Non-small Cell Lung Cancer
Conditions
Keywords
cancer, metastatic, locally advanced, lung, non-small cell lung cancer, NSCLC, epidermal growth factor receptor, EGFR, T790M, CO-1686, unresectable, recurrent, EGFR-directed therapy, irreversible EGFR inhibitor, TIGER, Rociletinib
Brief summary
The purpose of this study is to compare the anti-tumor efficacy of oral single-agent rociletinib, as measured by investigator assessment of the PFS, with that of single-agent cytotoxic chemotherapy in patients with EGFR-mutated, advanced/metastatic NSCLC after failure of at least 1 previous EGFR-directed TKI and at least 1 line of platinum-containing doublet chemotherapy.
Detailed description
This is a Phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of oral rociletinib at 500 mg BID and 625 mg BID compared with that of single-agent cytotoxic chemotherapy, in patients with previously treated mutant EGFR NSCLC. Eligible patients are those with mutant EGFR NSCLC previously treated with at least 1 EGFR inhibitor and at least 1 line of platinum-containing chemotherapy doublet for advanced/metastatic NSCLC. After providing informed consent to participate and screening to confirm eligibility, patients will be randomized 1:1:1 to receive either oral rociletinib 500 mg BID, oral rociletinib 625 mg BID, or single-agent cytotoxic chemotherapy (investigator choice of pemetrexed, gemcitabine, docetaxel, or paclitaxel; choice of chemotherapy agent must be specified before randomization).
Interventions
DRUGRociletinib
DRUGPemetrexed or gemcitabine or paclitaxel or docetaxel
Sponsors
Clovis Oncology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All patients must meet all of the following inclusion criteria: 1. Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with radiological progression on the most recent therapy received 2. Documented evidence of a tumor with 1 or more EGFR activating mutations excluding exon 20 insertion 3. Disease progression confirmed by radiological assessment while receiving treatment with single agent EGFR-TKI (e.g., erlotinib, gefitinib, afatinib, or dacomitinib) or EGFR-TKI in combination with other targeted therapy (e.g. bevacizumab, immunotherapy) 4. Multiple lines of prior treatment are permitted and there is no specified order of treatment, but in the course of their treatment history, patients must have received and have radiologically documented disease progression following: At least 1 line of prior treatment with a single-agent EGFR-TKI (e.g., erlotinib, gefitinib, afatinib, or dacomitinib) If EGFR-TKI is a component of the most recent treatment line, the washout period for the EGFR-TKI is a minimum of 3 days before the start of study drug treatment AND A platinum-containing doublet chemotherapy (either progressed during therapy or completed at least 4 cycles without progression with subsequent progression after a treatment-free interval or after a maintenance treatment). If cytotoxic chemotherapy is a component of the most recent treatment line, treatment with chemotherapy should have been completed at least 14 days prior to start of study treatment. When an EGFR-TKI is given in combination with platinum-containing doublet chemotherapy, treatment with the EGFR-TKI may continue until at least 3 days before start of treatment. 5. Have undergone a biopsy of either primary or metastatic tumor tissue within 60 days prior to start of treatment and have tissue sent to the central laboratory prior to randomization 6. Measureable disease according to RECIST Version 1.1 7. Life expectancy of at least 3 months 8. ECOG performance status of 0 to 1 9. Age ≥ 18 years (in certain territories, the minimum age requirement may be higher e.g., age ≥ 20 years in Japan and Taiwan, age ≥ 21 years in Singapore) 10. Patients should have recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤ 1 from any significant chemotherapy-related toxicities 11. Adequate hematological and biological function 12. Written consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study specific evaluation
Exclusion criteria
