Second-line Combination Therapy Research Articles

Real-world efficacy and safety of durvalumab-tremelimumab as second-line systemic therapy after atezolizumab-bevacizumab in unresectable hepatocellular carcinoma.

The efficacy and safety of immune-checkpoint inhibitors (ICI) for the treatment of unresectable hepatocellular carcinoma are known. We explored ICI rechallenges with direct switching from 1 ICI regimen to another. This retrospective study included 16 patients who received atezolizumab-bevacizumab (Atezo+Bev) and durvalumab-tremelimumab (Dur+Tre) as the first-line and second-line combination therapy, respectively, at Hiroshima University Hospital. The radiological response and adverse event were evaluated in all patients. Of the 16 patients, 12 were male, and the median age at Atezo+Bev induction was 71 years. The reasons for medication changes were disease progression in 11 patients and adverse events in 5 patients. With Atezo+Bev and Dur+Tre initiation, the Barcelona-Clinic Liver-Cancer stage (A/B/C) progressed in 9/6/3 and 3/4/9 patients and the Child-Pugh classification (A/B/C) progressed in 12/4/0 and 9/6/3 patients, respectively. The disease control rate and overall response rate of Atezo+Bev were 87.5% and 58.3%, respectively, and of Dur+Tre were 62.5% and 0%, respectively. The most common immune-related adverse event in both the Atezo+Bev and Dur+Tre groups was colitis; 3 of the 5 patients with colitis on Atezo+Bev treatment had colitis with Dur+Tre, and 2 had exacerbations. Regarding liver function, ALBI score significantly decreased during Atezo+Bev, but not Dur+Tre, treatment. In patients with colitis following Atezo+Bev, subsequent Dur+Tre treatment may induce colitis recurrence or exacerbation. For immune-related adverse events other than colitis, Dur+Tre could provide relatively safe disease control while maintaining liver function.

Envafolimab in combination with lenvatinib and albumin paclitaxel for previously treated advanced gastric/gastroesophageal junction adenocarcinoma: Preliminary analysis of a phase II, two-cohort study.

e16039 Background: The combination of first-line chemotherapy and PD-1 has emerged as a standard treatment, enhancing the efficacy in advanced gastric/gastroesophageal junction (GEJ) cancer. The efficacy of the combination of second-line chemotherapy and PD-1/PD-L1 remains unclear. This study aims to observe the efficacy of Envafolimab plus tyrosine kinase inhibitors (TKIs) and second-line chemotherapy in the treatment of patients with advanced GEJ adenocarcinoma. Methods: This prospective, open-label, phaseⅡ, two cohort study was conducted to assess the efficacy and safety of Envafolimab-based therapy in patients experiencing progression after initial first-line treatment. Eligible patients with HER2-negative, microsatellite stable (MSS), advanced GEJ adenocarcinoma were consecutively enrolled and assigned into cohort A or cohort B, according to whether they received PD-1 inhibitors in the first-line treatment. Patients in both cohorts received Envafolimab (200mg, hypodermic injection, days 1 and 15, Q4W) combined with Lenvatinib (8mg/12mg, po, once a day) and albumin paclitaxel (100mg/m2, IV, days 1, 8 and 15, Q4W, up to 6 cycles) until disease progression, unacceptable toxicity, or patients refusal to continue treatment. The primary endpoint was objective response rate(ORR) per iRECIST v1.1, and the secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. The efficacy and safety data in this analysis were from patients in cohort A who previously failed in first-line chemotherapy and did not receive PD-1 or PD-L1 inhibitors ever. Results: From October 2022 to June 2023, cohort A enrolled 16 patients, and 15 of them were evaluable for efficacy analysis. The average age was 58.87 ±11.81 years, 80% patients were male. 6 patients had been tested for PD-L1 status, of which 1 (16.7%) was positive and 5 (83.3%) were negative. As of Jan29, 2024, the median follow-up was 10.6 months (95%CI = 8.67-12.53), the median number of treatment cycles was 7 cycles (IQR: 5, 8). Based on the iRECIST v1.1, the ORR was 60.00% (90% CI = 35.96%-80.91%), the DCR was 100.00% (90% CI = 81.90%-100.00%). The median PFS (mPFS) was 8.23 months (90% CI =6.27-8.61), and the median OS (mOS) was 10.6 months (90% CI =8.79-12.15). Overall incidences of adverse events (AEs) of any grade was 100%, and 75.00% (n = 12) had ≥ grade 3 AEs during treatment. Most treatment-related adverse events (TRAEs) of grade ≥3 included neutrophil count (56.25%), decreased leukocyte count (37.5%). Conclusions: In patients of advanced gastric cancer who have not previously received PD-1/PD-L1 inhibitors, this second-line combination therapy demonstrates promising preliminary effects. Clinical trial information: NCT06030934 .

