance status (p = 0.3), median PD-L1 % (p &gt; 0.9) and TMB (p = 0.2) were similar between the IO and ChemoIO groups. For patients receiving IO vs ChemoIO, there was no significant difference in OS (HR 0.8, 95% CI 0.6 to 1.08; p = 0.2). Median PFS was shorter (HR 0.7, 95% CI 0.6 to 0.9; p = 0.004) and ORR was lower (40% IO vs 55% ChemoIO, p = 0.002) in the IO group. Among patients with durable responses (&gt; 6 months), never smokers were less common in the IO group (6% vs 18%, p &lt; 0.001), but there was no difference in PD-L1 expression, TMB, or mutational ( KRAS, STK11, or KEAP1) profile to suggest differential predictors of benefit to IO or ChemoIO. Conclusions: In patients with PD-L1 high NSCLC, there was no survival benefit associated with the addition of chemotherapy to IO. There were also no clear differences in PD-L1 expression or molecular features associated with durable response to IO vs ChemoIO. These findings have implications for treatment selection in this population.

Efficacy of dabrafenib-trametinib combination in BRAF V600E-mutated metastatic non–small cell lung cancer: Results of the IFCT-2004 BLaDE cohort.

9082 Background: BRAF V600E mutations occur up to 2% of advanced non-small cell lung (NSCLC). Dabrafenib-trametinib (D-T) combination was associated with improved OS rates in phase II study and was approved in the 1st-line setting and further. The IFCT-2004 BLaDE study reports the D-T combination efficacy in a large French real-world multicenter cohort of advanced BRAF V600E-mutated NSCLC. Methods: Patients (pts) with advanced NSCLC harboring BRAF V600E mutation diagnosed between 01.01.2016 and 31.12.2019 and treated with D-T combination (D 300 mg + T 2 mg daily) whatever the treatment line were included. Demographic, clinical, pathological data were collected as well as data of efficacy and reason of treatment discontinuation. The primary endpoint was 12 months-OS rate in pts receiving the D-T as 2nd-line or subsequent treatment (L2+). Results: 163 pts were included in 54 centers through 32 national testing labs: 50.3 % were female, 30.2% never-smokers, 95.1 % had adenocarcinoma and PDL1 was &gt; 1% in 78.2%. Median age was 68.3 years. At D-T initiation, 80.8 % of pts were PS 0/1, 93.9 % were stage IIIB/C ineligible for surgery or local therapy and IV, 20.9% had brain metastases and 27% received D+T as 1st line treatment (L1). At the data cutoff (30.06.2021), median (m) follow-up was 27.4 months [95% CI 22.2-31.9] and 47 pts (28.8%) remained on study treatment. 12 months-OS rate in pts receiving D+T in L2+ (n = 119) was 67.4% [95% CI 57.8-75.3] with a median progression-free survival (mPFS) of 10.4 months [95% CI 7.3-13.1]. In the 44 pts receiving D+T in L1, 12 months-OS rate was also 67.4% [95% CI 51.2-79.3] with a mPFS of 18.2 months [95% CI 7.7-21.3]. Objective response rates were 73.8% [95% CI 65.5 - 82.2] and 82.9% [95% CI 71.4 - 94.4], disease progression was observed as best response in 3.7% [95% CI 0.1 - 7.3] and 0% in L2+ and L1, respectively. Other efficacy results are detailed in the table. D-T discontinuation for toxicity was reported in 10.3% of pts. 51.2% and 43.7% of pts received subsequent treatment in L2+ and L1 respectively. For L2+ pts, subsequent treatments were immunotherapy (IO)-based in 37.2 % and chemotherapy in 58.3%. For L1 pts, subsequent treatments were (IO)-based in 42.9% and chemotherapy in 42.7%. Conclusions: Our series confirms significant efficacy of D-T combination in BRAF V600E-mutated metastatic NSCLC. These results in real-world conditions are consistent with registration studies but also support its use in 1st line setting. [Table: see text]

A phase Ib/II study of AK112, a PD-1/VEGF bispecific antibody, as first- or second-line therapy for advanced non–small cell lung cancer (NSCLC).

