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Alex I. Spira
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FP02 - Health Services Research/Health Economics (ID 120)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Health Services Research/Health Economics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP02.02 - Real-World Outcomes Among Advanced Non-Small Cell Lung Cancer Patients Re-Treated with Immunotherapy in the US (ID 3706)
00:00 - 00:00 | Presenting Author(s): Alex I. Spira
- Abstract
Introduction
Immunotherapy (IO)-based regimens (alone or in combination with chemotherapy) are the current standard of care for the first-line (1L) treatment of advanced non-small cell lung cancer (aNSCLC). However, many patients undergoing 1L IO progress and need subsequent treatment. Currently, there is limited information regarding outcomes for patients who receive subsequent treatment following 1L IO for aNSCLC. This real-world study aimed to assess treatment patterns and clinical outcomes among patients retreated with IO-based regimens as second-line (2L) therapy following 1L IO in a US community oncology setting.
Methods
A retrospective observational study was conducted to identify patients from the US Oncology iKnowMed database who received 1L IO-based therapy followed by 2L treatment for aNSCLC between October 1, 2016 and September 30, 2019. Data were collected up to March 31, 2020 to allow at least 6 months of potential follow-up for each patient. Clinical trial participants, those under the age of 18, or those treated for other primary cancer were excluded. Patients were determined to have transitioned from 1L to 2L therapy if there was a change in regimen (e.g., Pembrolizumab to Nivolumab), the addition of a new antineoplastic agent, or a gap of at least 90 days between treatments. Baseline patient characteristics were described, and treatment outcomes were estimated from 2L initiation (i.e., index date) using Kaplan-Meier methods.
Results
The study population included 490 patients: 30% (n=149) received IO-based 2L treatment while 70% (n=341) received non-IO 2L therapies. The three most common non-IO 2L therapies included chemotherapy (n=253), chemotherapy+targeted therapy (n=53), and targeted therapy (n=35). Prior 1L treatment patterns showed 56% (n=276) received 1L IO monotherapy, 40% (n=194) received 1L combination IO+chemotherapy, and 4% (n=20) received some other form of IO therapy (e.g., IO+IO). Key findings are reported in the table below.
TABLE 1: Patient Characteristics and Outcomes for Patients Initiating 2L Treatment
ConclusionIO-Based
Non-IO based
(n=149)
(n=341)
Patient Characteristics
Median Age at 2L Treatment Initiation (years)
70
69
Male (%)
53.7
52.5
No History of Smoking (%)
12.8
16.1
Squamous Histology (%)
22.2
15.5
ECOG Status (%)
0
12.8
15.5
1
57.1
53.7
2+
16.4
17.3
Not Available
14.8
13.5
PD-L1 (%)
<1%
11.4
16.7
1-49%
7.4
12.9
50%+
39.6
32.6
Not Available
41.6
37.9
Median 1L Treatment Duration (Months)
3.3
3.7
2L Treatment Outcomes
Median 2L Treatment Duration (Months)
4.5
2.5
Median Overall Survival (Months)
18.4
10.6
Patients who received IO or non-IO based therapies in 2L appeared similar, although a higher proportion of patients who received 2L IO retreatment had PD-L1 ≥50%. Retreatment with IO did not suggest to negatively affect outcomes, and unadjusted treatment duration and survival were longer in patients receiving 2L IO (p-value=0.02). Stratifications by 1L therapy (IO monotherapy and IO+chemotherapy) were consistent with the combined results reported below. Further study on the effects of 1L treatment duration and optimal duration of overall IO therapy are warranted.
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OA03 - Promising Antibody-Drug Conjugate and Cytotoxic Therapy in NSCLC (ID 100)
- Event: WCLC 2020
- Type: Oral
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 10:30 - 11:30, Scientific Program Auditorium
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OA03.03 - Datopotamab Deruxtecan (Dato-DXd; DS-1062), a TROP2 ADC, in Patients With Advanced NSCLC: Updated Results of TROPION-PanTumor01 Phase 1 Study (ID 3407)
10:30 - 11:30 | Presenting Author(s): Alex I. Spira
- Abstract
- Presentation
Introduction
Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein that is overexpressed in NSCLC and other solid tumors. DS-1062 is a TROP2 directed ADC comprising a novel topoisomerase 1 inhibitor (exatecan derivative, DXd), a tetrapeptide-based linker, and a TROP2 directed monoclonal antibody. DS-1062 has demonstrated promising safety and antitumor efficacy in an ongoing phase 1 study in patients with advanced/metastatic NSCLC (NCT03401385); the MTD was declared as 8.0 mg/kg. The study was expanded to include 80 patients at 8 mg/kg and 50 patients each at 4 mg/kg and 6 mg/kg. Updated interim results for 133 patients treated at these doses are reported here.
