Safety and tolerability of lapatinib in combination with taxanes (T) in patients with breast cancer (BC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1027-1027 ◽  
Author(s):  
J. P. Crown ◽  
H. A. Burris ◽  
S. Jones ◽  
K. M. Koch ◽  
A. Fittipaldo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Adverse Events ◽  
Safety Profile ◽  
Clinical Studies ◽  
Kinase Inhibitor ◽  
Safety Data ◽  
Systemic Exposure ◽  
Clinical Activity ◽  
Grade 3

1027 Background: Lapatinib (L) is an oral, dual ErbB1/B2 tyrosine kinase inhibitor. T are mainstay of BC treatment. The side-effects seen with T in combination with gefitinib and erlotinib include neutropenia, diarrhea and rash. Based on preclinical synergy, early clinical studies with L and paclitaxel (P) or docetaxel (D) were studied. Methods: We summarize pharmacokinetics (PK) and preliminary safety data from 192 patients. Results: PK analysis for EGF10009 (q3w), show systemic exposure was increased for both L (21%) and P (23%) at doses of 1500mg daily and 175mg/m2/q3w, respectively. PK analysis in EGF10021 , (L 1250 mg & D 75 mg/m2 with prophylactic pegfilgrastim) indicated no significant effect on systemic exposure of either agent. Toxicities across all studies include i.e., for all patients = grade 3, neutropenia (7.3%), diarrhea (18.2%), rash (3.6%). The rate of adverse events for neutropenia and rash were similar to each agent alone, however diarrhea was more common. The frequency and severity of diarrhea was increased in studies EGF10009 and EGF102580 where no proactive treatment of diarrhea was introduced, whereas in EGF105764, with proactive treatment, currently no =grade 3 diarrhea has been reported. The data show that the combination of L and P has clinical activity (>70% RR reported in EGF102580). Conclusions: T plus L combinations have a predictable and manageable safety profile and clinical activity of P plus L combination was observed. Proactive diarrhea management is essential for these combinations. Based on the PK data, no dose adjustments are required, and any dose adjustments should be toxicity-based. Ongoing clinical studies investigating the combinations of L with T, and combinations of L with T plus trastuzumab will be reported in the future. [Table: see text] No significant financial relationships to disclose.

Safety profile of avelumab in patients with advanced solid tumors: A JAVELIN pooled analysis of phase 1 and 2 data.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Karen Kelly ◽  
Jeffrey R. Infante ◽  
Matthew H. Taylor ◽  
Manish R. Patel ◽  
Michael S. Gordon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Safety Profile ◽  
Phase 1 ◽  
Safety Data ◽  
Pooled Analysis ◽  
Clinical Activity ◽  
Thyroid Disorder ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Grade 3

3059 Background: Avelumab is a fully human IgG1 anti–PD-L1 antibody with clinical activity in several tumor types. Pooled safety data from a large phase 1 trial in various tumors and a phase 2 trial in Merkel cell carcinoma (NCT01772004, NCT02155647) were analyzed to further characterize the safety profile of avelumab. Methods: Patients (pts) received avelumab 10 mg/kg 1-hour IV Q2W until progression, unacceptable toxicity, or withdrawal. Treatment-related adverse events (TRAEs) were graded by NCI CTCAE. In post hoc analyses, immune-related adverse events (irAEs) were identified via an expanded AE list and medical review, and infusion-related reaction (IRR) events were identified based on prespecified MedDRA terms, occurring within 1 day or related symptoms that resolved within 2 days of infusion. Results: In 1,738 pts analyzed (phase 1, n = 1,650; phase 2, n = 88) who received ≥1 dose of avelumab for a median of 12 weeks (range 2-138), the most common any grade TRAEs were fatigue (n = 307, 18%), IRR (n = 295, 17%), and nausea (n = 150, 9%). 177 pts (10%) had a grade ≥3 TRAE; most common were fatigue and elevated lipase (17 [1%] each). TRAEs led to discontinuation in 107 pts (6%). Four pts (0.2%) died due to a TRAE. Any grade irAEs occurred in 247 pts (14%), which were grade ≥3 in 39 pts (2%) and considered serious in 43 pts (2%). The most common any grade irAEs were thyroid disorder (n = 98, 6%) and rash (n = 90, 5%). Other irAEs (eg, colitis, hepatitis, pneumonitis, adrenal insufficiency, myositis) each occurred in < 2%. irAEs led to discontinuation in 34 pts (2%). IRR or related symptoms (eg, chills, pyrexia, hypersensitivity) occurred in 439 pts (25%), which were grade 3 in 9 pts (0.5%) and grade 4 in 3 pts (0.2%). An IRR occurred at first infusion in 79% and within first 4 doses in 99%; 63/439 pts (14%) had IRR recurrence in later cycles. IRR led to dose interruption in 152 (9%), infusion rate reduction in 124 (7%), and discontinuation in 35 pts (2%). Conclusions: This large pooled analysis confirms that avelumab has an acceptable safety profile. A minority of pts experienced a grade ≥3 TRAE or irAE and discontinuation due to TRAEs was uncommon. IRRs mostly occurred at first infusion and the rate of recurrence was low. Clinical trial information: NCT01772004, NCT02155647.

