Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-EGFR response.

BackgroundThis retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval.MethodsEighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival.ResultsRetreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156).ConclusionOur data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed

Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours

BackgroundThe phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K-AKT-mTOR) signalling pathway is aberrantly activated in several cancers. Notch signalling maintains cell proliferation, growth and metabolism in part by driving the PI3K pathway. Combining the mTOR inhibitor ridaforolimus with the Notch inhibitor MK-0752 may increase blockade of the PI3K pathway.MethodsThis phase I dose-escalation study (NCT01295632) aimed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of combination oral ridaforolimus (rising doses starting at 20 mg, 5 days/week) and oral MK-0752 (1800 mg once weekly) in patients with solid tumours. No intrapatient dose escalation was permitted.ResultsTwenty eight patients were treated on study. Ridaforolimus doses were escalated from 20 to 30 mg/day. Among 14 evaluable patients receiving ridaforolimus 20 mg, one DLT (grade 2 stomatitis, second episode) was reported. Among eight evaluable patients receiving ridaforolimus 30 mg, three DLTs were reported (one each grade 3 stomatitis, grade 3 diarrhoea, and grade 3 asthenia). The MTD was 20 mg daily ridaforolimus 5 days/week+1800 mg weekly MK-0752. The most common drug-related adverse events included stomatitis, diarrhoea, decreased appetite, hyperglycaemia, thrombocytopenia, asthenia and rash. Two of 15 (13%) patients with head and neck squamous cell carcinoma (HNSCC) had responses: one with complete response and one with partial response. In addition, one patient experienced stable disease ⩾6 months.ConclusionsCombined ridaforolimus and MK-0752 showed activity in HNSCC. However, a high number of adverse events were reported at the MTD, which would require careful management during future clinical development

Abstract P5-20-06: Phase 1 dose escalation with ZW25, a HER2-targeted bispecific antibody, in patients (pts) with HER2-high breast cancer (BC)

Abstract Background: ZW25, a novel IgG1-like bispecific antibody, targets the same domains of HER2 as trastuzumab (T) and pertuzumab (P). In preclinical studies, ZW25 demonstrated increased tumor cell binding density and internalization relative to T and activity in T-resistant cell lines as well as models of HER2-low to high cancers. Initial dose escalation data demonstrated that once-weekly ZW25 was well tolerated at all doses evaluated and associated with single-agent anti-tumor activity in pts with heavily pre-treated (tx) HER2-expressing cancers. Methods: 3+3 dose escalation of ZW25 given weekly (QW; 5, 10 or 15 mg/kg) or biweekly (Q2W; 20 mg/kg) in 4-week cycles. Eligibility included HER2 IHC 1, 2 or 3+ or FISH+ BC, progression after T, P and T-DM1, and measurable or non-measureable disease per RECIST 1.1. Active brain metastases were excluded. Baseline brain MRI was performed in QW cohorts only if pts had prior history (hx) of CNS mets, and in all Q2W pts regardless of hx. Assessments included AEs, LVEF, immunogenicity, PK and tumor response every 2 cycles. Results: 8 pts with HER2-high BC were tx with ZW25 QW at 5 (n=2), 10 (n=2) or 15 mg/kg (n=4); 20 mg/kg Q2W is enrolling. 5/8 pts were HR+; 7 had measurable disease, 6 visceral disease, and 3 stable CNS disease. Median years since initial dx was 6 (range 5-16). Prior tx included T and T-DM1 (n=8); P (n= 6), and lapatinib (n=5). Median number of prior HER2-targeted regimens for metastatic disease was 6 (range 3-7) and non-hormonal HER2 regimens was 5 (range 3-7). ZW25 was well tolerated with no DLTs or decreases in cardiac function. Most common related AEs (all Gr 1 or 2) were diarrhea (n=4), infusion reaction (IR) (n=4) and vomiting (n=3). All IRs occurred only with 1st dose. There were no treatment-related SAEs. Related Gr 3 AEs (hypophosphatemia, fatigue and arthralgia) were reported in 1 pt (10 mg/kg). At data cut-off, pts had received 2-10 cycles of treatment, with 3 pts active. Best overall response was 2 PR (10 mg/kg), 3 SD (1 at 5 mg/kg, 2 at 15 mg/kg), and 3 PD (1 at 5 mg/kg, 2 at 15 mg/kg) for a disease control rate of 63%. Decreases in target lesions were seen in 6/7 patients with at least one tumor re-staging. One pt with SD (5 mg/kg; active on study) had an 8% decrease after C2, and 29% decrease after C8. One PR pt with prior hx of brain mets had a 33% decrease after C2 and 44% decrease after C4, although was found to have new leptomeningeal disease (LMD) at that time. Two additional pts with systemic SD (15 mg/kg; no prior hx of CNS mets) were also considered to have PD due to symptomatic brain mets. One of these pts remains on study after receiving stereotactic radiotherapy. Conclusions: ZW25 was associated with single-agent anti-tumor activity and systemic disease control in HER2-high BC pts after a median of 6 prior HER2-targeted regimens for metastatic disease. Systemic disease control was maintained despite PD due to brain mets or LMD. The presence of CNS disease in an unscreened population is consistent with the biology of late-stage HER2-high BC. The activity and tolerability of ZW25 support further evaluation as a single agent and in combination including with CNS-directed therapies in early and late lines of treatment for HER2-expressing BC. Citation Format: Hamilton E, Meric-Bernstam F, Infante J, Murthy R, Patnaik A, Piha-Paul SA, Tolcher A, Hausman D, Royer N, Beeram M. Phase 1 dose escalation with ZW25, a HER2-targeted bispecific antibody, in patients (pts) with HER2-high breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-06.</jats:p