Methods
Eligible patients were aged ≥18 (US) or ≥20 (Japan) years with advanced/metastatic NSCLC refractory to/relapsed from standard treatment, had measurable disease per RECIST v1.1, and had tumor tissue available for retrospective TROP2 analysis (eligible regardless of TROP2 expression level). Primary objectives are identification of the maximum tolerated dose, safety, and tolerability. Secondary objectives include efficacy (including response by blinded independent central review [BICR]), pharmacokinetics, and incidence of antidrug antibodies.
Results
As of June 15, 2020, 133 patients were treated with ≥1 dose of DS-1062 at 4.0 mg/kg (n = 29), 6.0 mg/kg (n = 24), and 8.0 mg/kg (n = 80). Patients received a median of 4 cycles (range, 1-26) of DS-1062 (1 cycle = 21 days). At study entry, 108 (81%) had received prior immunotherapy and 119 (90%) had received prior platinum-based chemotherapy (preliminary); 126 (95%) had stage IV disease; and 117 (88%) and 15 (11%) had nonsquamous and squamous NSCLC, respectively. In 125 response-evaluable patients (≥1 post baseline tumor assessment or discontinued study treatment), 1 had a confirmed complete response (CR; at 6.0 mg/kg) by BICR, and 32 had partial responses (PRs) by BICR (8 PRs in 29 patients at 4.0 mg/kg, 4 PRs in 20 patients at 6.0 mg/kg, and 20 PRs in 76 patients at 8.0 mg/kg); 29 CRs/PRs were confirmed, and 4 are awaiting confirmation. Among 29 confirmed responders, the probability of having an ongoing response at 6 months was >80% (based on the Kaplan-Meier method). Disease control rate (confirmed CR/PR + stable disease) was 79% (95% confidence interval [CI], 60.3%-92.0%) at 4.0 mg/kg, 75% (95% CI, 50.9%-91.3%) at 6.0 mg/kg, and 79% (95% CI, 68.1%-87.5%) at 8.0 mg/kg. Any-grade treatment-emergent adverse events (TEAEs) were reported in 128 patients (96%); most frequent TEAEs (≥30%) included nausea (50%), stomatitis (44%), alopecia (40%), and fatigue (33%). Sixty-four patients (48%) experienced grade ≥3 TEAEs (most frequently dyspnea [5%]). There were 12 patients (9%) with interstitial lung disease adjudicated by an independent adjudication committee as treatment related (1 [4%] at 6.0 mg/kg [G2] and 11 [14%] at 8.0 mg/kg [7 at G1-2 and 4 at G3-5]). Fourteen patients [11%] discontinued treatment because of TEAEs. At data cutoff, 49 patients (37%) remained on study treatment. Updated results will be presented.
Conclusion
DS-1062 demonstrated encouraging antitumor activity across doses in pretreated patients with prior progression on standard treatment, accompanied by a manageable safety profile.
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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): Alex I. Spira
- 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): Alex I. Spira
- 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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P77 - Immunotherapy (Phase II/III Trials) - Combining Different Immunotherapeutic Approaches (ID 254)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P77.02 - Efficacy of Tiragolumab + Atezolizumab in PD-L1 IHC and TIGIT Subgroups in the Phase II CITYSCAPE Study in First-Line NSCLC (ID 3501)
00:00 - 00:00 | Author(s): Alex I. Spira
- Abstract
Introduction
The immunomodulatory receptor TIGIT (T-cell Immunoreceptor with Ig and ITIM domains) is a novel inhibitory immune checkpoint on activated T cells and natural killer cells in multiple cancers. Tiragolumab (tira) is a humanized IgG1/kappa monoclonal antibody that binds TIGIT to prevent its interaction with its ligand PVR (CD155). Because PD-L1 expression is considered a hallmark of pre-existing immunity and is positively correlated with TIGIT expression, we investigated the combination of tira + atezolizumab (atezo) in patients with newly diagnosed PD-L1-positive metastatic NSCLC in the phase II CITYSCAPE trial. We recently reported an improvement in progression-free survival (PFS) with the tira + atezo combination over atezo monotherapy in patients whose tumors showed high PD-L1 expression (≥50% TPS or tumor proportion score) by the pharmDx immunohistochemistry (IHC) 22C3 assay (PFS hazard ratio [HR] 0.30, 95% confidence interval [CI]: 0.15-0.61) [Rodriguez-Abreu. ASCO 2020]. To determine whether these results were consistent across different PD-L1 IHC assays, we assessed the efficacy of tira + atezo in PD-L1 subgroups defined by the SP263 IHC assay. We also evaluated whether TIGIT expression was associated with tira + atezo efficacy.