Safety of a trastuzumab biosimilar, used under routine clinical practice conditions in adult HER2+ breast cancer patients in Morocco.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13024-e13024
Author(s):  
Hassan Errihani ◽  
Narjiss Berrada ◽  
Mouna Khouchani ◽  
Abdelkader Acharki ◽  
Kamal Lahbabi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Practice ◽  
Adverse Events ◽  
Early Breast Cancer ◽  
Real World ◽  
Safety Profile ◽  
Safety Data ◽  
Routine Clinical Practice ◽  
Her2 Breast Cancer

e13024 Background: Hertraz, the first trastuzumab biosimilar was approved in Morocco in 2017. Real world data on trastuzumab biosimilars are very limited or not available. HERLife is a prospective, non-interventional phase IV study program that investigated the experience of using Hertraz, a biosimilar for trastuzumab (Herceptin), under routine clinical practice conditions in Morocco. The primary aim of this study was to confirm the acceptable safety and tolerability of Hertraz. Methods: Ninety-nine patients with HER2-positive breast cancer treated with Hertraz were enrolled from 8 public and private sector hospitals and followed up for 12 months as part of this non-interventional study. Cardiac events (LVEF) and other unexpected or serious adverse events were monitored. The study arms consisted of patients with early breast cancer (Arm 1, n=70) and metastatic breast cancer (Arm 2, n=29) whose median age was 53 years in both groups. Results: Switching from Herceptin to Hertraz was observed in 45% of 29 MBC patients and 27% of 70 EBC patients. Switching was done at a median of 4th cycle. Pertuzumab was used in combination with Hertraz in 69% and 19% of patients in the metastatic and neoadjuvant settings, respectively. Two patients had a decline in LVEF. One patient treated with Hertraz alone and one patient treated with Hertraz and pertuzumab developed a decrease in LVEF requiring a three-week treatment discontinuation of Hertraz. Treatment of Hertraz was continued after 1 skipped cycle without occurrence of new side effects. No other trastuzumab related adverse events was observed. Four patients in the metastatic group and 2 patients in the early breast cancer arm had a relapse in the 12 months of clinical follow-up. Conclusions: The management of HER2+ breast cancer in Morocco follows the international recommendations. This is the first real world safety data of Hertraz from Morocco. The 12-month follow-up treatment with Hertraz showed an acceptable cardiac safety profile. In cases where there was a switch from Herceptin to Hertraz or Hertraz combined with pertuzumab, the safety profile was similar to that previously reported in other studies.

A phase I dose-escalation study of volasertib (BI 6727) combined with nintedanib (BIBF 1120) in advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2556-2556 ◽  
Author(s):  
Filippo G. De Braud ◽  
Stefano Cascinu ◽  
Gianluca Spitaleri ◽  
Korinna Pilz ◽  
Laura Clementi ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Safety Profile ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Day Treatment ◽  
Single Agent ◽  
Safety Data ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