Any of the following criteria will exclude patients from study participation: 1. Any other malignancy associated with a high mortality risk within the next 5 years and for which the patients may be (but not necessarily) currently receiving treatment Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enroll in the trial provided all chemotherapy was completed \> 6 months prior and/or bone marrow transplant \> 2 years prior 2. Known pre-existing interstitial lung disease 3. Tumor small cell transformation by local assessment, irrespective of presence of T790M+ component 4. Patients with leptomeningeal carcinomatosis are excluded. Other central nervous system (CNS) metastases are only permitted if treated, asymptomatic, and stable (not requiring steroids for at least 2 weeks prior to randomization and the patient is neurologically stable i.e. free from new symptoms of brain metastases) 5. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and that treatment cannot be either discontinued or switched to a different medication (known to have no effect on QT) before starting protocol-specified treatment (see http://crediblemeds.org/ for a list of QT-prolonging medications) 6. Prior treatment with rociletinib, or other drugs that target T790M+ mutant EGFR with sparing of WT-EGFR including but not limited to osimertinib, HM61713, and TAS-121 7. Any contraindications for therapy with pemetrexed, paclitaxel, gemcitabine or docetaxel unless a contraindication with respect to one of these drugs will not affect the use of any of the others as a comparator to rociletinib 8. Any of the following cardiac abnormalities or history: 1. Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTCF) \> 450 msec 2. Inability to measure QT interval on ECG 3. Personal or family history of long QT syndrome 4. Implantable pacemaker or implantable cardioverter defibrillator 5. Resting bradycardia \< 55 beats/min 9. Non-study related surgical procedures ≤ 7 days prior to randomization. In all cases, the patient must be sufficiently recovered and stable before treatment administration 10. Females who are pregnant or breastfeeding 11. Refusal to use adequate contraception for fertile patients (females and males) while on treatment and for 6 months after the last dose of study treatment (rociletinib and chemotherapy irrespective of single cytotoxic agent used) 12. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study (e.g., substance abuse, uncontrolled intercurrent illness including uncontrolled diabetes, active infection, arterial thrombosis, and symptomatic pulmonary embolism) 13. Any other reason the investigator considers the patient should not participate in the study 14. Treatment with live vaccines initiated less than 4 weeks prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) | Cycle 1 Day 1 to End of Treatment, up to approximately 35 months. This Time Frame includes the cross-over period, however, participants who crossed over to rociletinib were not analyzed for PFS. | PFS was calculated as 1+ the number of days from the date of randomization to documented radiographic progression as determined by the investigator, or death due to any cause, whichever occurs first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of one or more new lesions is also considered progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Cycle 1 Day 1 to date of death, assessed up to 3 years | OS was calculated as 1+ the number of days from randomization to death due to any cause. Patients without a documented date of death were censored on the date the patient was last known to be alive. |
| Percentage of Participants With Confirmed Response | Cycle 1 Day 1 to End of Treatment, up to approximately 35 months. This Time Frame includes the cross-over period, however, participants who crossed over to rociletinib were not analyzed for best overall confirmed response. | Percentage of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Overall Response (OR),is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment was dependent on the achievement of both measurement and confirmation criteria. |
| Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment | Cycle 1 Day 1 to End of Treatment, up to approximately 35 months | DOR in patients with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from date that any of these best responses is first recorded until first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. PR is at least a 30% decrease in sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Overall Response is the best response from start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). |
| Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling | Cycles 2 Day 1 to Cycle 7 Day 1, or approximately 6 months | Blood samples were drawn for PK analysis at 21 ± 3 day intervals for the first 6 months (Day 1 of Cycles 2 to 7 inclusive). The sample could be taken predose or postdose. Plasma concentrations are presented for Rociletinib and 3 metabolites (M460, M502, M544). |
Countries
Australia, France, Germany, Italy, Netherlands, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
149 subjects recruited from 83 sites in 10 countries and randomized (1:1) to treatment with rociletinib or single-agent cytotoxic chemotherapy (investigator's choice of pemetrexed, gemcitabine, docetaxel, or paclitaxel). Crossover to rociletinib treatment permitted for comparator chemotherapy treated subjects but only after eligibility confirmed.