PD09-01: Target-Based Therapeutic Matching in Early-Phase Clinical Trials in Patients with Advanced Breast Cancer and PIK3CA Mutations.

Abstract Background: Therapeutic matching based on underlying molecular abnormalities showed promising results in early-phase clinical trials. PIK3CA mutations may predict response to therapies with PI3K/AKT/mTOR inhibitors. Methods: Tumors from patients with breast cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Results: Of 54 patients analyzed, 15 (28%) had PIK3CA mutations. PIK3CA mutations were found in 5/9 (56%) metaplastic, 3/8 (38%) HER2−positive, 7/29 (24%) hormone receptor-positive, and 0/8 (0%) triple negative (excluding metaplastic) breast cancers (P=0.07). Of the 15 patients with PIK3CA mutations, 12 (80%) were treated in clinical trials containing a PI3K/AKT/mTOR pathway inhibitor (median age, 54; median number of prior therapies, 3). Of these 12 patients, 3 (25%, 95% CI 0.09−0.53) had stable disease for more than 6 months (SD≥6 months; n=1) or a partial response (PR; n=2). Breast cancer patients without PIK3CA mutations treated on the same protocols had a rate of SD≥6 months/PR of 8% (1/12; 95% CI 0.01−0.35, p=0.6). Of the 4 patients with a H1047R mutation treated with agents targeting the PI3K/AKT/mTOR pathway, 3 (75%) had SD≥6 months (n=1) or a PR (n=2) compared to 0 of 8 patients (0%) with other PIK3CA mutations (P=0.045). Patients with H1047R mutations had a median progression-free survival (PFS) of 8.5 months compared to 2 months in patients with other PIK3CA mutations (p=0.13). Conclusion: Heavily pretreated patients with PIK3CA-mutant advanced breast cancer had a SD≥6 months/PR rate of 25% on protocols incorporating PI3K/AKT/mTOR. Patients with mutation H1047R had significantly longer SD≥6 months/PR rate compared to those with other PIK3CA mutations. Our observations suggest that screening for PIK3CA mutations is warranted in larger numbers of patients with advanced breast cancer when treatment with PI3K/AKT/mTOR pathway inhibitors is planned. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-01.</jats:p

Abstract P4-13-11: Everolimus, letrozole and trastuzumab in estrogen receptor and HER2-positive patients with metastatic breast cancer and other solid tumors: Evaluating synergy and overcoming resistance

