Virtual Library
Start Your Search
F. Cappuzzo
Author of
-
+
MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
-
+
MINI03.03 - Pembrolizumab 2 mg/kg Q3W for Previously Treated, PD-L1-Positive Advanced NSCLC (ID 3024)
16:55 - 17:00 | Author(s): F. Cappuzzo
- Abstract
- Presentation
Background:
In patients with previously treated NSCLC enrolled in KEYNOTE-001 (NCT01295827), the anti–PD-1 antibody pembrolizumab (MK-3475) has demonstrated promising efficacy and manageable safety when given at dosages of 10 mg/kg once every 2 weeks (Q2W) or once every 3 weeks (Q3W). In a prospectively defined validation set from KEYNOTE-001, the greatest efficacy was observed in patients whose tumors expressed PD-L1 in ≥50% of tumor cells. Here, we present data for patients with previously treated, PD-L1–positive advanced NSCLC enrolled in a KEYNOTE-001 expansion cohort added to evaluate pembrolizumab 2 mg/kg Q3W.
Methods:
Patients had measurable disease, ECOG performance status of 0 or 1, and adequate organ function. Prior therapy with ≥1 platinum-doublet chemotherapy regimen was required; an appropriate tyrosine kinase inhibitor was required for patients with sensitizing EGFR mutations or ALK translocations. All patients had PD-L1–positive tumors, defined as staining in ≥1% of tumor cells as determined by a prototype IHC assay using the 22C3 antibody. The percentage of PD-L1–stained tumor cells was also determined by a clinical trial IHC assay using the same antibody. Patients received pembrolizumab 2 mg/kg Q3W until investigator-determined progression according to immune-related response criteria, intolerable toxicity, patient withdrawal, or investigator decision. Response was assessed centrally every 9 weeks by RECIST v1.1.
Results:
Of the 55 patients enrolled, 41 (74.5%) received ≥2 prior therapies. Three (5.5%) patients experienced grade 3-5 drug-related AEs (grade 3 colitis and pneumonitis and grade 5 cardiorespiratory arrest). After a minimum of 27 weeks of follow-up by central radiology review of tumor imaging (median, 7.7 months; range, 6.4-9.7 months), confirmed overall response rate (ORR) in the 52 patients with centrally evaluable disease at baseline was 15.4% (95% CI, 6.9%-28.1%) and the disease control rate (DCR, complete response + partial response + stable disease) was 50.0% (95% CI, 35.8%-64.2%). At the time of analysis, all responses were ongoing, and the median response duration was not reached (range, 2.1+ to 6.2+ months). Median progression-free survival (PFS) was 3.3 months (95% CI, 2.0-6.0 months), with a 6-month PFS rate of 37.7%. Median overall survival (OS) was not reached, and the 6-month OS rate was 75.8%. In the 25 (45.5%) patients who had PD-L1 expression in ≥50% of tumor cells, confirmed ORR was 30.4% (95% CI, 13.2%-52.9%), DCR was 56.5% (34.5%-76.8%), median PFS was 4.2 months (95% CI, 1.9 months-NR), and 6-month PFS and OS rates were 49.0% and 81.8%, respectively.
Conclusion:
In this previously treated cohort of patients with PD-L1–positive advanced NSCLC, pembrolizumab 2 mg/kg Q3W demonstrated robust and durable antitumor activity, with improved efficacy in patients with PD-L1 staining in ≥50% of tumor cells.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:Y. Yatabe, R. Perez-Soler
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
-
+
MINI05.05 - Discussant for MINI05.01, MINI05.02, MINI05.03, MINI05.04 (ID 3531)
17:05 - 17:15 | Author(s): F. Cappuzzo
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
-
+
MINI14.15 - Discussant for MINI14.10, MINI14.11, MINI14.12, MINI14.13, MINI14.14 (ID 3343)
12:05 - 12:15 | Author(s): F. Cappuzzo
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MINI 31 - ALK (ID 158)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Malik, I. Ou
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 1a-1f
-
+
MINI31.04 - Intracranial Efficacy of First-Line Crizotinib vs. Chemotherapy in ALK-Positive NSCLC (ID 1238)
18:45 - 18:50 | Author(s): F. Cappuzzo
- Abstract
- Presentation
Background:
The ongoing multicenter, randomized, open-label phase III study PROFILE 1014 recently demonstrated superior efficacy of crizotinib compared with chemotherapy in patients with previously untreated advanced ALK-positive NSCLC (Solomon et al, N Engl J Med 2014). Intracranial efficacy of crizotinib vs. chemotherapy was compared prospectively in this trial.