2556 Background: Volasertib (V) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF, and FGF receptors. Both have shown clinical activity with a manageable safety profile in patients (pts) with advanced solid tumors. This study was designed to determine the maximum tolerated dose (MTD) of V combined with N in these pts. Methods: Cohorts of 3–6 pts received V (100–450 mg IV Q3W) + oral standard dose N (200 mg BID continuously, except V infusion day). Treatment continued until clinical progression. Up to 12 pts were treated at the MTD for additional safety data. Primary endpoint was the MTD; secondary endpoints were pharmacokinetics (PK), overall safety, and preliminary efficacy. Results: 30 pts were treated (median age, 56.5 yr; ECOG PS 0/1/2, 33%/60%/7%; ≥3 prior therapies, 87%). At V doses >200 mg, 7 pts experienced 13 dose-limiting toxicities (DLTs) during cycle 1: increased alanine aminotransferase [ALT] or aspartate aminotransferase [AST], neutropenia and thrombocytopenia. The MTD was V 300 mg (Table). At the MTD, the most common all grade (Gr) adverse events (AEs) were neutropenia (69%), asthenia and thrombocytopenia (62% each), increased ALT, increased AST and diarrhea (54% each). Median (range) duration on treatment was 4 (1–18) cycles. Treatment was discontinued due to progressive disease (80%), DLT (3%) and other non-AE related reasons (17%). 2 objective responses were observed (1 complete [breast cancer] and 1 partial [NSCLC]), both with the 300 mg dose. 6 pts had SD for ≥ 6 mo. PK data will be presented at the meeting. Conclusions: MTD of V + standard dose N (200 mg BID) was determined to be 300 mg Q3W (the same as the recommended phase II single agent dose of V in solid tumors). This combination had a manageable safety profile without unexpected or overlapping toxicities and showed preliminary antitumor activity. Clinical trial information: NCT01022853. [Table: see text]

The clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15081-e15081
Author(s):  
Min Yuan ◽  
Juemin Fang ◽  
Zhongzheng Zhu ◽  
Wei Mao ◽  
Hui Wang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Hand Foot Syndrome ◽  
Prior Systemic Therapy ◽  
Grade 3

e15081 Background: Anlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We reported results from the clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors. Methods: 21 patients with advanced lung, gallbladder, endometrial, gastric, pancreatic, penile cancers and melanoma were treated since January 2019. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21 days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or unacceptable toxicity. Radiologic imaging was performed every 6 weeks for the first year of therapy. Results: Among 21 enrolled patients, 11 tumor types were represented, with lung, gallbladder, endometrial cancers and sarcoma being the most common.Most patients had received prior systemic therapy for metastatic disease (76.2%). The objective response rate (ORR) was 19.1%, including one complete responses (CR) (4.8%) and three partial responses (PR) (14.3%) and a disease control rate (DCR = CR+PR+SD) of 81.0% (17 of 21). One CR and three PRs have lasted 4, 4, 5 and 8 months, respectively. Thirteen patients (61.9%) had stable disease (SD) that lasted 1.5 to 13 months. Treatment-related adverse events occurred in 12 patients (57.1%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included hand-foot syndrome (n = 1) and hypertension (n = 2). Conclusions: anlotinib can be administered combined with anti-PD-1 antibodies with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.

Trastuzumab biosimilar (Kanjinti) in breast cancer patients: One-center retrospective observational study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13015-e13015
Author(s):  
Agnieszka I. Jagiello-Gruszfeld ◽  
Izabela Lemanska ◽  
Elzbieta Brewczynska ◽  
Katarzyna Pogoda ◽  
Roman Dubianski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Real World ◽  
Safety Profile ◽  
Safety Data ◽  
Her2 Positive ◽  
Reference Drug ◽  
Her2 Positive Breast Cancer ◽  
Metastatic Setting ◽  
Positive Breast Cancer

e13015 Background: The switch of anti-HER2 therapy from the reference drug Herceptin to a biosimilar has presented challenges to the clinics. Real world data on trastuzumab biosimilars are very limited or not available. In our clinic we perform observational retrospective study to confirm safety and efficacy Kanjinti. Methods: 195 patients (pts) with HER2-positive breast cancer were treated with Kanjinti from Jul.18. 2018 to Jan.29.2020. Cardiac events (↓LVEF) and other unexpected or serious adverse events were monitored in all pts. 34 pts received carboplatin, docetaxel pertuzumab and trastuzumab biosimilar in neoadjuvant setting, 99 received trastuzumab biosymilar in monotherapy or with other cytostatic drugs in neoadjuvant or adjuvant setting, and 62 received docetaxel, pertuzumab and Kanjinti in metastatic setting. Results: Pertuzumab was used in combination with Kanjinti in 49% of pts (32% in the 1st. line of palliative tretment and 17% in the neoadjuvant settings, respectively).Switching from Herceptin to Kanjinti was observed in 65% of MBC patients and 37% of EBC patients. Switching was done at a median of 4th cycle. 6 patients had a decline in LVEF. No other trastuzumab related adverse events was observed. Conclusions: The management of HER2 positive breast cancer in our clinic follows the international recommendations. This is the first real world safety data of Kanjinti from Poland. The 12-month follow-up treatment with Kanjinti an acceptable cardiac safety profile. In cases where there was a switch from Herceptin to Kanjinti or Kanjinti combined with pertuzumab, the safety profile was similar to that previously reported in other studies.