Participants by arm
| Arm | Count |
|---|---|
| Rociletinib 500 mg BID Starting dose of 500mg. Taken orally twice daily (continuous 21 day treatment cycle). Treatment duration until radiographically confirmed disease progression. | 53 |
| Rociletinib 625 mg BID Starting dose of 625mg. Taken orally twice daily (continuous 21 day treatment cycle). Treatment duration until radiographically confirmed disease progression. | 22 |
| Chemotherapy Pemetrexed - 500 mg/m2 pemetrexed given intravenously on Day 1 of each 21-day cycle.
Gemcitabine - 1250 mg/m2 gemcitabine given intravenously on Day 1 and 8 of each 21-day cycle.
Paclitaxel - 80 mg/m2 paclitaxel given intravenously on a weekly basis as part of a continuous 21-day cycle; i.e. dosing will be on Days 1, 8, and 15 of each 21-day cycle.
Docetaxel - 75 mg/m2 docetaxel (60 mg/m2 for patients residing in East-Asian territories) given intravenously on Day 1 of each 21-day cycle.
or 35 mg/m2 docetaxel given intravenously on a weekly basis as part of a continuous 21-day cycle; i.e. dosing will be on Days 1, 8, and 15 of each 21-day cycle.
Treatment duration until radiographically confirmed disease progression. | 74 |
| Total | 149 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 | 6 |
| Overall Study | Death | 3 | 3 | 3 |
| Overall Study | Miscellaneous | 0 | 0 | 4 |
| Overall Study | Missing | 0 | 0 | 1 |
| Overall Study | Physician Decision | 2 | 0 | 5 |
| Overall Study | Progressive Disease | 42 | 14 | 49 |
| Overall Study | Study Terminated by Sponsor | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 6 |
Baseline characteristics
| Characteristic | Total | Rociletinib 500 mg BID | Rociletinib 625 mg BID | Chemotherapy |
|---|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 10.84 | 61.6 years STANDARD_DEVIATION 11.66 | 63.4 years STANDARD_DEVIATION 12.3 | 61.4 years STANDARD_DEVIATION 9.84 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 4 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 136 Participants | 46 Participants | 22 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 3 Participants | 0 Participants | 3 Participants |
| History of CNS Metastases | 63 Participants | 23 Participants | 9 Participants | 31 Participants |
| Number of Previous Therapies | 3.0 Therapies | 3.0 Therapies | 3.0 Therapies | 3.0 Therapies |
| Race/Ethnicity, Customized Asian | 59 Participants | 23 Participants | 6 Participants | 30 Participants |
| Race/Ethnicity, Customized Non-White, Non-Asian | 13 Participants | 6 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 77 Participants | 24 Participants | 15 Participants | 38 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 59 Participants | 23 Participants | 6 Participants | 30 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 4 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 77 Participants | 24 Participants | 15 Participants | 38 Participants |
| Sex: Female, Male Female | 87 Participants | 35 Participants | 13 Participants | 39 Participants |
| Sex: Female, Male Male | 62 Participants | 18 Participants | 9 Participants | 35 Participants |
| Time Since Diagnosis of NSCLC | 40.1 Months STANDARD_DEVIATION 28.29 | 42.6 Months STANDARD_DEVIATION 35.54 | 37.5 Months STANDARD_DEVIATION 16.92 | 39.0 Months STANDARD_DEVIATION 25.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 53 | 3 / 22 | 3 / 73 | 6 / 36 | 0 / 3 |
| other Total, other adverse events | 53 / 53 | 21 / 22 | 71 / 73 | 35 / 36 | 3 / 3 |
| serious Total, serious adverse events | 23 / 53 | 7 / 22 | 23 / 73 | 18 / 36 | 1 / 3 |
Outcome results
Primary
Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)
PFS was calculated as 1+ the number of days from the date of randomization to documented radiographic progression as determined by the investigator, or death due to any cause, whichever occurs first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of one or more new lesions is also considered progression.
Time frame: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months. This Time Frame includes the cross-over period, however, participants who crossed over to rociletinib were not analyzed for PFS.