Methods:
Patients with previously untreated advanced non-squamous ALK-positive NSCLC (N=343) were randomized 1:1 to receive crizotinib 250 mg orally BID (n=172) or intravenous chemotherapy (pemetrexed 500 mg/m[2 ]+ cisplatin 75 mg/m[2] or carboplatin at AUC 5–6; all q3w for ≤6 cycles; n=171). Patients with treated brain metastases that were stable for ≥2 weeks with no ongoing requirement for corticosteroids were eligible. Treatment was continued until PD. Continuation of, or crossover to, crizotinib after PD (per independent radiology review [IRR]) was allowed for patients randomized to crizotinib or chemotherapy, respectively. Brain scanning was performed every 6 weeks in patients with baseline brain metastases and every 12 weeks in those without baseline brain metastases. Protocol-specified efficacy endpoints included PFS (primary endpoint), ORR, OS, and 12- and 18-month OS, as well as intracranial TTP. Intracranial DCR at 12 and 24 weeks was also evaluated. Efficacy was evaluated in the ITT population and in two subgroups of patients: those with and without baseline brain metastases.
Results:
Of 343 patients in the ITT population, 79 had brain metastases at baseline identified by IRR (23%) and 263 did not (77%; data not reported for one patient). Baseline characteristics of patients randomized to receive crizotinib or chemotherapy were generally well balanced within these two patient subgroups. Among the patients with baseline brain metastases, a significantly higher proportion achieved intracranial disease control with crizotinib than with chemotherapy at 12 weeks (33/39 [85%] vs. 18/40 [45%], respectively; P=0.0003) and at 24 weeks (22/39 [56%] vs. 10/40 [25%]; P=0.006). There was a numerical improvement in prospectively measured intracranial TTP with crizotinib in the ITT population (HR 0.60, P=0.069), as well as in patients either with baseline brain metastases (HR 0.45, P=0.063) or without baseline brain metastases (HR 0.69, P=0.323). The frequency of progression in the brain was low in the ITT population (15%) and in patients with and without baseline brain metastases (27% and 11%, respectively). Overall PFS was significantly longer with crizotinib than with chemotherapy in both subgroups (brain metastases present: HR 0.40, P=0.0007, median 9.0 vs. 4.0 months; brain metastases absent: HR 0.51, P≤0.0001, median 11.1 vs. 7.2 months), as it was in the ITT population (HR 0.45, P<0.0001, median 10.9 vs. 7.0 months). Twenty-five patients in the crizotinib arm of the study experienced intracranial PD; 22 of these patients received crizotinib for ≥3 weeks beyond PD and 19 also received intracranial radiotherapy.
Conclusion:
In this prospective assessment of intracranial efficacy, crizotinib demonstrated significantly greater intracranial disease control and overall efficacy compared with chemotherapy in patients with baseline brain metastases. These findings provide further confirmation of crizotinib as the standard of care for patients with previously untreated advanced ALK-positive NSCLC, including those patients with brain metastases at baseline.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MTE 12 - Therapy for Driver Mutation Positive Advanced NSCLC (Ticketed Session) (ID 64)
- Event: WCLC 2015
- Type: Meet the Expert (Ticketed Session)
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 07:00 - 08:00, 103
-
+
MTE12.01 - Therapy for Driver Mutation Positive Advanced NSCLC (ID 1997)
07:00 - 08:00 | Author(s): F. Cappuzzo
- Abstract
- Presentation
Abstract:
Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide, with a median survival that rarely exceeds 10–12 months in unselected patients with metastatic disease treated with conventional chemotherapy. In the last decade, identification of key genetic events driving tumor growth and metastatic spread led to the concept of oncogene-addiction. According to this model, the inhibition of certain molecular drivers by targeted agents could be effective in reducing tumor burden and improving patient survival. Several molecular alterations have been described in NSCLC, particularly in adenocarcinomas, especially, but not exclusively, in the never/ former smoker population. The most notable examples are the epidermal growth factor receptor (EGFR) activating mutations, mainly represented by deletion in exon 19 or the L858R substitution in exon 21, and the echinoderm microtubule protein like-4/anaplastic lymphoma kinase (EML4-ALK) translocation. Although only 12–15% of NSCLC tumors are EGFR mutated or ALK-rearrangement-positive, this translates into a considerable number of patients affected worldwide. In metastatic NSCLC, presence of EGFR activating mutations confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib. Indeed, nine large randomized trials comparing an EGFR-TKI versus standard platinum based chemotherapy have clearly demonstrated the superiority of the target agent in prolonging progression-free survival (PFS), improving response rate (RR) along with a more favorable safety profile. Similarly, in presence of EML4-ALK translocation, the ALK inhibitor crizotinib produces higher RR and longer PFS when compared to standard chemotherapy, both in first and second line setting. Unfortunately, no