publication date: May. 18, 2018
FDA finds survival deficit in some patients taking Keytruda or Tecentriq as monotherapy in urothelial cancer with low expression of PD-L1
FDA has alerted health care professionals, oncology clinical investigators, and the public about decreased survival associated with the use of Keytruda (pembrolizumab) or Tecentriq (atezolizumab) as monotherapy in clinical trials to treat patients with metastatic urothelial cancer who have not received prior therapy and who have low expression of the protein programmed death ligand 1.
In two ongoing clinical trials (KEYNOTE-361 and IMVIGOR-130), the Data Monitoring Committees’ early reviews found patients in the monotherapy arms of both trials with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.
There was no change in the adverse event profile of Keytruda or Tecentriq. Both Merck, manufacturer of Keytruda, and Genentech, manufacturer of Tecentriq, have stopped enrolling patients whose tumors have PD-L1 low status to the Keytruda or Tecentriq monotherapy arms per the DMCs’ recommendations.
The clinical trials compare platinum-based chemotherapy combined with Keytruda or Tecentriq to platinum-based chemotherapy alone.
Both trials enrolled a third arm of monotherapy with Keytruda or Tecentriq to compare to platinum-based chemotherapy alone. The monotherapy arms remain open only to patients whose tumors have PD-L1 high status.
The combination arms and the chemotherapy arms of both studies also remain open. The FDA is reviewing the findings of the ongoing clinical trials and will communicate new information as necessary.
Both Keytruda and Tecentriq are approved under accelerated approval for the treatment of locally advanced or metastatic urothelial carcinoma patients who are not eligible for cisplatin-containing chemotherapy, irrespective of PD-L1 status. Patients taking Keytruda or Tecentriq for other approved uses should continue to take their medication as directed by their health care professional.
Health care professionals should be aware that the populations enrolled in the ongoing clinical trials were eligible for platinum-containing chemotherapy, and therefore differ from those enrolled in the trials that led to the accelerated approvals of both Keytruda and Tecentriq in the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy, the agency said.
FDA recommends providers select patients for the treatment of locally advanced or metastatic urothelial cancer using the criteria described in Section 14 of each label. These criteria supported the approvals for Keytruda and Tecentriq for initial monotherapy in cisplatin-ineligible patients. Keytruda and Tecentriq are approved by FDA for the treatment of multiple types of other cancers.
Tecentriq and Avastin plus carboplatin and paclitaxel show longer remissions vs. Avastin plus carboplatin and paclitaxel in metastatic NSCLC
Genentech announced positive results from the phase III IMpower150 study of Tecentriq (atezolizumab) and Avastin (bevacizumab) plus carboplatin and paclitaxel for the first-line treatment of chemotherapy-naïve people with metastatic non-squamous non-small cell lung cancer.
Genentech is a unit of Roche.
This interim analysis showed that Tecentriq and Avastin plus carboplatin and paclitaxel helped people live significantly longer, compared with Avastin plus carboplatin and paclitaxel (median overall survival = 19.2 versus 14.7 months; hazard ratio = 0.78, 95 percent CI: 0.64-0.96; p=0.016) in the intention-to-treat wild-type population, a co-primary endpoint of the study.
An OS advantage was observed in all pre-specified exploratory biomarker-selected subgroups analyzed, which included people with EGFR- and ALK-positive mutations who had received an appropriate targeted therapy, and those with varying levels of PD-L1 expression or with negative PD-L1 expression.
People with liver metastases treated with the Tecentriq combination also had a survival advantage. The safety profile of the Tecentriq and Avastin plus carboplatin and paclitaxel combination was consistent with the safety profiles of the individual medicines, and no new safety signals were identified with the combination.
At this interim analysis, the combination of Tecentriq plus carboplatin and paclitaxel (Arm A) did not show a statistically significant OS benefit when compared to the combination of Avastin plus carboplatin and paclitaxel (Arm C). Arm A will continue as planned to the final analysis. Safety in the Tecentriq plus carboplatin and paclitaxel arm appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination.