Methods
PD-L1 expression was assessed prospectively using 22C3 IHC and retrospectively with SP263 IHC, both of which yield a tumor cell (TC) membrane staining score. TIGIT expression on tumor-infiltrating immune cells (IC) was assessed with an exploratory IHC assay.
Results
Among the 135 enrolled patients with PD-L1-positive NSCLC (intent-to-treat [ITT] population), 113 had results from the SP263 assay and 105 had results from the TIGIT assay. The biomarker-evaluable populations (BEP) for both of these assays were similar to the ITT population. Comparable PFS improvement with tira + atezo relative to atezo monotherapy was seen in PD-L1–high (≥50% TC) subgroups defined by SP263 (PFS HR 0.23, 95% CI: 0.10–0.53) when compared with PD-L1-high subgroups defined by 22C3. However, for patients whose tumors were defined as TIGIT-high (≥5% IC), no strong association with PFS improvement was observed.
ConclusionBiomarker subgroup
Subgroup, n (BEP, N)
PFS HR (CI) relative to atezo monotherapy arm
ITT (PD-L1 IHC 22C3 >1% TPS)
135 (135)
0.58 (0.39–0.88)
PD-L1 IHC 22C3 (≥50% TPS)
58 (135)
0.30* (0.15–0.61)
PD-L1 IHC SP263 (≥50% TC)
45 (113)
0.23* (0.10–0.53)
TIGIT IHC (≥5% IC)
49 (105)
0.62* (0.30–1.32)
*Unstratified HR
Prevalence of PD-L1 subgroups in the BEP was comparable with previous reports for both IHC assays. The PFS benefit observed with tira + atezo in patients with tumors defined as PD-L1-high by 22C3 was also observed using the SP263 IHC assay, but not in tumors classified as TIGIT-high using an exploratory TIGIT IHC assay. Our results suggest that PD-L1 expression, assessed by 22C3 or SP263, may be a biomarker for tira + atezo combination therapy in metastatic PD-L1-positive untreated NSCLC.
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P90 - Targeted Therapy - Clinically Focused - Misc. Topics (ID 267)
- 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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P90.03 - A Phase 2 Trial of MRTX849 in Combination with Pembrolizumab in Patients with Advanced Non-Small Cell Lung Cancer with KRAS G12C Mutation (ID 2968)
00:00 - 00:00 | Presenting Author(s): Alex I. Spira
- Abstract
Introduction
KRAS is the most frequently mutated oncogene in cancer and a key mediator of the signaling cascade that promotes cellular growth and proliferation. Activating KRAS mutations drive increased cell growth, proliferation, and survival, and also decreased apoptosis in animal models. KRAS G12C tumor mutations occur in approximately 14% of patients with non-squamous non–small cell lung cancer (NSCLC).
MRTX849 is a selective small-molecule inhibitor of KRAS G12C that covalently and irreversibly binds to and locks mutant KRAS in its inactive form. MRTX849 was optimized for a long half-life and extensive tissue distribution to enable inhibition of KRAS G12C throughout the entire dosing interval. Preliminary results from a Phase 1/2 study of MRTX849 monotherapy demonstrated antitumor activity and tolerability across multiple KRAS G12C tumor types, including patients with NSCLC previously treated with both platinum-doublet chemotherapy and immune checkpoint inhibitors.