9040 Background: Besides the well-known antiangiogenic effects, anti-VEGF agents also modulate the tumor immune micro-environment, leading to synergic anti-tumor effects. AK112 is a humanized IgG1 bispecific antibody against PD-1 and VEGF. Here, we reported results of an ongoing phase Ib/II trial of AK112 in advanced NSCLC pts. Methods: Pts with stage IIIB/IIIC/IV NSCLC, ECOG PS 0-1 and negative oncogenic drivers were enrolled and given AK112 (10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W or 30 mg/kg Q3W) intravenously. The primary endpoints were ORR per RECIST v1.1 and safety. Results: At data cutoff (January 5, 2022), 94 pts were enrolled: median age 66.0 years (range: 48-75), PS 1 90.4%, male 85.1%, non-squamous 48.9%, PD-L1 positive (TPS ≥1%) 70.2% and treatment-naïve 84.0%. Of 83 pts evaluable for efficacy, ORR (unconfirmed, similarly hereinafter) and DCR were 22.2%/88.9%, 44.0%/92.0%, 37.9%/93.1% and 100%/100% at doses of 10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W and 30 mg/kg Q3W, respectively. When doses of AK112 &gt; 10mg/kg Q3W, ORR and DCR were 42.9% (24/56) and 92.9% (52/56) in 56 evaluable pts, 56.3% (18/32) and 100% (32/32) in pts with TPS≥1% at 1st line setting, and 23.5% (4/17) and 76.5% (13/17) in pts with PD-L1 TPS &lt; 1%, respectively. Grade≥3 treatment-related adverse events (TRAEs) occurred in 10.6% (10/94) pts, in which the most common event (occurring in &gt; 1 pt) was pneumonia (2.1%, 2/94). No TRAEs led to permanent treatment discontinuation. Most frequent TRAEs (incidence ≥10%) were proteinuria (17.0%), hypertension (16.0%), lipase increase (12.8%), alanine aminotransferase increase (12.8%), blood urea increase (10.6%), apolipoprotein E increase (10.6%) and hyperglycaemia (10.6%). No significant difference in the incidences of TRAEs were observed between non-squamous and squamous pts. Conclusions: In advanced NSCLC, AK112 was well-tolerated and presented remarkable anti-tumor efficacy. Further phase III studies are planned to validate the findings of this study. Clinical trial information: NCT04900363.

Time-of-day infusion of immunotherapy may impact outcomes in advanced non-small cell lung cancer patients (NSCLC).

e21126 Background: Circadian rhythms have shown direct impact on toxicity and efficacy of anticancer treatments. Adaptive immune responses related to (or associated with) check point inhibitor (CPI) administration may have lower intensity later in the day. Notably, emerging evidence suggests that the time-of-day administration of different immunotherapies could have survival implications in different tumor types. Methods: We extracted de-identified data from curated the Real-World database of the Oncoclínicas Group, including 21 community-oncology practices in Brazil with EHR information on time-of-day administration of CPI in patients with advanced NSCLC. Only patients treated with single-agent CPIs with palliative intent (Nivolumab, Pembrolizumab or Atezolizumab) from Jan 2018 through Dec 2021 were analyzed. The primary endpoint was a comparative analysis of the median Time to Treatment Discontinuation (TTD) of CPI stratified according to time-of-day administration using a propensity-score (PS) matching model. On the basis of previous reports, we selected the cutoff of 20% of CPI doses administered after 4:00 pm as the late-day subgroup. Variables included in PS matching were: age (&lt; 60, 60+); line of therapy (1st, 2ndor beyond); gender (male, female), and CPI agent (Pembrolizumab vs. others). Results: From a total of 1,603 patients with advanced NSCLC treated at Oncoclínicas during the study period, 508 received CPI as per inclusion criteria. Median age was 73 years (36-94), 66% were male, 63% received CPI in the 1stline setting, 50% with Pembrolizumab. Overall, 219 CPI infusions (15%) occurred after 4:00 pm and 9% of the patients (n = 43) qualified as late-day infusion subgroup (more than 20% of infusions after 4pm). Median TTD was 4.9 months (CI 95%, 2.83-13.5) in these patients. In the PS matched population with early-day infusions (2:1, n = 86), median TTD was 14 months (CI 95%, 8.87-23.4). Overall, with 73 events in 129 patients, we found a significantly increased risk of treatment discontinuation in the late-day subgroup (HR 1.61, CI95% 1.0-2.6, p = 0.05). With only 33 death events and median follow-up of 11 months, median overall survival was not reached in late-day or early-day subgroups (HR 1.25, CI95% 0.6-2.6, p = 0.5). Conclusions: This preliminary and exploratory real-world data analysis suggests that the time-of-day administration of CPI in patients with advanced NSCLC could have a meaningful impact on patient outcomes, in line with studies conducted in melanoma. This simple and inexpensive intervention merits further exploration in prospective controlled clinical trials.

