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Rachel E. Sanborn
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OA04 - New Data from Rare EGFR Alterations (ID 223)
- Event: WCLC 2020
- Type: Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
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OA04.04 - Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer (ID 3031)
11:45 - 12:45 | Author(s): Rachel E. Sanborn
- Abstract
- Presentation
Introduction
Despite sharing similar tumor biology to other epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) tumors, no targeted therapies have been approved for NSCLC harboring EGFR Exon 20 insertion mutations (Exon20ins). The standard of care remains platinum-based chemotherapy for the front-line, with no clear subsequent options available. Amivantamab (JNJ-61186372) is a novel, fully human EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations, as well as MET mutations and amplifications, and has received FDA Breakthrough Therapy Designation for the treatment of patients with EGFR Exon20ins NSCLC after platinum-based chemotherapy. Here we present updated results on the Exon20ins cohort from the CHRYSALIS study (NCT02609776).
Methods
The dose escalation phase enrolled patients with advanced NSCLC to determine the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg for ≥80 kg) amivantamab. The dose expansion phase assessed the safety and efficacy of amivantamab in patients with EGFR- and MET-mutant NSCLC treated at the RP2D. Disease response was assessed by the investigator per RECIST v1.1 and is presented for those patients with Exon20ins NSCLC who had progressed on prior platinum-based chemotherapy, were treated at the RP2D, and had at least 3 post-baseline disease assessments (18 weeks) or discontinued, progressed, or died prior to the 3rd assessment (the Post-Platinum Cohort). The data cutoff date was 8 Jun 2020.
Results
In the Post-Platinum Cohort (n=81), median age was 62 (42 – 84), 59% were women, 49% were Asian, median prior lines of therapy was 2 (1 – 7), and 53% were never-smokers. At a median follow-up of 6.5 months (1.1 – 29.3), investigator-assessed overall response rate (ORR) was 36% (29/81; 95% CI, 25 – 47), with all responders achieving partial response (PR). The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 73% (59/81; 95% CI, 62 – 82). Responses were durable at a median of 6.8 months (95% CI, 5.0 – not reached) with ongoing responses in 18/29 (longest at 16+ months). Median progression-free survival was 8.3 months (95% CI, 5.5 – 12.7) and median overall survival was 22.8 months (95% CI, 14.0 – not reached).
Among all phase 1 patients, across a variety of EGFR genomic alterations and lines of therapy, treated with amivantamab monotherapy at the RP2D (n=258), the most common adverse events (AEs) were rash (78%), infusion related reaction (IRR; 65%), and paronychia (40%). Additional EGFR-related AEs were stomatitis (19%), pruritus (19%), and diarrhea (11%). Grade ≥3 AEs were reported in 39% of patients; 14% were considered treatment-related, with rash (3%) and IRR (2%) being most frequent. No treatment-related deaths were reported. The incidence of treatment-related AEs leading to dose reduction and discontinuation was 10% and 3%, respectively.
Conclusion
Amivantamab treatment led to promising efficacy with durable responses in patients with EGFR Exon20ins NSCLC post-platinum doublet and continues to demonstrate a manageable safety profile in over 250 patients treated at the RP2D. A phase 3 study, PAPILLON, evaluating amivantamab in combination with chemotherapy in the front-line setting is in planning stages.
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P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)
- Event: WCLC 2020
- Type: Posters
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P01.06 - CX-2029, a Probody Drug Conjugate Targeting CD71 in Patients With Selected Tumor Types: PROCLAIM-CX-2029 Dose Expansion Phase (ID 3264)
00:00 - 00:00 | Author(s): Rachel E. Sanborn
- Abstract
Introduction
CX-2029 is a Probody® drug conjugate (PDC) of monomethyl auristatin E (MMAE), a potent microtubule inhibitor, directed against transferrin receptor 1, CD71. CD71 mediates iron uptake and is highly expressed on both malignant and normal cells, precluding antibody-drug conjugate (ADC) targeting. PDCs are masked ADCs, unmasked by tumor-associated proteases, thereby restricting target engagement to the tumor. Both the CD71 PDC and ADC had significant activity in multiple xenograft tumor models; however, in toxicology studies, the PDC was tolerable at doses consistent with efficacy in nonclinical tumor models while the ADC was not.