Apatinib plus vinorelbine versus vinorelbine for advanced triple-negative breast cancer with failed first or second-line treatment: The NAN trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1075-1075
Author(s):  
Doudou Li ◽  
Zhonghua Tao ◽  
Biyun Wang ◽  
Leiping Wang ◽  
Jun Cao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Disease Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Line Treatment ◽  
Second Line ◽  
Grade 3 ◽  
To Receive

1075 Background: No standard treatment exists for triple negative breast cancer (TNBC) with failure of multi-line therapies. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for TNBC. We aimed to evaluate the safety and efficacy of adding apatinib to chemotherapy in patients with metastatic TNBC with failed first/second-line treatment. Methods: This randomized, open-label, phase 2 trial recruited patients with advanced TNBC who failed to receive first or second-line treatment. A total of 66 patients were randomly assigned, in a 1:1 ratio, to receive vinorelbine 25 mg/m2 (days 1, 8, 15) or vinorelbine 20 mg/m2 (days 7, 14, 21) with apatinib (250 mg once daily, days 1-5, 8-12, 15-19, if tolerable, the second cycle started with 500 mg per day) in 28-day cycles. The efficacy was evaluated every two treatment cycles (8 weeks ± 3 days). According to the RECIST criterion, patients with CR, PR and SD continued treatment until disease progression or unacceptable toxicity or withdrawal of consent. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rate (ORR) and safety. Results: Between Sep 14, 2017 and Dec 08, 2020, 66 patients underwent randomization. Median follow-up was 21.3 months. 33 received apatinib plus vinorelbine and 32 received vinorelbine (1 was withdrawal of consent). Median PFS was significantly longer in the apatinib plus vinorelbine group than in the vinorelbine group (3.8 months vs. 1.9 months; hazard ratio for disease progression or death, 1.76; 95% confidence interval [CI], 1.02 to 3.05; P= 0.039). Median OS was 14.6 months with apatinib plus vinorelbine and 14.1 months with vinorelbine (HR,1.34; 95% CI, 0.60 to 3.00; P= 0.469). The ORR was 48.5% in the apatinib plus vinorelbine group and 31.3% in the vinorelbine group ( P= 0.156). The most common treatment-related hematologic grade 3–4 adverse events in those treated with apatinib plus vinorelbine versus vinorelbine, respectively, were leukopenia (42.4% vs. 34.4%), granulocytopenia (57.6% vs. 28.1%), anemia (9.1% vs. 12.5%) and thrombocytopenia (3.1% vs. 3.0%). The most frequent grade 3 nonhematologic toxicities were hand–foot syndrome (21%), proteinuria (9%), hypertension (9%) and increased ALT (9%) and which only occurred in apatinib plus vinorelbine group. No treatment-related nonhematologic grade 4 adverse events or treatment-related deaths were observed. Conclusions: Collectively, among patients with advanced TNBC with failed first/second-line treatment, apatinib plus vinorelbine show a promising benefit in PFS compared to vinorelbine monotherapy. Apatinib plus vinorelbine regimen shows promising efficacy and manageable toxicity, which might be a previously unappreciated therapeutic option for advanced TNBC. Clinical trial information: NCT03254654 .