MRTX849 demonstrated reconditioning of the tumor microenvironment and enhanced potential to present antigens resulting in an enhanced immune response in KRAS G12C tumor models— both of which are predicted to augment susceptibility to immune checkpoint inhibition. MRTX849 has also resulted in durable complete responses in a KRAS G12C syngeneic tumor model in combination with a PD-1 antagonist whereas both monotherapy treatments in this study resulted in progression. These data support the rationale to evaluate MRTX849 in combination with immune checkpoint inhibitors in patients with first-line (1L) advanced/metastatic NSCLC.
Methods
Study 849-007 is a global, open-label Phase 2 study being conducted in the US, EU and Canada at approximately 40 sites to evaluate the clinical activity of MRTX849 administered in combination with pembrolizumab as 1L treatment for patients with advanced NSCLC harboring a KRAS G12C mutation. The primary endpoint is Objective Response Rate (ORR) as defined by RECIST 1.1. Secondary and exploratory objectives include evaluation of safety, additional efficacy endpoints, pharmacokinetics (PK), pharmacodynamics (PD), and correlative biomarkers. This study utilizes Simon's optimal two-stage design to derive the sample size.
Subjects will be enrolled in two cohorts based on PD-L1 Tumor Proportion Score (TPS): TPS < 1% (Cohort A; n=56) and TPS ≥ 1% (Cohort B; n=57). The planned regimen for MRTX849 is 600 mg twice daily (BID), administered orally on a continuous basis. Pembrolizumab will be administered by IV infusion, 200 mg every three weeks (Q3W). Subjects will receive study treatment until disease progression, unacceptable adverse events, or receipt of maximal number of cycles per local standard-of-care or investigator decision. This study is expected to initiate before the end of 2020.
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PS01 - Presidential Symposium (Japanese, Mandarin, Spanish Translation Available) (ID 143)
- Event: WCLC 2020
- Type: Plenary
- Track: N.A.
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 07:00 - 09:00, Scientific Program Auditorium
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PS01.07 - CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer (ID 3037)
07:00 - 09:00 | Author(s): Alex I. Spira
- Abstract
- Presentation
Introduction
Outcome in patients with advanced non-small cell lung cancer (NSCLC) on second- or third-line therapies is poor, with a response rate of <20% and median progression-free survival (PFS) of <4 months. Approximately 13% of patients with lung adenocarcinomas harbor KRAS p.G12C mutation. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. In the phase 1 cohort of the CodeBreaK 100 trial (NCT03600883), sotorasib was well tolerated and demonstrated a confirmed response rate of 32.2%, a median duration of response (DoR) of 10.9 months, and a median PFS of 6.3 months in patients with heavily pretreated NSCLC. Here, we present for the first time the primary analysis from the registrational phase 2 portion of the trial.
Methods
This international, single-arm, phase 2 study evaluated the efficacy and safety of sotorasib, administered orally once daily at 960 mg, in the cohort of patients with locally advanced or metastatic KRAS p.G12C mutant NSCLC. Key inclusion criteria: centrally confirmed KRAS p.G12C; progression on anti-PD-1/PD-L1 immunotherapy and/or platinum-based combination chemotherapy, and targeted therapy if EGFR, ALK, and ROS1 alterations were identified; and ≤3 prior lines of therapy. Patients with untreated active brain metastases were excluded. Primary endpoint was confirmed objective response rate (ORR), assessed by blinded independent central review per RECIST 1.1. Key secondary endpoints included disease control rate (DCR), PFS, DoR, and safety.
Results
Data cutoff was September 1, 2020. A total of 126 patients were enrolled and received at least 1 dose of sotorasib. Median follow-up time on study was 9.3 months (range: 1.1+ to 12.2). Median age was 63.5 years (range: 37 to 80), and 117 (92.9%) were former or current smokers. 72 (57.1%) patients received 2 or 3 prior lines of anticancer therapy. 91.3% received anti-PD-1/PD-L1 immunotherapy, and 81.0% received both platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapy. Per central review, 123 patients had at least 1 measurable lesion at baseline and were evaluated for efficacy. 46 patients experienced a confirmed response (2 complete responses and 44 partial responses), resulting in an ORR of 37.4% (95% Cl: 28.8–46.6). At a median follow-up of 6.9 months for DoR, 52.2% of responders remained on treatment without progression. DCR was 80.5% (95% Cl: 72.4–87.1). Median PFS was 6.7 months (95% Cl: 4.9–8.1). Treatment-related adverse events (TRAEs) of any grade occurred in 88 (69.8%) patients and led to discontinuation in 9 (7.1%) patients. Grade ≥3 TRAEs were reported in 26 (20.6%) patients; those that occurred in >3% of patients were alanine aminotransferase increase (8/126, 6.3%), aspartate aminotransferase increase (7/126, 5.6%), and diarrhea (5/126, 4.0%). No fatal TRAEs were reported.