Efficacy and safety of inetetamab-containing regimens in patients with HER2-positive metastatic breast cancer in first-line/second-line setting.

e13013 Background: Inetetamab is a novel recombinant humanized anti-human epidermal growth factor receptor-2 (HER-2) monoclonal antibody. This real-world retrospective study assessed the efficacy and safety of inetetamab-based combination regimens in first-line/second-line treatment of HER2-positive metastatic breast cancer (MBC). Methods: This study retrospectively recruited HER2-positive MBC patients who received inetetamab-based combination regimens from June 2020 to May 2023. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Results: A total of 329 patients were enrolled and included in the efficacy analysis. The most frequently used treatment strategy was inetetamab plus pyrotinib-contained regimens (205/329, 62.3%). Patients treated with first-line regimens benefited the most, with a median PFS of 14.5 versus (vs.) 10.0 months (first-line- vs. second-line combination therapy of inetetamab, pyrotinib and chemotherapy, p <0.001), 18.0 vs. 17.0 months (first-line- vs. second-line combination therapy of inetetamab, pertuzumab and chemotherapy, p=0.096), and 14.0 vs. not applicable months (first-line- vs. second-line inetetamab plus chemotherapy, p=0.229). The complete response (CR) was observed in 14 (4.3%) patients. The ORR was 54.4% (95%CI, 49.0%-59.7%), and the DCR was 99.4% (95%CI, 97.8%-99.8%). Diarrhea (39.2%) and white blood cell count decreased (33.0%) were the most common adverse events (AEs). The grade 3 and higher AEs were observed in 29.5% of the whole study cohort. Conclusions: Inetetamab-based combinations therapy demonstrated promising clinical activity and a manageable safety profile in patients with HER2-positive MBC, especially in the first-line setting.

Efficacy and safety of switching other tyrosine kinase inhibitors to regorafenib combined with primary PD-1 antibodies in patients with hepatocellular carcinoma.

e14612 Background: Currently, formal tyrosine kinase inhibitors (TKIs) such as sorafenib or lenvatinib in combination with PD-1/PD-L1 immune checkpoint inhibitor had achieved promising results in patients with hepatocellular carcinoma (HCC). However, a portion of patients experienced drug-resistant tumor progression and/or severe adverse events associated with TKIs during the course of treatment, resulting in unfavorable disease control and poorer overall survival. Therefore, a better medication strategy is urgently needed in aim to improve the prognosis of these patients who experienced discontinuing medication of TKIs. Methods: We reviewed the medical data of 23 HCC patients with disease progression after received sorafenib or lenvatinib combined with PD-1 antibodies from Jan Feb 2020 to Sep 2021 at the Fifth Medical Center of PLA General Hospital in China. These patients had switched to regorafenib PO for 3 weeks on/1 week off combined with primary PD-1 antibodies after experienced tumor progression and/or severe adverse events with respect to sorafenib or Lenvatinib. All patients were followed up regularly. Changes of tumor lesions, survival data and adverse events (AEs) were detailed recorded after switched. All AEs were evaluated according to the CTCAE v5. Results: Initially, 20 (87.0%) patients were treated with lenvatinib and 3 (13.0%) patients were treated with sorafenib before switched to regorafenib. Of all patients, tumor progression caused 15 (65.2%) switching and severe AEs caused 8 (34.8%) switching, and the initial daily dose of regorafenib were 80mg (95.6%) and 40 mg (4.4%), respectively. Before switched to regorafenib, the most common mild AEs were hypertension, hypothyroidism and granulocytopenia, and the most common severe AEs were rash, hepatitis, and lung infections. In contrast, the most common AEs was mild hoarseness after switched to regorafenib. During the follow-up, 12 (52.2%) patients died, 3 (13.0%) patients lost and 8 (34.8%) patients sustained survival. The overall median survival time (MST) was 22.47 months [95% confidence interval (CI): 2.98 months to 41.96 months], the MST after switched to regorafenib was 10.53 months (95% CI: 0.257 months to 20.81 months). Of note, size of tumor lesion decreased in 7 (30.4%) patients and increased in 3 (13.0%) patients, and the other 13 (56.6%) patients could not be evaluated due to incomplete data after switching to regorafenib. Conclusions: For patients who are resistant to other TKIs, switching to regorafenib showed good efficacy and manageable safety. Therefore, this treatment protocol can be considered as a potential treatment for patients without clinical benefits after first or second-line combination therapy.