Phase II study of sagopilone (ZK-Epo) in patients with recurrent metastatic breast cancer (MBC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1083-1083
Author(s):  
P. H. Morrow ◽  
S. G. Divers ◽  
L. Provencher ◽  
S. Luoh ◽  
T. M. Petrella ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Metastatic Breast ◽  
Sensory Neuropathy ◽  
Median Number ◽  
Breast Cancer Cell Lines ◽  
Clinical Activity ◽  
Stabilizing Agents ◽  
Grade 3 ◽  
Stage 1

1083 Background: Sagopilone is a novel, fully synthetic epothilone, which represents a new class of microtubule stabilizing agents. It has shown significant pre-clinical activity in taxane resistant breast cancer cell lines and in tumor models, as well as clinical activity in both taxane naïve and pretreated MBC. Methods: MBC patients who received ≤ 3 prior anthracycline and taxane containing chemotherapies were eligible. Sagopilone was given either at 16 mg/m2 (arm A) or at 22 mg/m2 (arm B, amended additional cohort) IV over 3 hours every 21 days for up to 6 cycles. The primary end point was tumor response by RECIST. The Simon 2-Stage design required 3 responders in the first 24 evaluable patients in stage 1 and 10 responders in 65 evaluable patients to declare success. Results: Between June 2006 and June 2008, 65 patients were enrolled and treated (39 in arm A, 26 in arm B). Majority of metastases were in lymph nodes (62%), liver (55%), bone (49%), lung (37%), and cutaneous sites (19%). Median number of cycles delivered was 2 (1–17). Neither arm met Stage 1 criteria for responders. Nevertheless, 2 patients in arm A and 1 in arm B had confirmed partial response, and lasted 4, 7, and 2 months, respectively. 26% patients in arm A, and 42% in arm B had stable disease. 42 patients discontinued study prior to cycle 6 due to progressive disease/death, 14 due to adverse events, and 1 due to other reasons. All 65 patients are evaluable for safety. Adverse events documented or reported in ≥ 20% patients are: sensory neuropathy 80% (23% grade 3), nausea 57% (no grade 3), fatigue 45% (12% grade 3), vomiting 29% (no grade 3), myalgia 28% (5% grade 3), diarrhea 25% (2% grade 3), insomnia 25% (no grade 3), pain in extremity 25% (2% grade 3), headache 23% (5% grade 3), arthralgia 22% (5% grade 3), constipation 22% (2% grade 3). Conclusions: Sagopilone had limited activity in these heavily pretreated MBC patients. It appeared tolerable at both dose levels. [Table: see text]

A multicenter, phase Ib/2 study of varlitinib plus gemcitabine and cisplatin (gem/cis) for treatment of naïve, advanced, or metastatic biliary tract cancer (BTC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 319-319
Author(s):  
Do-Youn Oh ◽  
Wei-Peng Yong ◽  
Li-Tzong Chen ◽  
Ji-Won Kim ◽  
Alex Yuang-Chi Chang ◽  
...  
Keyword(s):  
Safety Profile ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Her Family ◽  
Tract Cancer ◽  
First Line Therapy ◽  
Combination Methods ◽  
Response To Chemotherapy ◽  
Grade 3

319 Background: BTC is a rapidly progressing cancer with limited response to chemotherapy. First line therapy (gem/cis) was defined in the ABC-02 study (Valle et al), where a 26% response was seen. HER family receptors are overexpressed and may be involved in tumour proliferation and survival in BTC. Varlitinib, a reversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, shows potent activity as monotherapy in preclinical BTC models and clinical activity in BTC patients (pts) in phase (ph) 1 trials. We conducted a ph Ib/2 study of varlitinib plus gem/cis in BTC to understand the safety profile and determine the maximum tolerated dose (MTD) of the combination. Methods: A modified 3+3+3 escalation design was used in Ph1b, with 2 varlitinib dose levels (200 and 300 mg BID) plus gem/cis on Day 1 and 8 in a 3 week cycle. The primary objectives are to determine the MTD and to characterize the safety profile. Secondary objectives are to assess the preliminary efficacy and to evaluate the pharmacokinetics of varlitinib and any circulating metabolites. Results: As of 10 Sep 2018, 21 pts were enrolled (11 in 200 mg cohort and 10 in 300 mg cohort, with 9 and 4 evaluable for MTD, respectively). Dose limiting toxicities (DLTs) were observed in 3 pts (1 G3 unconjugated hyperbilirubinemia and 1 G3 ALT transaminitis/G4 AST transaminitis in 200 mg cohort; 1 G4 thrombocytopenia/G3 febrile neutropenia/G3 AST elevation in 300 mg cohort). In 19 pts who were on varlitinib ≥ 1 month, 7 had partial response and 10 achieved stable disease (all > 12 weeks), giving the overall response rate of 37% and the disease control rate of 89%. The median PFS for the 200 mg cohort was 248 days and was not reached for the 300 mg cohort. The most common (≥ 30%) all-grade adverse events (AEs) regardless of causality were thrombocytopenia (62%), neutropenia (52%), anorexia (38%), nausea (38%), diarrhoea (38%), and anaemia (33%); the most common (≥ 15%) grade ≥ 3 AEs were neutropenia (48%), thrombocytopenia (33%), and anaemia (19%). Conclusions: Varlitinib plus gem/cis was well tolerated in the 200 mg cohort; the 300 mg cohort is ongoing. Preliminary anti-tumour activity was observed. Data will be updated at the time of presentation. Clinical trial information: NCT02992340.