patient with metastatic oncogene-addicted NSCLC can achieve a definitive cure and after a median time of 8–12 months, all patients eventually develop acquired resistance to targeted therapy. So far, several studies of tumor samples obtained at the time of treatment failure have identified different potential mechanisms responsible for acquired resistance to targeted agents. In the majority of cases resistance is the consequence of a biological event occurring in the target (target-dependent acquired resistance), whereas in other cases acquired resistance is the consequence of the activation of other pathways (target-independent acquired resistance). As for EGFR mutant NSCLCs the emergence of the secondary T790M mutation in the tyrosine kinase domain of EGFR account for up to 60% of erlotinib or gefitinib failure, investigations have focused on the potential efficacy of a new class of drugs that could irreversibly inhibit T790M clones, with reduced activity against wild-type EGFR. This new class of agents includes several new drugs under clinical development, with rociletinib and AZD9291 to-date being the most promising. A large phase I-II study evaluated the efficacy of rociletinib in patients with EGFR mutations who progressed during previous treatment with an EGFR inhibitor. In patients with centrally confirmed T790M-positive tumors, RR was approximately 60% with a median PFS that exceeded 1 year. However, also patients whose tumors were T790M-negative gained some benefits from rociletinib with a RR of 29% and median PFS of approximately 6 months. In a phase I trial conducted in patients who failed first- or second-generation EGFR-TKI, AZD9291 produced a RR of 50%. Importantly, RR was 61% in patients harboring a T790M mutation, whereas in T790M-negative cases RR was 21% with a median PFS of only 3 months. Results of ongoing trials with rociletinib and AZD9291 will better clarify the role of third generation EGFR-TKIs in the treatment algorithm of EGFR mutant NSCLC. Similarly, for the vast majority of ALK positive NSCLCs, resistance is mediated by an ALK dominant mechanism, such as mutations in the kinase domain of ALK gene or ALK fusion gene amplification. So far, a number of mutations have been identified and they seem to confer different sensitivities to second-generation ALK inhibitors. In addition, there are an increasing number of patients for which disease progression occurs only in the central nervous system (CNS), supporting the hypothesis of an inadequate CNS drug penetration. Several novel and more potent second-generation ALK inhibitors are currently under investigations in clinical trials. Among them, ceritinib and alectinib gained the FDA breakthrough therapy designation for ALK-positive NSCLC due to the encouraging results that emerged from a phase I-II trials. Beyond EGFR mutations and ALK translocation, novel biomarkers have been linked with adenocarcinoma histology, including ROS1 fusion gene, MET amplification or mutations, BRAF and HER2 mutations, for which many targeted drugs are currently under investigation. ROS1 rearrangements and MET amplification represent two additional molecular aberrations candidate as predictors for crizotinib sensitivity. Indeed, results from expansion cohorts of the PROFILE 1001 phase I suggested the potential efficacy of crizotinib in lung cancer patients with ROS1 translocation or MET amplification. Another promising target is BRAF mutation, a rare event occurring in 1% to 3% of adenocarcinoma patients, including those with a history of smoking. Recently, combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib emerged as a suitable strategy in patients with BRAF mutant NSCLC. Dual BRAF/MEK axis inhibition translated into a RR of 63% with an acceptable toxicity profile. In conclusion, targeted agents are rapidly changing the natural history of NSCLC, with several new agents entering onto clinical practice. In the next few years, the major challenge will be to define the optimal sequence of targeted agents as well as their combination with novel strategies including immunotherapy.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P1.01-076 - TIGER-1: A Phase 2/3 Study of First Line Rociletinib or Erlotinib in EGFR-Mutant NSCLC (ID 944)
09:30 - 09:30 | Author(s): F. Cappuzzo
- Abstract
Background:
Activating EGFR mutations including the L858R mutation and exon 19 deletions (del19) are key drivers of non-small cell lung cancer (NSCLC) in 10%–15% of patients of European and 30%–35% of Asian descent.[1] Acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib can be driven by additional EGFR mutations, with exon 20 T790M accounting for 50%–60% of cases.[2] Rociletinib (CO-1686) was designed to inhibit T790M as well as L858R and del19 while sparing wild-type EGFR and has demonstrated response rates up to 67% in patients with T790M mutations who had progressed on first or later line EGFR inhibitor therapy. Rociletinib continues to be well tolerated by patients in ongoing studies.[3] Given that T790M mutated subclones commonly emerge during treatment with existing EGFR inhibitors, early targeting of T790M along with initial activating mutations is a rational approach to delay progression.