80P Efficacy, FDA approval, innovativeness, clinical evidence, and price of breast, ovarian, endometrial, and cervical cancer drugs

This study analyzes the innovativeness, clinical evidence, and efficacy of new drug indications with US Food and Drug Administration (FDA) approval for breast, ovarian, endometrial, and cervical cancer. We identified 26 drugs with FDA approval in 55 gynecological cancer indications from 2000 to 2021. For each indication, we collected drug, indication, and clinical trial characteristics from FDA labels. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk (RR) for tumor response were meta-analyzed. Monthly treatment costs were calculated for US patients covered under Medicare & Medicaid. Of 55 indications, 36 received approval for breast, 12 for ovarian, 3 for endometrial, and 4 for ovarian cancer. Drugs acted via a targeted (84%), immune-regulating (13%), and cytotoxic (4%) mechanism of action. Approval was granted to 34 (62%) small-molecules, 16 (29%) antibodies, and 5 (9.1%) antibody-drug conjugates. Indications were predominantly first-or second-line (82%) combination therapies (62%) with a biomarker (84%). Indications frequently received the orphan (24%), fast track (20%), accelerated approval (27%), priority review (82%), and breakthrough therapy (40%) designation. Approval was mostly supported by double-blind (51%) phase 3 (75%) randomized-controlled (82%) trials enrolling a median of 521 patients (IQR: 302-724) for 3.8 years (IQR: 2.5-5.2). On average, new drugs HRs were 0.79 for OS (95%CI: 0.75-0.82) and 0.55 for PFS (95%CI: 0.50-0.60), whereas tumor response was 1.48 (95%CI: 1.37-1.60). Novel drugs increased patient survival by a median of 3.20 months for OS (IQR, 2.0-4.90 months) and 4.75 months for PFS (IQR, 2.40-7.10 months). Greater OS benefits were observed for drugs with a biomarker (HR: 0.76 vs. 0.84, p=.034). In 2022, Gynecological cancer drugs cost an average of $13,053.30 per month. Over the past 22 years, the approval of innovative and effective drugs transformed the landscape of gynecological cancer treatments. Especially biomarker-guided targeted therapies resulted in substantial improvements in OS and PFS. However, rising drug prices pose a challenge to healthcare systems and patient access.

Current status and prospects of anti-angiogenic small-molecule tyrosine kinase inhibitors in the therapy of soft tissue sarcoma

Chemotherapy is the main systemic treatment for patients with advanced soft tissue sarcoma, and immunotherapy is only effective for some special subtypes. Anti-angiogenic small molecule tyrosine kinase inhibitors represented by pazopanib and anlotinib are the main drugs of targeted therapy. They have been clearly recommended as the second-line treatment of non-specific soft tissue sarcoma in guidelines. In recent years, in addition to second-line monotherapy in patients with advanced sarcoma, some studies have been carried out in second-line combination therapy, maintenance therapy, first-line therapy and neoadjuvant therapy. This article briefly reviews the application status and prospect of anti-angiogenic small molecule tyrosine kinase inhibitors in advanced soft tissue sarcoma.

Interpatient Heterogeneity in Drug Response and Protein Biomarker Expression of Recurrent Ovarian Cancer.

Simple SummaryRecurrent ovarian-cancer patients face low 5-year survival rates despite chemotherapy. Oncologists may choose from a variety of guideline-recommended second-line therapeutic options without knowing which one works best. Thus, therapy alterations and adjustments are often required. We analyzed the response that 30 tumor lesions had to certain treatments in our patient-derived ovarian-cancer spheroid model. In addition, we characterized samples by immunohistochemical staining for new druggable molecular targets. Our results might help in tailoring future therapies for individual patients with recurrent ovarian cancer.Recurrent ovarian-cancer patients face low 5-year survival rates despite chemotherapy. A variety of guideline-recommended second-line therapies are available, but they frequently result in trial-and-error treatment. Alterations and adjustments are common in the treatment of recurrent ovarian cancer. The drug response of 30 lesions obtained from 22 relapsed ovarian cancer patients to different chemotherapeutic and molecular agents was analyzed with the patient-derived ovarian-cancer spheroid model. The profile of druggable biomarkers was immunohistochemically assessed. The second-line combination therapy of carboplatin with gemcitabine was significantly superior to the combination of carboplatin with PEGylated liposomal doxorubicin (p < 0.0001) or paclitaxel (p = 0.0007). Except for treosulfan, all nonplatinum treatments tested showed a lesser effect on tumor spheroids compared to that of platinum-based therapies. Treosulfan showed the highest efficacy of all nonplatinum agents, with significant advantage over vinorelbine (p < 0.0001) and topotecan (p < 0.0001), the next best agents. The comparative testing of a variety of treatment options in the ovarian-cancer spheroid model resulted in the identification of more effective regimens for 30% of patients compared to guideline-recommended therapies. Recurrent cancers obtained from different patients revealed profound interpatient heterogeneity in the expression pattern of druggable protein biomarkers. In contrast, different lesions obtained from the same patient revealed a similar drug response and biomarker expression profile. Biological heterogeneity observed in recurrent ovarian cancers might explain the strong differences in the clinical drug response of these patients. Preclinical drug testing and biomarker profiling in the ovarian-cancer spheroid model might help in optimizing treatment management for individual patients.

Nivolumab plus ipilimumab in second-line combination therapy for older patients with esophageal squamous cell cancer (AIO-STO-0117 trial).

