Posted: November 12, 2019
More than 7,700 delegates from around the world attended the IASLC 2019 World Conference on Lung Cancer (WCLC). With sessions and workshops on every aspect of thoracic oncology patient care, the conference offered attendees from all specialties an opportunity to learn about novel research and hear from the field’s top experts. The summaries offered throughout this issue of ILCN represent just a few topics presented at the meeting. Become an IASLC member to access the full Virtual Library content for this and other live meetings.
LIBRETTO-001 Shows LOXO-292 Successfully Targets RET Fusion NSCLC
There are currently no approved agents to treat RET fusion–positive NSCLC, but that will likely change after the presentation of interim data from the LIBRETTO-001 trial. Selpercatinib, an investigational agent better known as LOXO-292, showed an objective response rate of 68% in previously treated patients and 85% in treatmentnaive patients, according to a primary analysis set of 105 patients enrolled on the trial.
The sponsor plans to file a New Drug Application for the agent with the U.S. Food and Drug Administration before the end of 2019, said presenter Alexander Drilon, MD. “The first RET fusion was discovered in 1985, yet we still have no regulatory approval for the treatment of RET-dependent cancers,” Dr. Drilon said. “RET fusions are bona fide lung cancer drivers, and we have shown they are bona fide druggable targets.”
Multikinase inhibitors tested in the past exhibited modest clinical activity in RET fusion–positive NSCLC but induced significant toxicity. PD-1 and PD-L1 inhibitors appear to be less effective in driver-positive NSCLC, including RET fusions.
Dr. Drilon noted that RET fusions drive 2% of NSCLC, up to 20% of thyroid cancers, and lesser numbers of other solid tumors. Up to half of the patients with advanced disease have brain metastases.
LIBRETTO-001 is an open-label phase I/II trial that includes patients with RET fusion–positive NSCLC, thyroid cancer and other cancers. The interim data presented in Barcelona included a primary analysis set of the first 105 consecutive patients with NSCLC enrolled in trial.
Of 105 patients whose disease had progressed on prior chemotherapy, checkpoint inhibitors, multikinase inhibitors, or combination treatments, 68% realized an objective response.
There were two complete responders at data cutoff for the analysis and two more apparent complete responders awaiting confirmation. Among patients with brain metastases, 91% had an objective response. In a smaller group of 34 treatment-naive patients, 85% achieved an objective response.
Median duration of response to date in the primary analysis was 20.3 months, and median progression-free survival (PFS) was 18.4 months. Th e problem, Dr. Drilon noted, is that the medians are not statistically stable because there has been such a low number of events in the study population.
The durability of response is even murkier in the treatment-naive population. Neither the median duration of response nor PFS can be determined because there have been so few events.
“A large number of patients remain on treatment and have not [had disease progression],” Dr. Drilon indicated. “These patients have not yet reached the endpoint.”
The reported safety profile of selpercatinib includes all 531 patients and is extremely good, according to Dr. Drilon. The most common treatment-emergent adverse event is dry mouth, reported in 32% of patients, followed by diarrhea (31%), hypertension (29%), and increased AST (28%) and ALT (26%) levels.
Most adverse events were judged as not treatment-related, Dr. Drilon said. There were relatively few serious adverse events, and only nine patients (1.7%) discontinued treatment due to treatment-related adverse events.
“We have been trying to target RET fusion for some time now with only modest results,” said discussant Robert C. Doebele, MD, PhD, University of Colorado.
“Selpercatinib succeeded where other agents have not. We are very likely to have some very good options for our patients with RET fusion–positive NSCLC” in the near future, Dr. Doebele said. ✦
Results From First-In-Human Trial for KRAS G12C Treatment Reported
An abstract presented during an Oral Abstract Session dedicated to new approaches and targets in NSCLC suggests that new, more highly targeted therapies may improve outcomes for patients with molecular variants that cannot currently be treated effectively.
The most common undruggable NSCLC mutation is KRAS G12C, found in 11% of patients with NSCLC and about 14% of all lung adenocarcinomas. There is no approved target-specific treatment for KRAS G12C–mutant tumors, which are also seen in up to 3% of other solid tumors.
One of the new potential treatments for KRAS G12C is AMG 510, a novel small-molecule oral agent that selectively targets KRAS G12C and irreversibly locks it into an inactive GDP-bound state.
Ramaswamy Govindan, MD, Alvin J. Siteman Cancer Center of Washington University School of Medicine, presented results of the first-in-human trial with AMG 510. The trial has enrolled 34 patients with NSCLC to date, with 23 evaluable based on the timing of their enrollment and treatment status. Another 42 patients with other KRAS G12C–positive tumors were accrued but not included in the analysis presented during WCLC.