Conclusion
In the phase 2 CodeBreaK 100 trial, sotorasib provided deep responses and durable clinical benefit with a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C, validating the previous phase 1 results. After four decades of scientific effort, sotorasib may have the potential to be the first targeted treatment option for this patient population with a high unmet need. Updated data including DoR, PFS, and biomarkers will be presented.
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PS02 - Presidential Symposium (Re-Broadcast) (Japanese, Mandarin, Spanish Translation Available) (ID 275)
- Event: WCLC 2020
- Type: Plenary
- Track: N.A.
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 18:00 - 20:00, Scientific Program Auditorium
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PS02.07 - CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer (ID 4290)
18:00 - 20:00 | Author(s): Alex I. Spira
- Abstract
Introduction
Outcome in patients with advanced non-small cell lung cancer (NSCLC) on second- or third-line therapies is poor, with a response rate of <20% and median progression-free survival (PFS) of <4 months. Approximately 13% of patients with lung adenocarcinomas harbor KRAS p.G12C mutation. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. In the phase 1 cohort of the CodeBreaK 100 trial (NCT03600883), sotorasib was well tolerated and demonstrated a confirmed response rate of 32.2%, a median duration of response (DoR) of 10.9 months, and a median PFS of 6.3 months in patients with heavily pretreated NSCLC. Here, we present for the first time the primary analysis from the registrational phase 2 portion of the trial. Methods
This international, single-arm, phase 2 study evaluated the efficacy and safety of sotorasib, administered orally once daily at 960 mg, in the cohort of patients with locally advanced or metastatic KRAS p.G12C mutant NSCLC. Key inclusion criteria: centrally confirmed KRAS p.G12C; progression on anti-PD-1/PD-L1 immunotherapy and/or platinum-based combination chemotherapy, and targeted therapy if EGFR, ALK, and ROS1 alterations were identified; and ≤3 prior lines of therapy. Patients with untreated active brain metastases were excluded. Primary endpoint was confirmed objective response rate (ORR), assessed by blinded independent central review per RECIST 1.1. Key secondary endpoints included disease control rate (DCR), PFS, DoR, and safety. Results
Data cutoff was September 1, 2020. A total of 126 patients were enrolled and received at least 1 dose of sotorasib. Median follow-up time on study was 9.3 months (range: 1.1+ to 12.2). Median age was 63.5 years (range: 37 to 80), and 117 (92.9%) were former or current smokers. 72 (57.1%) patients received 2 or 3 prior lines of anticancer therapy. 91.3% received anti-PD-1/PD-L1 immunotherapy, and 81.0% received both platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapy. Per central review, 123 patients had at least 1 measurable lesion at baseline and were evaluated for efficacy. 46 patients experienced a confirmed response (2 complete responses and 44 partial responses), resulting in an ORR of 37.4% (95% Cl: 28.8–46.6). At a median follow-up of 6.9 months for DoR, 52.2% of responders remained on treatment without progression. DCR was 80.5% (95% Cl: 72.4–87.1). Median PFS was 6.7 months (95% Cl: 4.9–8.1). Treatment-related adverse events (TRAEs) of any grade occurred in 88 (69.8%) patients and led to discontinuation in 9 (7.1%) patients. Grade ≥3 TRAEs were reported in 26 (20.6%) patients; those that occurred in >3% of patients were alanine aminotransferase increase (8/126, 6.3%), aspartate aminotransferase increase (7/126, 5.6%), and diarrhea (5/126, 4.0%). No fatal TRAEs were reported. Conclusion
In the phase 2 CodeBreaK 100 trial, sotorasib provided deep responses and durable clinical benefit with a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C, validating the previous phase 1 results. After four decades of scientific effort, sotorasib may have the potential to be the first targeted treatment option for this patient population with a high unmet need. Updated data including DoR, PFS, and biomarkers will be presented.