303 Background: Overall survival of patients with advanced and refractory esophageal squamous cell carcinoma (ESCC) is poor. Most patients are 65 years or older, present with advanced and metastatic disease and suffer from extensive co-morbidity and decreased functionality. While approved therapies beyond first-line therapy have not been available for decades, just recently treatment with PD-1 antibodies has shown to improve progression-free and overall survival in this patient cohort. Thus, we assessed the combination of nivolumab and ipilimumab in this vulnerable and older patient population. Methods: In this multi-center, open-label phase II trial older patients with ESCC with progression or recurrence of disease following first-line therapy were treated with nivolumab and ipilimumab. Patients had to pass a brief geriatric assessment using the G8 screening tool in combination with the Deficit Accumulation Frailty Index (DAFI). A safety run–in phase was initiated with nivolumab (240mg fixed dose Q2W). Following a safety assessment, patients then went on to receive the combination therapy of nivolumab/ipilimumab (nivolumab 240 mg fixed dose Q2W; ipilimumab 1 mg/kg Q6W), in case safety was critical patients were allowed to continue with nivolumab monotherapy. The primary outcome was overall survival. Progression-free survival, quality of life and adverse events were also assessed. Results: In total 66 evaluable patients (16 female, 50 male) with ESCC were enrolled in this trial after successful geriatric assessment, median age was 70.5 years (range 55-84 years). 44 patients were treated with the combination therapy of nivolumab and ipilimumab, 22 patients with nivolumab only. The primary endpoint was met with a median OS of 7.2 months (95% CI, 5.7 to 12.4 months) (p &lt; 0.006; versus historical control treated with standard chemotherapy). Median PFS was 2.7 months (95% CI, 2.5 to 2.9 months). ORR was 18.2% (95% CI, 9.8 to 29.6), all cases were partial responses. Grade 3 or more treatment related adverse events were observed in ̃25% of patients. Conclusions: The combination therapy of nivolumab and ipilimumab demonstrates improved overall survival and sustained confirmed responses in the second line therapy of older European patients with ESCC. Geriatric assessment is feasible in the setting of a prospective immune therapy trial. Overall, the RAMONA trial confirmed efficacy and safety of combination checkpoint inhibitor therapy in G8 prescreened older patients with ESCC in Europe beyond first line therapy. Clinical trial information: NCT03416244.

Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib.

Simple SummaryThe combination of atezolizumab and bevacizumab has changed the therapeutic algorithm of advanced hepatocellular carcinomas. Therefore, the place of tyrosine kinase inhibitors, and among them, lenvatinib, which exhibits promising antitumour activity compared to other TKIs, needs to be redefined. Lenvatinib is still an option in case of contra-indication of immunotherapy or anti-vascular endothelial growth factor (anti-VEGF), but its place can also be discussed in second-line treatment. Otherwise, emerging strategies are currently being studied to assess the efficacy of the combination of lenvatinib with immunotherapy or loco-regional treatment for advanced HCC, as well as the efficacy of lenvatinib alone or in combination at earlier stages of the disease. The aim of this review was to define potential indications for lenvatinib treatment in different clinical situations of hepatocellular carcinoma.The systemic treatment of hepatocellular carcinoma is changing rapidly. Three main classes of treatment are now available. Historically, multi-targeted tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib as first-line; regorafenib and cabozantinib as second-line) were the first to show an improvement in overall survival (OS). Anti-vascular endothelial growth factor (anti-VEGF) antibodies can be used in first-line (bevacizumab) or second-line (ramucirumab) combination therapy. More recently, immuno-oncology (IO) has profoundly changed therapeutic algorithms, and the combination of atezolizumab-bevacizumab is now the first-line standard of care. Therefore, the place of TKIs needs to be redefined. The objective of this review was to define the place of TKIs in the therapeutic algorithm at the time of IO treatment in first-line therapy, with a special focus on lenvatinib that exhibits one of the higher anti-tumoral activity among TKI in HCC. We will discuss the place of lenvatinib in first line (especially if there is a contra-indication to IO) but also after failure of atezolizumab and bevacizumab. New opportunities for lenvatinib will also be presented, including the use at an earlier stage of the disease and combination with IOs.