The primary endpoints for the open-label dose-escalation study were dose-limiting toxicities and safety. Key secondary endpoints included pharmacokinetics, objective response rate, duration of response, disease control rate, progression-free survival, and duration of stable disease.
Dosing in the trial included 180 mg, 360 mg, 720 mg, and 960 mg. All doses were given orally once daily.
“Because AMG 510 is so highly selective, we expected to see relatively few adverse events,” Dr. Govindan said. “We were not disappointed in the safety profile.”
The cohort is fairly typical of advanced NSCLC: 83% of patients enrolled had received two or more previous lines of therapy. All patients had confirmed KRAS G12C mutation by molecular testing of tumor biopsies, and none had active brain metastases. Median age was 67 years, 18% were female, and 94.1% had an ECOG performance score of one or two.
“As expected, we did not see many toxicities,” Dr. Govindan reported. “A third of patients had treatment-related toxicities, mostly grade 1 or 2, no grade 4. There were no dose-limiting toxicities, no serious adverse events related to treatment, and no adverse events that led to discontinuation of treatment.”
There were four deaths not related to treatment, and eight serious adverse events also not related to treatment.
The maximum-tested dose, 960 mg daily, yielded the best tumor response and change in tumor burden from baseline. All patients on the 960 mg dose exhibited disease control, with 54% having a partial response.
The first response to treatment came quickly, after approximately 5 weeks, and that response is ongoing, Dr. Govindan said. The mean duration of treatment when data were censored for the report was 15 weeks, with some patients on treatment for more than 42 weeks. Pharmacokinetics for the 960 mg daily dose were good, he continued.
Half-life of the drug is 5.5 hours. Therapeutic concentrations were seen on 2-hour assays for 24 hours.
“There is no need to go to twice-daily dosing because we have full KRAS G12C inhibition over 24 hours,” Dr. Govindan said in response to a question. “And because inhibition is complete with this agent, there is no advantage to giving more drug.”
A phase II monotherapy trial and phase I combination therapy trial are now enrolling patients. ✦
CheckMate 817 Trial Demonstrates Safety of Nivolumab Plus Ipilimumab in Advanced NSCLC
The most recent CheckMate 817 trial results have shown that first-line flat-dose nivolumab plus weight-based ipilimumab exhibited a consistent and reasonable safety profile in special populations with advanced NSCLC, including those with an ECOG performance status (PS) score of 2. Additionally, patients with either high tumor mutational burden (TMB) or higher tumor PD-L1 expression appeared to exhibit improved efficacy (ORR, PFS).
“In this trial, we wanted to see how the combination of ipilimumab and nivolumab performed in patients with advanced NSCLC, particularly in a population with other comorbidities, such as impaired performance status, asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV, who are frequently excluded from registration trials,” said Fabrice Barlesi, MD, PhD, associate editor of the IASLC Lung Cancer News and abstract presenter.
The trial population included two cohorts of patients diagnosed with treatment-naive, advanced NSCLC. Cohort A included patients with an ECOG PS of 0-1, while cohort A1 included 198 patients who had an ECOG PS of 2 or of 0–1 with one of the aforementioned comorbidities. Cohort A1 patients were grouped as ECOG PS 2 (n = 139) and all other special populations (AOSP; n = 59). Patients with known EGFR mutations or ALK translocations sensitive to available targeted therapy were excluded from either cohort.
In both cohorts, nivolumab 240 mg Q2W plus ipilimumab 1 mg/kg Q6W was administered for 2 years or until disease progression/ unacceptable toxicity. Safety and efficacy endpoints were assessed; cohort A1 analyses were exploratory.
“Overall, we found that the rate of treatment-related adverse events (TRAEs), including TRAEs leading to discontinuation or fatal events, were comparable in the two cohorts,” Dr. Barlesi indicated. “Additionally, median PFS, duration of response and PFS by TMB showed encouraging results. Results of an updated analysis are pending.”
Specifically, within cohort A1, grade 3-4 TRAEs were numerically higher in the AOSP subgroup versus the subgroup with an ECOG PS of 2; TRAEs leading to discontinuation were similar across populations. Overall response rate (ORR) was 25% in cohort A1 (patients with an ECOG PS of 2, 19%; AOSP, 36%) and 36% in cohort A. PFS was numerically shorter in cohort A1, as would be expected in this frail population, compared to cohort A; high TMB (≥10 mut/Mb) and higher PD-L1 expression (≥ 1% or ≥ 50%) were associated with numerically longer PFS in both cohorts.