Abstract Background Combining anti-estrogen therapy with HER2 and mTOR inhibitors may be synergistic and overcome resistance to hormonal and anti-HER2 therapies in patients with estrogen receptor (ER)-positive and HER2 receptor amplified and/or mutant advanced cancers. Patients and Methods We evaluated the mTOR inhibitor everolimus, aromatase inhibitor letrozole and anti-HER2 antibody trastuzumab in patients with ER-positive, HER2-positive and/or mutant, solid tumors (confirmed by IHC, FISH, and/or HER2 sequencing). The primary objectives were to determine maximum tolerated dose (MTD) and toxicity and to evaluate response. Secondary objectives were to correlate activity with genomic and proteomic signatures. Next-generation sequencing (NGS) was performed either using a 50-gene panel or externally by Foundation Medicine (Cambridge, MA, USA). Results Nine of 10 patients enrolled are currently evaluable for toxicity and response including 7 patients with breast cancer, one patient with ovarian cancer, and one patient with cervical cancer. The median age was 57 years (range, 33-66 years) and the median number of prior therapies in the metastatic setting was 5 (range, 2-7). Of these nine patients, six were HER2+ (by IHC and/or FISH) and three had HER2 mutations (in the absence of HER2 overexpression or amplification). Dose Level (DL) 1 consisted of trastuzumab loading dose of 4mg/kg IV and maintenance dose of 2 mg/kg IV every 21 days, everolimus 5 mg PO daily and letrozole 2.5 mg PO daily. DL2 consisted of trastuzumab loading dose of 6mg/kg IV and maintenance dose of 4 mg/kg IV every 21 days, everolimus 5 mg PO daily and letrozole 2.5 mg PO daily. DL3 consists of trastuzumab loading dose of 6 mg/kg IV and maintenance dose of 4 mg/kg IV every 21 days, everolimus 7.5 mg PO daily and letrozole 2.5 mg PO daily. Currently patients are being enrolled in DL3 and no DLTs have been observed. Additional dose levels are planned with increased trastuzumab and everolimus to the FDA approved doses or until MTD is reached. The most common grade 1 and 2 treatment-related toxicities were fatigue (6 patients), anemia and constipation (2 patients each). No grade 3 or 4 toxicities have been reported. Median time to treatment failure (TTF) was 7.4 months (95% CI 5.2-9.6). One patient with breast cancer and a HER2 mutation experienced a partial response (PR) with a 32% decrease in measurable disease. This patient had no prior HER2-targeted therapy and previously progressed while on letrozole and while on exemestane and everolimus. Six additional patients experienced stable disease (SD) ≥ 6 months, 5 with breast cancer and 1 with cervical cancer. Of these 6 patients, 1 had a HER2 mutation and another had a PIK3CA mutation. Conclusions Combination treatment with everolimus, letrozole and trastuzumab is well tolerated and active in ER+, HER2+ and/or mutant solid tumors, including breast and cervical cancer. Clinical benefit (PR/SD≥6 months) was seen in 7 of 9 patients (78%), including patients with HER2 mutations in the absence of overexpression and/or amplification and patients with no genomic alterations in the PI3K/AKT/mTOR pathway. Enrollment is ongoing. Citation Format: Janku F, Hong DS, Atkins JT, Karp DD, Tsimberidou AM, Piha-Paul SA, Subbiah V, Naing A, Fu S, Moulder SL, Tripathy D, Meric-Bernstam F, Wheler JJ. Everolimus, letrozole and trastuzumab in estrogen receptor and HER2-positive patients with metastatic breast cancer and other solid tumors: Evaluating synergy and overcoming resistance. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-11.</jats:p

Abstract S5-07: Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028

Abstract Background: The programmed cell death 1 (PD-1) pathway is used by tumors to evade immune surveillance. Pembrolizumab is a humanized anti–PD-1 monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab has shown robust antitumor activity against several advanced malignancies, including triple-negative breast cancer. We assessed the safety and efficacy of pembrolizumab in patients with PD-L1–positive, ER+/HER2-negative advanced breast cancer. Methods: KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) is an ongoing multicohort, open-label phase 1b study evaluating the safety and efficacy of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Key eligibility criteria for this cohort include ER+ and HER2-negative tumor status defined by institutional standards, locally advanced or metastatic disease, ECOG performance status of 0 or 1, failure of or inability to receive standard therapy, and PD-L1 expression in stroma or in ≥1% of tumor cells as assessed at a central laboratory using a prototype immunohistochemistry assay with the 22C3 antibody (Merck). Pembrolizumab was administered at a dose of 10 mg/kg every 2 weeks for up to 24 months or until confirmed progression or intolerable toxicity. Response is based on RECIST v1.1 as assessed by investigator review every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary efficacy end point is overall response rate (ORR). Results: Of the 248 patients with ER+/HER2-negative breast cancer who had evaluable tumor samples screened for PD-L1 expression, 48 (19%) had PD-L1–positive tumors. Of these, 25 patients were enrolled. Median age was 53 years (range, 36-79), and 44% of patients had an ECOG performance status of 1. Patients were heavily pretreated, with 76% having received ≥3 prior lines of therapy for advanced disease, including 48.0% who received ≥5 prior lines. Analyses of ORR, duration of response, and adverse events are ongoing and will be completed by September 4, 2015. Conclusion: Data from this KEYNOTE-028 cohort will provide information on the antitumor activity and safety of pembrolizumab in patients with heavily pretreated, PD-L1–positive, ER+/HER2-negative advanced breast cancer. Citation Format: Rugo HS, Delord J-P, Im S-A, Ott PA, Piha-Paul SA, Bedard PL, Sachdev J, Le Tourneau C, van Brummelen E, Varga A, Saraf S, Pietrangelo D, Karantza V, Tan A. Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-07.</jats:p