Abstract 1002: A bi-steric mTORC1 inhibitor that selectively reactivates 4EBP1 and induces regression of MYC-driven hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) accounts for ~90% of all liver cancers and is the third leading cause of cancer deaths in the world. HCC patients have a 5-year survival rate of 31%. Current treatments for HCC are scarce and have limited efficacy. These treatments include first-line therapy Sorafenib and second-line combination therapy nivolumab (anti-PD-1) with ipilimumab (anti-CTLA-4). The former therapy increased survival by less than 3 months and the latter increased survival from 37% to 68%. However, patient responses are variable and limited. Thus, there is a need to identify new therapies for HCC with sustained and efficacious therapeutic effects. Revolution Medicines has developed a class of selective mTORC1 inhibitors, termed ‘bi-steric', which comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. RMC-5552 is the first clinical candidate of this class and clinical testing is planned in 2021. Bi-steric mTORC1 inhibitors exhibit potent and selective (&amp;gt;10-fold) inhibition of mTORC1 over mTORC2 and durably suppress p-S6K and p-4EBP1. Several lines of evidence suggest that inhibition of the mTORC1 pathway may result in synthetic lethality of MYC-driven HCC. Thus, we hypothesize that MYC-driven HCC tumors are sensitive to mTORC1 inhibition and p-4EBP1 suppression (4EBP1 reactivation). To test this hypothesis, we first evaluated the short-term in vivo effect of two representative bi-steric tool compounds, RM-001 and RM-006 (also known as RMC-6272) in the LAP-tTA/TRE-MYC mouse model of MYC-driven HCC. We compared their anti-tumor activity to first-line HCC therapy Sorafenib. Our results show that a single dose of RM-006 induced HCC regression in 80% of mice while RM-001 reduced HCC growth in 68% of mice and Sorafenib reduced tumor growth in 50% of mice. Mechanistically, we found that RM-006 potently and durably inhibits the phosphorylation of mTORC1 downstream effectors 4EBP1 and S6 (a direct substrate of the mTORC1 substrate S6K), and decreased protein expression levels of MYC. Our results show for the first time that inhibition of mTORC1 with concomitant suppression of p-4EBP1 drove regression in MYC-driven HCC tumors, and the significant anti-tumor activity of RM-006 may result from sustained reduction of MYC protein levels due to reduced protein translation upon 4EBP1 reactivation. Future directions will aim at defining whether RM-006 affects global MYC-regulated cell-intrinsic and host immune pathways. These preclinical data highlight a potential therapeutic opportunity for the investigational bi-steric mTORC1 inhibitor RMC-5552 in combination with immune checkpoint inhibitors to overcome MYC-mediated immune suppression. Under this potential therapeutic paradigm HCC patient survival may be extended via a dual mechanism that reduces MYC levels via 4EBP1 reactivation and that rescues anti-tumor immune surveillance. Citation Format: Wadie D. Mahauad-Fernandez, Yu C. Yang, Ian Lai, Jangho Park, James W. Evans, Mallika Singh, Jacqueline A. Smith, Dean W. Felsher. A bi-steric mTORC1 inhibitor that selectively reactivates 4EBP1 and induces regression of MYC-driven hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1002.

Associations between second-line glucose-lowering combination therapies with metformin and HbA1c, body weight, quality of life, hypoglycaemic events and glucose-lowering treatment intensification: The DISCOVER study.

To explore the effects of second-line combination therapies with metformin on body weight, HbA1c and health-related quality of life, as well as the risks of hypoglycaemia and further treatment intensification in the DISCOVER study, a 3-year, prospective, global observational study of patients with type 2 diabetes initiating second-line glucose-lowering therapy. Adjusted changes from baseline in weight, HbA1c and 36-item Short Form Health Survey version 2 (SF-36v2) summary scores at 6, 12, 24 and 36 months were assessed using linear mixed models. Risk of hypoglycaemia and further intensification were assessed using interval censored analyses. At baseline, 7613 patients received metformin in combination with a sulphonylurea (SU; 40.9%), a dipeptidyl peptidase-4 (DPP-4) inhibitor (48.3%), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor (8.3%) or a glucagon-like peptide-1 (GLP-1) receptor agonist (2.4%). After 36 months, all combinations showed similar reductions in HbA1c (0.8%-1.0%), however, metformin plus a DPP-4 inhibitor, an SGLT-2 inhibitor or a GLP-1 receptor agonist was associated with greater weight loss (1.9, 2.9 and 5.0kg, respectively) than metformin plus an SU (1.3kg, P < .0001). Proportions of further treatment intensification were similar across combinations (19.9%-26.2%). Patients prescribed metformin plus an SU more often reported one or more hypoglycaemic events (11.9%) than other combinations (3.9%-6.4%, P < .0001). SF-36v2 summary scores were typically lowest among patients prescribed metformin and an SU. Combinations of metformin with an SU were associated with the lowest weight reduction, highest risk of hypoglycaemia and lower SF-36v2 scores.

1590-P: Effects of Second-Line Metformin Combination Therapies on Weight, HbA1c, and Risk of Hypoglycemia over 3 Years: The DISCOVER Study