Abstract P1-18-13: Efficacy and safety of palbociclib plus endocrine therapy in Black and Hispanic patients with hormone receptor positive/human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC) participating in the PALOMA trials

Abstract Background: The PALOMA clinical trials have shown that palbociclib (PAL) plus endocrine therapy (ET) is a safe and effective treatment for HR+/HER2- ABC. However, Black and Hispanic patients are underrepresented in clinical trials and the efficacy and safety of CDK4/6 inhibitors in these populations have not been reported. This post hoc analysis describes the efficacy and safety of PAL + ET in Black and Hispanic patients with HR+/HER2- ABC enrolled in the PALOMA trials. Methods: Postmenopausal patients were treated with letrozole (LET) + PAL on a 125 mg/d, 3/1 weekly schedule or LET alone (PALOMA-1) or LET + placebo (PBO; PALOMA-2) in the 1st line setting. In PALOMA-3, pre/postmenopausal patients were treated with fulvestrant (FUL) + PAL or PBO, with or without a luteinizing hormone releasing hormone agonist, in the ≥1st-line setting. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Treatment-emergent adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for AEs. Results: In PALOMA-2, Black and Hispanic patients comprised 9.8% of the population and had a median age of 58 yrs (PAL + LET arm; n=47) and 54 yrs (PBO + LET arm; n=18). Patients treated with PAL + LET had more visceral disease (62% vs 50%), lung involvement (51% vs 22%), de novo disease (45% vs 22%) and less prior systemics (55% vs 78%) compared to patients treated with PBO + LET. In PALOMA-3, Black and Hispanic patients comprised 9.2% of the population and had a median age of 57 yrs in both the PAL + FUL (n=29) and PBO + FUL (n=19) arms, with baseline characteristics being generally similar between the two arms. PAL+ ET prolonged median PFS in PALOMA-2 and -3 and prolonged median OS in PALOMA-3 compared to PBO + ET (Table 1). In pooled analyses of these patients from PALOMA 1-3 (n=120), the most common grade 3/4 AEs with PAL + ET were neutropenia (57.7%), leukopenia (24.4%), and anemia (3.8%), similar to the rates in the pooled PALOMA 1−3 overall as-treated population (Table 2). None of these grade 3/4 AEs were reported with PBO + ET in the Black/Hispanic subgroup (Table 2). Febrile neutropenia or pulmonary embolism were not reported in either arm. The rate of dose reduction due to AEs was 37.2% with PAL + ET, similar to the rates of dose reduction across the populations in the PALOMA trials (39.4%−42.2%). Conclusion: In Black/Hispanic pts with HR+/HER2- ABC enrolled in the PALOMA-2 and -3 trials, PAL + ET, in the first or greater lines, was an efficacious treatment option with no increased toxicity rates. These findings support the continued use of PAL + ET as a standard of care in these patients. Considering the substantial burden of breast cancer in Black and Hispanic patients, their relatively small representation in the PALOMA trial program highlights the need to increase diversity in clinical trials. Clinical trial identification: Pfizer (NCT00721409, NCT01740427, NCT01942135) Table 1.Median PFS and OS in the ITT population and Black and Hispanic patients from PALOMA-2 and -3Median (95% CI), moHazard Ratioa (95% CI)PAL + ETPBO + ETPAL + ET vs PBO + ETPFSPALOMA-2ITT [n=666]27.6 (22.4-30.3)14.5 (12.3-17.1)0.56 (0.46-0.69)Black and Hispanic [n=65]27.4 (13.8-NE)13.8 (8.1-30.7)0.61 (0.31-1.2)PALOMA-3ITT [n=521]11.2 (9.5-12.9)4.6 (3.5-5.6)0.50 (0.40-0.62)Black and Hispanic [n=48]11.1 (4.5-12.0)1.9 (1.8-5.7)0.56 (0.28-1.14)OSPALOMA-3ITT [n=521]34.8 (28.8-39.9)28.0 (23.5-33.8)0.79 (0.64-0.97)Black and Hispanic [n=48]35.6 (24.0-58.2)21.0 (14.3-35.4)0.48 (0.23-0.97)ET=endocrine therapy; ITT=intent to treat; NE=not estimable; OS=overall survival; PAL=palbociclib; PBO=placebo; PFS=progression free survival.aEstimated from an unstratified Cox proportional hazards model. Table 2.Grade 3/4 treatment emergent adverse events in the overall as-treated population and Black and Hispanic subgroup pooled from the PALOMA trialsPooled PALOMAPooled Black/HispanicAE, No. (%)PAL + ET (n=872)ETa (n=471)PAL + ET (n=78)PBO + ET (n=42)Any AE662 (75.9)110 (23.4)53 (67.9)12 (28.6)Neutropenia570 (65.4)5 (1.1)45 (57.7)0Leukopenia233 (26.7)2 (0.4)19 (24.4)0Anemia40 (4.6)9 (1.9)3 (3.8%)0Thrombocytopenia17 (1.9)1 (0.2)1 (1.3%)1 (2.4)Infections45 (5.2)12 (2.5)1 (1.3%)1 (2.4)AE=adverse event; ET=endocrine therapy; PAL=palbociclib; PBO=placebo.aEndocrine therapy with placebo (PALOMA-2 and 3) and without placebo (PALOMA-1). Citation Format: Claudine Isaacs, Reshma Mahtani, Filipa Lynce, Bethany Sleckman, Aurelio Castrellon, Sujith Kalmadi, Kathy Puyana Theall, Xin Huang, Eustratios Bananis, Hope S. Rugo. Efficacy and safety of palbociclib plus endocrine therapy in Black and Hispanic patients with hormone receptor positive/human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC) participating in the PALOMA trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-13.

Abstract P1-17-09: Efficacy of limited dose modifications for palbociclib-related grade 3 neutropenia in hormone receptor positive metastatic breast cancer