Abstract PD5-05: Neratinib for <i>ERBB2</i> mutant, HER2 non-amplified, metastatic breast cancer: Preliminary analysis from a multicenter, open-label, multi-histology phase II basket trial

Abstract Background: Somatic ERBB2 (HER2) mutations occur in approximately 2% of patients with breast cancer and are found in a predominantly mutually exclusive manner with ERBB2 amplification. These mutations result in increased signaling and oncogenic transformation. Neratinib, a pan-ERBB irreversible tyrosine kinase inhibitor, potently inhibits growth of ERBB2 mutant tumor cell lines and xenografts. An ongoing signal-seeking phase II 'basket' study is evaluating neratinib in patients with multiple histologies harboring ERBB2 mutations (NCT01953926). Novel mutations identified in enrolled patients were characterized for biologic activity in a variety of in vitro model systems. A preliminary analysis of the HER2 non-amplified metastatic breast cancer cohort is presented. Methods: Patients with ERBB2 mutant metastatic breast cancer documented by local testing methods received single-agent oral neratinib 240 mg once daily until progression or intolerable toxicity. High-dose loperamide prophylaxis was mandatory during cycle 1. The primary endpoint was the objective response rate at 8 weeks, defined using anatomic (RECIST 1.1) and/or metabolic (PET Response Criteria) assessments. Secondary endpoints were best overall response rate, clinical benefit rate, progression-free survival, duration of response, and safety. Results: 17 patients with metastatic breast cancer were enrolled and received neratinib (13 patients are evaluable for efficacy to date). Patients had a median of 3 prior anticancer regimens. Other baseline characteristics were: median age 59 years; bone involvement 71%; visceral disease 82%. Tumor characteristics were: ductal/lobular 76%/24%; ERBB2 mutation single nucleotide variants/indels 82%/18%; HER2 amplified/non-amplified 0%/100%; hormone receptor positive/negative 82%/18%. Five patients (39%) had an objective response at 8 weeks (95% CI 14–68%). In the patients who responded, ERBB2 mutations were: 1 complete response (L755S); 4 partial responses (L755S, V777L, V777L, and L869R). The most common all-grade adverse events (in ≥15% of patients) across all cohorts (n=93) were: diarrhea (62%), fatigue (28%), nausea (36%), vomiting (30%), anemia (15%), and constipation (29%). The most common grade 3/4 adverse event was diarrhea (14%, all grade 3). Updated efficacy results, centralized genomic analyses on archival tumor samples, and in vitro characterization of novel ERBB2 mutants will be presented. Conclusions: Single-agent neratinib shows encouraging signs of clinical activity in patients with heavily pretreated, ERBB2 mutant, HER2 non-amplified metastatic breast cancer. The breast cancer cohort demonstrated sufficient activity to meet the study's pre-specified efficacy requirements according to a Simon's two-stage design, and suggests that a confirmatory trial of neratinib for targeting ERBB2 driver mutations in metastatic breast cancer is warranted. Safety was acceptable and diarrhea was manageable with loperamide prophylaxis. Citation Format: Hyman DM, Piha-Paul SA, Rodón J, Saura C, Puzanov I, Shapiro GI, Loi S, Joensuu H, Hanrahan AJ, Modi S, Lalani AS, Xu F, Garza SJ, Cutler RE, Bryce R, Meric-Bernstam F, Baselga J, Solit DB. Neratinib for ERBB2 mutant, HER2 non-amplified, metastatic breast cancer: Preliminary analysis from a multicenter, open-label, multi-histology phase II basket trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD5-05.</jats:p