Methods
PROCLAIM-CX-2029 is an open-label, phase 1/2 study (NCT03543813) evaluating CX-2029 in patients with advanced solid tumors or diffuse large B-cell lymphoma (DLBCL). Results from the dose escalation component of the trial were previously reported (Johnson 2020). Clinical activity was observed at doses of 2 mg/kg and higher (all confirmed responses were observed in squamous histologies: non-small cell lung; head and neck cancers). The dose expansion in 4 selected tumor types is underway and is planned to enroll up to 25 patients per tumor type (Figure 1). Eligible patients are aged ≥18 years with Eastern Cooperative Oncology Group performance status of 0–1; adequate hematologic, renal, and hepatic function; and 1 of the following advanced malignancies: non–small cell lung cancer (squamous histology only); head and neck squamous cell carcinoma; esophageal cancer; or DLBCL. All patients must have received appropriate prior systemic therapy for their advanced disease. CX-2029 will be administered at 3 mg/kg in 21-day cycles until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary endpoint is overall response rate by Response Evaluation Criteria in Solid Tumors version 1.1 or modified Lugano classification for DLBCL. Secondary endpoints include duration of response, progression-free survival, overall survival, safety, and pharmacokinetics. Tumor specimens are required during screening (optional at 3-5 days following the first infusion) for assessment of CD71 parameters and possible correlation with response.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.62 - RAMOSE: An Open-Label Randomized Phase II Study of Osimertinib with or without Ramucirumab in TKI-Naïve EGFR-Mutant Metastatic NSCLC (ID 3246)
00:00 - 00:00 | Author(s): Rachel E. Sanborn
- Abstract
Introduction
The third-generation EGFR tyrosine kinase inhibitor osimertinib is currently used as a standard first-line therapy for patients with metastatic EGFR-mutant NSCLC. However, a majority of patients’ cancers will develop resistance to osimertinib in less than 2 years, with a median progression-free survival of approximately 19 months.
Preclinical models demonstrate upregulated VEGF signaling as a mechanism of acquired resistance to EGFR therapies, and improved efficacy when combining VEGF and EGFR inhibition. Ramucirumab, a monoclonal antibody targeting VEGF receptor 2, was recently approved by the US FDA in combination with erlotinib in patients with metastatic untreated EGFR-mutant NSCLC, based on a significant improvement in progression-free survival (PFS) with the combination seen in the RELAY trial.
A phase I study of osimertinib with ramucirumab (NCT02789345) demonstrated safety and feasibility of this combination. With this strong preclinical and clinical evidence, we are conducting a phase 2 trial to evaluate the osimertinib ramucirumab combination’s efficacy in treatment-naïve EGFR-mutant NSCLC.
Methods
RAMOSE (HCRN LUN-18-335; NCT03909334) is a randomized, open-label phase 2 study comparing osimertinib 80mg PO daily + ramucirumab 10 mg/kg IV q3 weeks (O + R) to osimertinib 80mg PO daily monotherapy (O) for initial treatment of metastatic EGFR-mutant NSCLC. Patients are randomized 2:1 to the O+R versus O groups, with stratification based on type of EGFR mutation and presence of CNS metastasis. The trial plans to enroll total of 150 patients, allocating 100 to O+R and 50 to O monotherapy. The primary endpoint is PFS. Secondary endpoints include ORR, OS and DCR, as well as safety/toxicity. Major inclusion criteria include patients with metastatic NSCLC harboring activating EGFR mutations (L858R or Exon 19 del). Major exclusion criteria include prior anti-EGFR or anti-VEGF treatments. Patients with stable CNS metastasis are allowed. We hypothesize an improvement of PFS from 18.9 months to 29.7 months, corresponding to a hazard ratio of 0.65.
The study is currently open at 9 sites in the USA, with additional sites planned. Hoosier Cancer Research Network is facilitating execution of the trial. Analysis by a study Data Safety Monitoring Board (DSMB) is performed annually. In addition, a planned interim analysis for efficacy will be performed after the first 75 subjects are enrolled.
Results
The trial opened to accrual in July 2019. As of July 02, 2020 (the data cutoff for planned DSMB analysis), 29 patients had been accrued. 25 of these patients were randomized (17 to O+R arm and 8 to O arm). Among the patients currently evaluable for toxicity (N=19), grade 3 or higher adverse events (AEs) were reported in 5/14 patients on O+R arm, versus 1/5 patients on O arm. In the O+R arm, grade 3 AEs included hypertension (n=1), pleural catheter infection (n=1), musculoskeletal pain (n=1), neutrophil count decreased (n=1), and dyspnea (n=1).
Conclusion
Early analysis from the RAMOSE trial shows no unexpected signals of toxicity with the combination of O+R. Enrollment for the trial is ongoing.