Background: We used DISCOVER, a 3-year observational study of people with T2D, to assess the effects of second-line metformin combination therapies on weight, HbA1c level and risk of hypoglycemia. Methods: Adjusted changes from baseline in weight and HbA1c level at 6, 12, 24 and 36 months were assessed using linear mixed models. An interval censored analysis was used to assess the risk of hypoglycemia. Results: At baseline, 7613 patients from 37 countries received second-line therapy with metformin and a dipeptidyl peptidase-4 inhibitor (DPP-4i; 48.3%), a glucagon-like peptide-1 receptor agonist (GLP-1 RA; 2.4%), a sodium-glucose co-transporter 2 inhibitor (SGLT2i; 8.3%) or a sulfonylurea (SU; 40.9%). When used in combination with metformin, GLP-1 RAs, SGLT2is and DPP-4is were associated with greater weight loss than SUs at all time points (Figure). Beyond 12 months, changes in HbA1c from baseline were similar for all combinations. Patients prescribed metformin and an SU had a greater occurrence of hypoglycemia over 3 years (11.9%) compared with the other combinations (3.9-6.4%). Conclusions: A high proportion of patients received metformin and a DPP-4i or an SU as a second-line therapy. All combinations showed a similar reduction in HbA1c. However, combinations of metformin and an SU were associated with the highest risk of hypoglycemia and the lowest weight reduction. Disclosure K. Khunti: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp &amp; Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Board Member; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp &amp; Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier. Speaker’s Bureau; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp &amp; Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. B. Charbonnel: Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; AstraZeneca. A. Cooper: Employee; Self; AstraZeneca. M.B. Gomes: None. L. Ji: None. P. Leigh: Employee; Self; AstraZeneca. Employee; Spouse/Partner; Merck Sharp &amp; Dohme Corp. A. Nicolucci: Consultant; Self; AstraZeneca. W. Rathmann: Advisory Panel; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Research Support; Self; Novo Nordisk Inc. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. M.V. Shestakova: None. A. Siddiqui: None. F. Tang: Research Support; Self; AstraZeneca. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. H. Chen: None. Funding AstraZeneca

Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer

ObjectivesEfficacy and safety of necitumumab when combined with pembrolizumab was assessed in patients with Stage IV non-small cell lung cancer (NSCLC) of squamous and nonsquamous histology, who had progressed after treatment with a platinum-based doublet. Materials and methodsThis single-arm, multicenter, phase Ib study had a dose-finding phase, in which escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W, and expansion cohorts. Patients were treated until progressive disease (PD), toxicity requiring cessation, protocol noncompliance, or withdrawal of consent. Efficacy was evaluated by overall response rate (ORR). ResultsIn 64 treated patients (32 patients [50 %] were programmed death-ligand 1 [PD-L1] negative), confirmed ORR was 23.4 % (95 % confidence interval [CI] 13.8 %–35.7 %). Two patients (3.1 %) had complete response (CR), 13 patients (20.3 %) had partial response (PR), 26 patients (40.6 %) had stable disease, 17 patients (26.6 %) had PD, and 6 patients (9.4 %) were not evaluable. Regardless of histology or PD-L1 status, median PFS (mPFS) was 4.1 months (95 % CI 2.4–6.9 months) and OS at 6 months was 74.7 % (61.5%–83.9%). Confirmed disease control rate was 64.1 % (95 % CI 51.5–75.7). Patients with programmed death-ligand 1 (PD-L1) ≥1% had numerically improved ORR and median progression-free survival when compared with patients with PD-L1 negative cancer. No dose-limiting toxicities were recorded and the combination of necitumumab 800 mg with pembrolizumab 200 mg was considered tolerable. ConclusionResults suggest modest benefits of second-line necitumumab and pembrolizumab combination therapy in patients with Stage IV NSCLC. Safety profiles were consistent with class effects typical of epidermal growth factor receptor inhibitors and immunotherapies with no additive toxicities.

Small molecule inhibition of lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) alone and in combination in Ewing sarcoma cell lines.

Ewing Sarcoma (ES) is characterized by recurrent translocations between EWSR1 and members of the ETS family of transcription factors. The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While inhibitors of both histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1) subunits of the NuRD complex demonstrate single agent activity in preclinical models, combination strategies have not been investigated. We selected 7 clinically utilized chemotherapy agents, or active metabolites thereof, for experimentation: doxorubicin, cyclophosphamide, vincristine, etoposide and irinotecan as well as the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509. All agents were tested at clinically achievable concentrations in 4 ES cell lines. All possible 2 drug combinations were then tested for potential synergy. Order of addition of second-line conventional combination therapy agents was tested with the addition of SP2509. In two drug experiments, synergy was observed with several combinations, including when SP2509 was paired with topoisomerase inhibitors or romidepsin. Addition of SP2509 after treatment with second-line combination therapy agents enhanced treatment effect. Our findings suggest promising combination treatment strategies that utilize epigenetic agents in ES.

The Role of CDK4/6 Inhibitors in Breast Cancer.

Oral inhibitors of CDK4/6 have been shown to increase response rates and prolong disease control when combined with endocrine therapy in hormone-responsive (HR+) HER2-negative advanced breast cancer. Palbociclib, ribociclib and abemaciclib are all approved in combination with non-steroidal aromatase inhibitors in first-line therapy for post-menopausal women, with a 40-45% improvement in progression-free survival seen with the addition of any of these CDK4/6 inhibitors. Additional approved indications, including first- and second-line combination therapy for pre-menopausal women, combination with fulvestrant and use as monotherapy, vary with each agent and are reviewed fully in the subsequent texts. These agents also differ in their toxicity profiles and monitoring requirements, and prescribers should be aware of the individual requirements for each agent. Current clinical trials are investigating the expanded use of these agents in other breast cancer subtypes, such as HER2-positive and triple-negative breast cancer, as well as in the adjuvant and neoadjuvant treatments of early breast cancer. Resistance to CDK4/6 inhibition can occur through multiple mechanisms. Rational combinations with other therapies, such as PI3K inhibitors, HER2-directed therapies and immunotherapy, are being explored.