scholarly journals Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study

2018 ◽  
Vol 36 (4) ◽  
pp. 391-398 ◽  
Author(s):  
Margaret K. Callahan ◽  
Harriet Kluger ◽  
Michael A. Postow ◽  
Neil H. Segal ◽  
Alexander Lesokhin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Dose Escalation ◽  
Objective Response ◽  
Safety Data ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Grade 3

Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

A phase II study of vorolanib (CM082) in combination with toripalimab (JS001) in patients with advanced mucosal melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10040-10040 ◽  
Author(s):  
Lu Si ◽  
Xinan Sheng ◽  
Lili Mao ◽  
Caili Li ◽  
Xuan Wang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Mucosal Melanoma ◽  
Clinical Activity ◽  
Effective Treatment Option ◽  
Grade 3 ◽  
Ecog Ps

10040 Background: Vorolanib (CM082) is a multi-target tyrosine kinase inhibitor including VEGF, PDGF, c-kit, and Flt-3. Toripalimab (JS001) is a humanized IgG4 mAb against programmed death-1 (PD-1) with clinical activity in metastasis melanoma but not in its mucosal subtype. In this phase II study (NCT03602547), we investigated the safety and efficacy of CM082 in combination with JS001 in patients (pts) with advanced mucosal melanoma. Methods: The study enrolled pts from 18 to 75 years-old with histologically confirmed metastatic mucosal melanoma, ECOG PS 0-1, no prior systemic anti-cancer treatment. Eligible pts were treated with CM082 tablet (150 or 200 mg once daily) combined with JS001 (240mg every 2 weeks, IV, Q2W) until confirmed disease progression or unacceptable toxicity. Clinical response was evaluated every 8 week. The primary endpoint was overall response rate (ORR) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of remission (DOR), and time to first remission (TTR) according to RECIST v1.1 and iRECIST. The safety was also assessed. Results: Between July 2018 and April 12, 2019, 40 pts (19 pts in 150mg group; 21 pts in 200mg group) were enrolled and 38 pts were evaluable for tumor response (150mg n = 18, 200mg n = 20), with 4 (22.2%) confirmed partial response (PR), 6 (33.3%) stable disease (SD) and 8 (44.4%) progression disease (PD) in the 150mg CM082 group; 3 (15%) PRs (including 2 unconfirmed), 10 (50%) SD, and 7 (35%) PD were reported in the 200mg CM082 group. Tumors shrank in 10 pts (56%) in the 150mg group and 10 pts (50%) in the 200mg group. At data cut-off (November 28, 2019), 29 pts had PFS events (150mg n = 12; 200mg n = 17). The median PFS was 5.7 (95% CI 2.0, NE) months and 5.6 (1.9, 7.7) months in the two groups, respectively. The most common treatment-related adverse events (AEs) were grade 1 or 2, including leukopenia, elevated LDH, increased ALT, neutropenia, increased AST, and elevated GGT. Common grade 3 or higher adverse events ( > 10%) were increased ALT (12 pts, 30%), increased AST (11 pts, 27.5%), neutropenia (6 pts, 15%) and elevated GGT (6 pts, 15%). Eight pts had 9 serious AEs (SAEs). The study is still ongoing and more data will be presented in the future. Conclusions: PFS benefit was observed in both 150mg and 200mg subgroups. This study demonstrated potentially improved efficacy with predictable toxicities of CM082 in combination with JS001 therapy, which may be an effective treatment option for pts with advanced mucosal melanoma. Clinical trial information: NCT03602547.

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