Abstract Background. Endocrine therapy plus CDK 4/6 inhibitors is the foremost treatment for hormone receptor (HR) positive metastatic breast cancers (mBC). Previously, we reported safety profiles of palbociclib use with grade 3 neutropenia in HR-positive mBC. Here, we investigated two cohorts’ patients who had received palbociclib with or without dose interruptions and/or reductions on afebrile grade 3 neutropenia in terms of efficacy outcomes. Patients and methods. The combined cohort of consecutive mBC patients who received palbociclib with letrozole in 1st line setting (in four major cancer centers in Republic of Korea) was reviewed. We classified patients into 4 groups: Group 1 (patients who maintained palbociclib dose on afebrile grade 3 neutropenia, representing limited dose modification scheme), Group 2 (patients who experienced any dose modification on afebrile grade 3 neutropenia, representing conventional dose modification scheme), Group 3 (patients without the event of afebrile grade 3 neutropenia), and Group 4 (patients who experienced only grade 4 neutropenia) within the first 5 cycles. The primary endpoint was PFS difference between Group 1 and Group 2, and secondary endpoints included PFS and overall survival difference in all groups, and safety profiles of each group. Results. A total of 434 eligible patients recruited from Jan 2017 to Sep 2020 were allocated into 4 groups; Group 1 (n=172, 40.1%), Group 2 (n=128, 29.5%), Group 3 (n=102, 23.5%), and Group 4 (n=30, 6.9%). The overall incidence of palbociclib dose reductions was 272 (62.7%) and dosing delay was 181 (42.2%) in all groups. The median time to first dose reduction for all eligible patients was 3 months (2-5 months) and the median time to second dose reduction was 9 months (2-30 months). At the 12th cycle of treatment, 70.5% (105/at-risk patients of 149) of Group 1 patients still remained on 125mg of palbociclib, whereas no patient was on 125mg dose level but 66.3% patients (65/at-risk patients of 98) were on 100mg in Group 2. At the median follow-up of 23.7 months (95% CI: 21.6-25.8), Group 1 patients showed significantly longer PFS than Group 2 patients (P-value = 0.036, 2-year PFS rate: 67.9% in Group 1 and 55.3% in Group 2). The OS between Group 1 and 2 was not significantly different. The favorable PFS trend of Group 1 over Group 2 was observed across all subgroups. The overall toxicity profiles were not significantly different between Group 1 and Group 2. Conclusion. Our study demonstrates that the clinical practice of limited dose modifications for palbociclib-related grade 3 neutropenia might have more therapeutic benefits than the conventional dose scheme without increasing toxicities. Permissive approach to afebrile grade 3 neutropenia and prospective clinical trials for this new dose scheme are warranted. Funding: This study was supported by a grant from Pfizer. Citation Format: Seul-Gi Kim, Min Hwan Kim, Sejung Park, Gun Min Kim, Jee Hung Kim, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Jung Hwan Ji, Joon Jeong, Kabsoo Shin, Jieun Lee, Hyung-Don Kim, Kyung Hae Jung, Joohyuk Sohn. Efficacy of limited dose modifications for palbociclib-related grade 3 neutropenia in hormone receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-09.