A systematic review of second-line controller combination therapy options for the management of asthma

First-line controller combination therapy for the management of asthma is a low-dose inhaled corticosteroid (LD-ICS) + a long-acting β-agonist (LABA), and second-line options are a LD-ICS + a leukotriene receptor antagonist (LTRA), LD-ICS + sustained-release theophylline (SR-T), and a medium-/high-dose ICS (HD-ICS). The purpose of this review is to assess the various second-line combination therapy options for the management of asthma. We systematically reviewed randomized controlled trials (RCTs) in adult patients with asthma, extracting and synthesizing data from eligible articles on study design, duration, randomization, blinding, withdrawal, run-in period, type of analysis, and names and doses of drugs. The primary outcome measure was change in percentage predicted forced expiratory volume in 1 second (% FEV1), and the secondary outcome was frequency of asthma exacerbations. Nine RCTs (three blinded and six open-label trials) were selected for the review. One study investigated LD-ICS + LTRA compared with HD-ICS, two studies investigated LD-ICS + SR-T compared with HD-ICS, and five studies investigated LD-ICS + LTRA compared with LD-ICS + SR-T. Only one of the nine RCTs compared all treatment options as mentioned in Global Initiative for Asthma (GINA) guidelines. Seven RCTs examined the primary outcome (change in % FEV1). No significant difference was observed (four RCTs; % FEV1) between LD-ICS + LTRA and LD-ICS + SR-T, but one RCT reported better clinical improvement with LD-ICS + LTRA than with LD-ICS + SR-T (% FEV1). Likewise, similar clinical effects (two RCTs) were observed between LD-ICS + SR-T and HD-ICS, one based on % FEV1 and the other based on exacerbation improvement. One RCT concluded that LD-ICS + LTRA was an effective and well-tolerated alternative to HD-ICS (exacerbation improvement). LD-ICS + LTRA resulted in greater clinical improvement when comparing all second-line treatment options in one RCT (% FEV1 and exacerbation improvement). All nine studies had a high risk of bias according to a modified Cochrane risk-of-bias tool for quality assessment of RCTs. Existing RCTs provide low-quality evidence of the superiority of second-line controller options for asthma management. This systematic review recommends that clinically relevant, stringently designed RCTs with appropriate sample sizes and durations are conducted to identify the best second-line controller option.

Treatment Patterns by EGFR Mutation Status in Non-Small Cell Lung Cancer Patients in the USA: A Retrospective Database Analysis.

Targeted therapies, including tyrosine kinase inhibitors (TKIs) that target the sensitizing epidermal growth factor receptor (EGFR) gene are recommended for patients with non-small cell lung cancer (NSCLC). Most patients with NSCLC who test positive for the EGFR mutation and receive TKIs develop resistance to these drugs. Questions remain regarding which treatment sequence is optimal for patients with EGFR-mutant NSCLC, and few studies have evaluated patterns of TKI treatment use in NSCLC, irrespective of EGFR mutation status, in a real-world setting. This population-based study aimed to evaluate treatment patterns at a national level in the USA. This retrospective observational study used data from the US Oncology Network's iKnowMed database. Patients with advanced NSCLC who initiated first-line therapy with erlotinib and/or intravenous chemotherapy between January 1, 2012 and June 30, 2015 and met all other study criteria were included. Descriptive analyses assessed demographic and clinical characteristics and treatment patterns among the overall study cohort, as well as for specific erlotinib treatment subgroups, stratified by EGFR status. Among the 3108 patients identified, 18.5% were EGFR positive, 49.8% were EGFR negative, and 31.7% were EGFR documented unknown. For the overall cohort, 18.4% received first-line erlotinib monotherapy, fewer than 1% received first-line combination therapy (erlotinib plus chemotherapy), 4.7% received second-line erlotinib monotherapy, and 3.3% received second-line combination therapy. First-line erlotinib monotherapy was used in 77.8% of all EGFR positive patients. Almost two-thirds of the overall cohort were not observed to have advanced to second-line therapy. As treatment options evolve, this study provides real-world treatment patterns that suggest concordance with NCCN guidelines and confirm the remaining need to understand sequencing of therapies and related outcomes. Eli Lilly and Company.

Overall survival and progression-free survival with endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: review.