Population: Intent-to-treat: All patients randomized. 1 patient in the Chemotherapy treatment group was not included in the analysis, due to discontinuation of study shortly after randomization and prior to first dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rociletinib 500 mg BID | Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) | 125.0 Days |
| Rociletinib 625 mg BID | Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) | 166.0 Days |
| Chemotherapy | Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) | 77.0 Days |
Secondary
Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment
DOR in patients with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from date that any of these best responses is first recorded until first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. PR is at least a 30% decrease in sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Overall Response is the best response from start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Time frame: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months
Population: The DOR was measured only in those patients with a confirmed Complete Response (CR) or Partial Response (PR). The overall number of participants analyzed in the Chemotherapy arm includes only participants treated with chemotherapy and not patients who crossed over into the rociletinib treatment groups.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rociletinib 500 mg BID | Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment | 335.0 Days |
| Rociletinib 625 mg BID | Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment | 275.0 Days |
| Chemotherapy | Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment | 206.0 Days |
Secondary
Overall Survival (OS)
OS was calculated as 1+ the number of days from randomization to death due to any cause. Patients without a documented date of death were censored on the date the patient was last known to be alive.
Time frame: Cycle 1 Day 1 to date of death, assessed up to 3 years
Population: Intent-to-treat: All patients randomized.1 patient in the Roci 500 and 2 patients in the Chemo treatment group were not included in the analysis because their OS data was not collected. 1 additional patient in the Chemo group was not included due to discontinuation from study shortly after randomization and prior to first dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rociletinib 500 mg BID | Overall Survival (OS) | 665 Days |
| Rociletinib 625 mg BID | Overall Survival (OS) | 541 Days |
| Chemotherapy | Overall Survival (OS) | 348 Days |
Secondary
Percentage of Participants With Confirmed Response
Percentage of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Overall Response (OR),is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment was dependent on the achievement of both measurement and confirmation criteria.
Time frame: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months. This Time Frame includes the cross-over period, however, participants who crossed over to rociletinib were not analyzed for best overall confirmed response.
Population: Intent-to-treat: All patients randomized. 1 patient in the Chemotherapy treatment group was not included in the analysis, due to discontinuation of study shortly after randomization and prior to first dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rociletinib 500 mg BID | Percentage of Participants With Confirmed Response | 17.0 percentage of participants |
| Rociletinib 625 mg BID | Percentage of Participants With Confirmed Response | 18.2 percentage of participants |
| Chemotherapy | Percentage of Participants With Confirmed Response | 8.2 percentage of participants |
Secondary
Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling
Blood samples were drawn for PK analysis at 21 ± 3 day intervals for the first 6 months (Day 1 of Cycles 2 to 7 inclusive). The sample could be taken predose or postdose. Plasma concentrations are presented for Rociletinib and 3 metabolites (M460, M502, M544).
Time frame: Cycles 2 Day 1 to Cycle 7 Day 1, or approximately 6 months
Population: A small subset of patients treated with rociletinib (ie, patients randomized to receive rociletinib or who crossed over to receive rociletinib following treatment with single agent cytotoxic chemotherapy). Note: 2 patients in the 625mg treatment group had M502 values at upper limit of quantification (ULOQ) which were set as missing values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rociletinib 500 mg BID | Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling | Rociletinib | 80.4 Plasma concentration (ng/mL) |
| Rociletinib 500 mg BID | Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling | M460 | 20.0 Plasma concentration (ng/mL) |
| Rociletinib 500 mg BID | Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling | M502 | 573.0 Plasma concentration (ng/mL) |
| Rociletinib 500 mg BID | Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling | M544 | 765.0 Plasma concentration (ng/mL) |
| Rociletinib 625 mg BID | Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling | M544 | 525.0 Plasma concentration (ng/mL) |
| Rociletinib 625 mg BID | Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling | Rociletinib | 207.0 Plasma concentration (ng/mL) |
| Rociletinib 625 mg BID | Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling | M460 | 555.0 Plasma concentration (ng/mL) |
| Rociletinib 625 mg BID | Plasma PK for Patients Treated With Rociletinib Based on Sparse Sampling | M502 | 3260.0 Plasma concentration (ng/mL) |