The combination of Tecentriq and Avastin plus carboplatin and paclitaxel was recently granted Priority Review from the FDA for the first-line treatment of chemotherapy-naïve people with metastatic non-squamous NSCLC. The FDA is expected to make a decision on approval by Sept. 5. IMpower150 is one of eight phase III lung cancer studies underway, evaluating Tecentriq alone or in combination with other medicines. Following the IMpower150 and IMpower131 studies, three more Phase III lung cancer studies are expected to report this year.
IMpower150 is a multicenter, open-label, randomized, controlled phase III study evaluating the efficacy and safety of Tecentriq in combination with chemotherapy (carboplatin and paclitaxel) with or without Avastin in people with stage IV or recurrent metastatic non-squamous NSCLC who had not been treated with chemotherapy for their advanced disease.
It enrolled 1,202 people of which those with ALK and EGFR mutations were excluded from the primary ITT analysis. People were randomized (1:1:1) to receive:
Tecentriq plus carboplatin and paclitaxel (Arm A), or
Tecentriq and Avastin plus carboplatin and paclitaxel (Arm B), or
Tecentriq plus carboplatin and paclitaxel (Arm C, control arm).
During the treatment-induction phase, people in Arm A received Tecentriq administered intravenously at 1200 mg in combination with intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, people received maintenance treatment with Tecentriq (1200 mg every 3 weeks) until loss of clinical benefit or disease progression.
IMpower150 was designed to formally compare Tecentriq plus chemotherapy (Arm A) versus Avastin plus chemotherapy (Arm C), only if Tecentriq and Avastin plus chemotherapy (Arm B) is shown to improve OS in the ITT-WT population compared to Avastin plus chemotherapy (Arm C).
People in Arm B received induction treatment with Tecentriq (1200 mg) and Avastin administered intravenously at 15 mg/kg in combination with intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. People then received maintenance treatment with the Tecentriq and Avastin regimen until disease progression (Avastin) or loss of clinical benefit/disease progression (Tecentriq).
People in Arm C received induction treatment with Avastin administered intravenously at 15 mg/kg plus intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. This was followed by maintenance treatment with Avastin alone until disease progression.
The co-primary endpoints were PFS and OS, as determined by the investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). The co-primary OS endpoint in IMpower150 was assessed in all randomized people without an EGFR or ALK genetic mutation (intention-to-treat wild-type). Key secondary endpoints included investigator-assessed PFS, OS and safety in the ITT population and in EGFR and ALK mutation subgroups. The study met its co-primary endpoints of OS and PFS per study protocol.
The safety profile of the Tecentriq and Avastin plus carboplatin and paclitaxel combination was consistent with the safety profiles of the individual medicines, and no new safety signals were identified with the combination.
Serious adverse events (grade III-IV) related to treatment were observed in 57 percent of people who received Tecentriq and Avastin plus carboplatin and paclitaxel compared to 49 percent of those who received Avastin plus carboplatin and paclitaxel.
Bone scan software calculates prognosis of advanced prostate cancer
A software tool to automatically calculate how extensively bones have been infiltrated by prostate cancer is both accurate and speedy, capturing key prognostic information related to survival and the development of symptoms over time.
The software, called the automated bone scan index, was tested in a large, global multi-center study led by Duke Cancer Institute researchers. Findings from the phase III study were published in JAMA Oncology.
The current method to measure bone metastases includes a CT or MRI scan along with a nuclear medicine test that involves a manual assessment of the bone metastases. Manual bone scan assessments using a formula based on bone mass and the number of cancer lesions can be done, but that process is both subjective and time-consuming, so is not used regularly in clinic.
The new automated Bone Scan Index is a software program that scans the radiographic studies and quantifies the degree of bone metastases in a matter of seconds. In the Duke-led study, 721 men with advanced, recurrent prostate cancer were evaluated using the aBSI software and followed for the duration of their care.
The researchers found that the aBSI technology was significantly better than the older, manual calculation at predicting survival time for the men regardless of how widespread their bone metastases were. Added to other key clinical information, the technology provided prognostic information about patient outcomes and improved the ability to predict the time to symptom progression and the onset of pain.
The study is lead by Andrew Armstrong, associate professor of medicine and surgery and associate director of the Duke Cancer Institute’s Prostate and Urologic Cancer Center; et al.