We reviewed randomized phase II/III trials comparing first- or second-line endocrine therapy as monotherapy or in combination with targeted therapies for treatment of postmenopausal patients with hormone receptor-positive advanced breast cancer. First-line was defined as treatment for endocrine therapy-naïve advanced breast cancer or advanced disease treated with endocrine therapy in the adjuvant/neoadjuvant setting. Second-line was defined as endocrine therapy for advanced breast cancer following disease progression on endocrine therapy for advanced disease. Publications reporting progression-free survival (PFS)/time to progression (TTP) or overall survival (OS) for FDA-approved agents anastrozole, exemestane, fulvestrant 250 mg, fulvestrant 500 mg, letrozole (0.5 and 2.5 mg), megestrol acetate, and tamoxifen as monotherapy, or in combination with everolimus, palbociclib or ribociclib, were assessed. First-line monotherapy with anastrozole, fulvestrant 500 mg or letrozole 2.5 mg significantly improved PFS/TTP versus comparator endocrine therapy; however, only fulvestrant 500 mg improved OS. For endocrine therapy in combination with targeted therapies, palbociclib plus letrozole 2.5 mg, and ribociclib plus letrozole 2.5 mg significantly improved PFS versus letrozole 2.5 mg alone first-line. For second-line monotherapies, exemestane, fulvestrant 500 mg and letrozole 2.5 mg significantly improved PFS/TTP versus comparator endocrine therapy; only fulvestrant 500 mg and letrozole 2.5 mg improved OS. For second-line combination therapies, everolimus plus exemestane, and palbociclib plus fulvestrant 500 mg, improved PFS versus endocrine therapy alone. In both first- and second-line settings, aromatase inhibitors demonstrated PFS benefits versus comparator endocrine therapy; however, fulvestrant 500 mg was the only endocrine therapy included in our review to show both PFS and OS advantages compared with other endocrine therapies. Targeted agents in combination with endocrine therapy have demonstrated PFS improvements both first- and second-line; OS data are awaited.

Resminostat and sorafenib combination therapy for advanced hepatocellular carcinoma in patients previously untreated with systemic chemotherapy.

252 Background: Resminostat is an oral hydroxamate-type inhibitor of class I, IIB, and IV histone deacetylases. A European Phase II study of second-line combination therapy with resminostat and sorafenib for hepatocellular carcinoma (HCC) in patients (pts) revealed a promising improvement in overall survival (OS). Here we report the findings on safety and efficacy of an Asian Phase I/II study on first-line combination therapy with sorafenib and resminostat in HCC pts. Methods: Pts with advanced or metastatic HCC considered Child-Pugh A and ECOG 0/1 were enrolled in Japan and Korea. Sorafenib was administered at 400 mg (bid) in both Phase I and II. Resminostat was administered on days 1 to 5 every 14 days. In Phase I, the dose of resminostat was escalated from 400 mg/day (DL1) to 600 mg/day (DL2). In Phase II, pts were randomly assigned to sorafenib monotherapy or sorafenib/resminostat combination therapy at a ratio of 1:1. The primary endpoint was time to progression (TTP). Tumor response was assessed according to RECIST version 1.1 every 6 weeks. Results: A total of 9 pts were enrolled in Phase I (DL1, 3 pts; DL2, 6 pts). Higher incidences of G3-4 toxicities, including one DLT (G4 thrombocytopenia), were observed at DL2. Therefore, DL1 was determined as the recommended dose for Phase II. A total of 170 pts were enrolled in Phase II. The median TTP was 2.8 months in the combination and control arm, respectively (HR: 0.984). No significant difference was observed in the median OS. Retrospective analysis revealed favorable results for the combination option in certain subgroups: for example, HBV+ (TTP: HR, 0.630; OS: HR, 0.846); no prior therapy (TTP: HR, 0.629; OS: HR, 0.590); and platelet count &gt; = 151.000 (TTP: HR, 0.646; OS: HR, 0.509). Conclusions: Although the primary endpoint was not reached in this Phase II all-comer HCC study, the results of the subgroup analysis suggest a population-specific effect for the combination therapy, especially in one which is HBV+. This warrants the further development of this combination as first-line therapy in a well-defined subset of pts with advanced HCC. Clinical trial information: NCT02400788.

Adding to the targeted therapy toolbox: BRAF and MEK inhibition in the treatment of BRAF V600E metastatic non-small cell lung cancer

Mutations in the BRAF oncogene are found in approximately 2–4% of non-small cell lung cancer (NSCLC). The most common mutation is associated with substitution of glutamic acid for valine at position 600 (V600E) within the BRAF kinase. Targeted therapy against the BRAF V600E mutant kinase has shown efficacy in other solid tumors including melanoma. In this setting, dual inhibition of both BRAF and the downstream mitogen-activated protein kinase kinase (MEK) improves survival compared to BRAF inhibition alone. Planchard et al . published two recent phase 2 trials evaluating the clinical activity and safety profile of second-line BRAF monotherapy (dabrafenib) and BRAF-MEK combination therapy (dabrafenib plus trametinib), respectively, in patients with stage IV BRAF V600E mutant NSCLC. Here, we review the pertinent findings from each of these studies, discuss their significance in context of the current literature, and consider their potential impact on the management of patients with NSCLC in the clinical setting.