MOUNTAINEER-02: Phase 2/3 study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma—Trial in progress.

TPS371 Background: Tucatinib (TUC), a highly selective HER2-directed tyrosine kinase inhibitor (TKI) approved in multiple regions for HER2+ metastatic breast cancer, is being developed as a novel therapy for patients (pts) with GI tumors including gastric or gastroesophageal junction adenocarcinoma (GEC). While trastuzumab (Tras) with chemotherapy is standard in the 1st-line setting for metastatic HER2+ GEC, no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy as 2nd-line therapy, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone.(Kulukian 2020) Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras for HER2+ mCRC.(Strickler 2019) The MOUNTAINEER-02 study is evaluating the efficacy and safety of TUC with Tras, ramucirumab (Ram), and paclitaxel (Pac) in pts with HER2+ GEC in the 2nd-line setting. Methods: MOUNTAINEER-02 (NCT04499924) is a phase 2/3 study evaluating TUC + Tras with Ram and Pac. Pts receive TUC 300 mg or placebo PO BID, Tras (6 then 4 mg/kg) or placebo (IV on Days 1 and 15 of each 28-day cycle), Pac (IV on Days 1, 8, 15), and Ram (IV on Days 1 and 15). Eligible pts have locally-advanced unresectable or metastatic HER2+ GEC and have received a HER2-directed antibody and 1 prior line of therapy for advanced disease. Pts must be ≥18 years of age, with an ECOG ≤1, and have had no prior exposure to Ram, anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Due to the potential impact of TUC on Pac metabolism, the study will include an initial Pac dose optimization stage. The open-label phase 2 part will determine the recommended dose of Pac (60 or 80 mg/m²) combined with TUC, Tras, and Ram in 6-18 pts, and evaluate safety and activity of the regimen in Cohorts 2A and 2B (30 pts each). The randomized, double-blind, phase 3 part will compare the efficacy and safety of TUC and Tras (Arm 3A; ̃235 pts) vs. placebo (Arm 3B; ̃235 pts), both in combination with Ram and Pac, and also evaluate activity of TUC with Ram and Pac (Arm 3C; ̃30 pts). The dual primary phase 3 endpoints are OS and PFS per investigator, with confirmed ORR as a key secondary endpoint. HER2 status is determined at baseline using a blood-based NGS assay, and IHC/ISH of fresh or archival tumor biopsies, if available. Pts must be HER2+ by blood-based NGS in Cohort 2A and phase 3; in Cohort 2B, pts must be HER2+ in a biopsy taken post-progression during/after 1st-line therapy, but HER2-negative by blood-based NGS. Disease assessments per RECISTv1.1 will occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites will be evaluated in a subset of pts, including a cohort with gastrectomies. Enrollment in phase 2 is ongoing. Clinical trial information: NCT04499924.