Methods:
TIGER-1 (NCT02186301) is a randomized, open label study of rociletinib vs erlotinib in patients with mutant EGFR NSCLC. Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced treatment-naive NSCLC (no prior therapy in the metastatic setting and no CNS disease), with documentation of ≥1 activating EGFR mutation (excluding exon 20 insertions) and biopsy within 60 days will be enrolled in this 2-part study. All patients will be randomized 1:1 to rociletinib (500 mg twice daily) or erlotinib (150 mg once daily) and treated until death, qualifying adverse events or disease progression. Patients will be stratified by sensitizing EGFR mutation (T790M, del19, L858R, or other) and territory (Asian vs non-Asian geography). The same patient eligibility criteria will be used for the Phase 2 and Phase 3 portions of TIGER-1. The phase 2 portion is currently enrolling and will transition to the Phase 3 portion upon enrollment of the 201[st] patient. The maturing Phase 2 dataset will contribute to decision-making rules for the Phase 3 interim analyses. The Phase 3 portion will incorporate larger cohorts; the final sample sizes will be determined by interim analyses where the chances of success will be estimated at pre-planned enrollment milestones. The primary endpoint is PFS; secondary efficacy endpoints include objective response rate, duration of response, disease control rate and overall survival. Safety will be assessed via standard adverse event reporting. PFS and OS will be summarized with Kaplan-Meier plots. The stratified log-rank and hazard ratio will compare PFS distributions for rociletinib- vs erlotinib-treated patients. Enrollment is ongoing. 1. Herbst R et al. N Engl J Med. 2008 2. Yu H et al. Clin Cancer Res. 2013 3. Sequist LV J Clin Oncol. 2014
Results:
Not applicable
Conclusion:
Not applicable
-
+
P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P3.04-005 - Discrepancies between ALK FISH and Capture Based NGS Test NEOplus and Clinical Outcome with ALK TKI Therapy (ID 2748)
09:30 - 09:30 | Author(s): F. Cappuzzo
- Abstract
Background:
Research in recent years has unraveled several gene fusions driving tumor development in lung cancer. Especially adenocarcinomas of the lung harboring ALK and ROS1 gene fusions exhibit striking sensitivity to ALK and ROS1 kinase inhibitors respectively, translating to dramatic responses in the clinic. Several different technologies are available to detect aberrant genomic structures. The most frequently used technologies include fluorescent in situ hybridization (FISH), currently considered as the “gold standard”, immunohistochemistry (IHC), RT-PCR based approaches and hybrid capture based NGS sequencing.
Methods:
Here, we describe a selection of tumor samples showing discrepant results between fluorescent in situ hybridization and hybrid capture based NGS sequencing. These included samples with positive FISH but negative NEOplus as well as negative FISH and positive NEOplus results. In addition, we used response data of targeted therapies to evaluate the true genetic phenotype of the tumor.
Results:
Overall, several lung adenocarcinomas showed discrepant results when FISH and NEOplus data were compared. First, one sample was tested positive for ALK rearrangement using FISH which was not confirmed using NEOplus. In line with this finding, the tumor did not respond to ALK TKI treatment. Second, a total of 4 cases were fusion negative by FISH but positive by NEOplus. Three out of 4 ALK positive cases showed clinical response to ALK kinase inhibition, the clinical results for case number 4 are pending. Interestingly, one of these responding tumors was also negative for ALK expression using IHC.
Conclusion:
In summary, we describe a selection of tumor samples with discrepant results for fusion detecting using FISH and NEOplus. Overall, in all of the cases for which clinical response data was available, tumor sensitivity was in line with the initial diagnosis generated by the NEOplus assay.