Outcome in patients of hormone receptor (HR) positive (Her 2) negative metastatic breast cancer treated with palbociclib – A real-world experience

Objectives: We present real-world outcome with the use of palbociclib in patients with HR-positive Her2-negative breast cancer treated at single center in India. Material and Methods: We conducted a medical audit of consecutive patients with HR-positive Her2-negative metastatic breast cancer, who were treated with palbociclib at our center between November 2016 and May 2020. Palbociclib was commenced at a dose of 125 mg orally once daily and a schedule of 21 days on therapy followed by 7 days off therapy was followed. Survival analysis included the Kaplan–Meier method using Statistical Package for the Social Sciences software (Version 26). HRs were calculated using Cox proportional hazard regression models and 95% confidence intervals (CIs) for the incidence estimates. Results: A total of 67 female patients were commenced on treatment with palbociclib between November 2016 and May 2020. The median age was 55 years (range 29–78 years). A total of 51 (76%) of these patients were postmenopausal and the remaining 16 were premenopausal. Baseline metastatic disease involved one organ/site in 23 (34%), two organs/sites in 32 (48%), three or more in 12 (18%). Bony metastasis alone was seen in 17 (25%) patients, visceral alone in 30 (45%), and the remaining 20 had both bony and visceral metastases. For these 67 patients, palbociclib was commenced as 1st line systemic therapy in 24 (36%) cases. Amongst the remaining 43 cases, it was 2nd line in 21 (31%); 3rd line and beyond in 22 (33%). Median PFS was 16.1 months (95% CI: 9.6–22.8) and median OS was 20.7 months (95% CI: 14.1–27.3). Median PFS for palbociclib use in first line was 18.7 months (95% CI: 4.6–32.9) while in subsequent lines, it was 13.8 months (95% CI: 9.8–17.9; log-rank P = 0.228). Median OS in patients who received palbociclib in first line was 23.2 months (95 % CI 20.1–26.3) and for those why received it in subsequent lines was 16.3 months (95 % CI: 12.5–20.1; P = 0.069). In total population, best response on imaging was CR in 11 (16%) cases (06 in 1st line setting and 05 in subsequent line setting); PR in 33 (49%); SD in 03; and progressive disease in 20. Median PFS with bone only metastasis: 20.9 months (95 % CI: 5.9–36.0), while with visceral metastasis 16.1 months (95% CI: 9.8–22.5; P = 0.537). Median OS with bone only metastasis: 22.7 months (95% CI: 17.8–27.5), while with visceral metastasis, it was 18.5 months (95% CI: 13.6–23.4; P = 0.314). Conclusion: Palbociclib is a useful addition in the management of HR +ve Her2 –ve breast cancer patients. Its benefit is confirmed in our real-world setting, both in the first and subsequent lines of therapy and the data are on similar lines as the global real-world data on palbociclib effectiveness.