“These findings are significant, as they are the first to demonstrate the activity of this combination outside of a strict phase III clinical trial.” –Dr. Fabrice Barlesi
“These findings are significant, as they are the first to demonstrate the activity of this combination outside of a strict phase III clinical trial. Finding that tolerability of combination nivolumab and ipilimumab in a frail population, with a PS of 2 or associated comorbidities, is comparable to patients with a PS of 0-1 is very interesting,” Dr. Barlesi said. ✦
Three Studies Show Lack of Correlation Between TMB and Outcomes
A post hoc study of the phase I/II KEYNOTE-021 study—the first to demonstrate the safety and efficacy of combination chemotherapy/PD-1 inhibitor for patients with locally advanced or metastatic NSCLC—included a total of 70 patients with tumor tissue available for tumor mutational burden (TMB) analysis. Corey Langer, MD, editor of the IASLC Lung Cancer News, and his colleagues aimed to determine whether TMB was associated with outcomes for patients treated with chemotherapy alone or in combination with pembrolizumab. Response to combination therapy was assessed according to TMB-high and TMB-low tumor types in a separate analysis.
No association between TMB and the combination’s efficacy was found for either objective response (p = 0.180), PFS (p = 0.187), or OS (p = 0.081). This was also true for the TMB analysis of 26 patients treated with chemotherapy alone (p = 0.861 to p = 0.763). In addition, no association between TMB and PD-L1 expression was found.
“Although I still think TMB has a potential role, … it certainly shouldn’t be used—at least, not yet—in therapeutic decision-making,” Dr. Langer said.
Chemotherapy With or Without Pembrolizumab
Similarly, OS, PFS, and response rates were similar in the TMB-evaluable and total patient population of KEYNOTE-189, which compared pembrolizumab plus pemetrexedplatinum chemotherapy with the same chemotherapy alone for patients with metastatic nonsquamous NSCLC. Of the 616 patients enrolled on the trial, 293 were TMB evaluable; of these, 207 were treated with combination therapy and 86 were treated with chemotherapy alone.
TMB status did not have a significant association with OS (p = 0.174), PFS (p = 0.075), or response (p = 0.072) for patients in the combination group. Respective p values for the chemotherapy subgroup were 0.856, 0.055, and 0.434.
As with the secondary analysis of KEYNOTE 021-C and G, investigators also found no association between TMB and PD-L1 expression in the combination arm (p = 0.27) or the chemotherapy subgroup (p = 0.92).
Nivolumab With or Without Ipilimumab
Results of the phase III S1400I trial of nivolumab plus ipilimumab versus nivolumab alone for previously treated stage IV squamous-cell lung cancer were presented earlier this year at the 2019 American Society of Clinical Oncology Annual Meeting. Although an exploratory analysis previously suggested an OS benefit with the combination for patients with TMB > 10 mut/mb and PD-L1 expression of < 5%, a new analysis has contradicted those findings.
The updated analysis evaluated whether TMB predicted improved OS for those patients with PD-L1 expression values from 0% to ≥ 50% who were treated with the combination. The analysis included 231 patients evaluable for TMB, 161 evaluable for PD-L1 expression, and 149 for both biomarkers. Investigators chose a cutoff of TMB ≥ 10 mut/mb for the analysis.
“Although I still think TMB has a potential role, … it certainly shouldn’t be used—at least, not yet—in therapeutic decision-making.” –Dr. Corey Langer
Analysis of TMB across the range of PD-L1 expression levels failed to identify improved OS for any specific subgroup, and neither biomarker was associated with improved OS for the combination. There was a trend toward interaction between TMB and PD-L1 (p = 0.06) favoring the combination, but an analysis of TMB < 10 mut/mb favored nivolumab monotherapy. ✦
Immunotherapy Plus Chemotherapy Improves Results in Extensive-Stage SCLC
The benefit of adding checkpoint inhibition to the current standard chemotherapy in extensive-stage SCLC capped the Presidential Plenary.
The data were part of a planned interim analysis of CASPIAN, a global, randomized, open label study comparing overall survival (OS) with durvalumab plus platinum-etoposide (EP) versus EP alone as first-line treatment for extensivestage (ES) SCLC. Adding durvalumab to platinum-etoposide reduced the likelihood of death by 27% compared to chemotherapy alone.
“Extensive-stage NCLC is an aggressive disease with limited treatment alternatives,” said presenter Luis Paz-Ares, MD. “Patients treated with etoposide and platinum (EP) may have high early response rates, but responses are not durable. We have already seen good clinical activity with checkpoint blockade, especially as first-line treatment, so it made sense to try the combination.”
Until very recently, EP had been the standard first-line treatment for ES-SCLC for more than 30 years.
Patients on the durvalumab + EP arm received up to four cycles of chemotherapy combined with durvalumab with durvalumab continued as maintenance therapy until disease progression or unacceptable toxicity. EP-only patients could receive up to six cycles of treatment and prophylactic cranial irradiation at the investigator’s discretion. The primary endpoint was OS. Secondary endpoints included progression-free survival, response rates, safety, tolerability, and health-related quality of life.
The trial had a third arm comparing durvalumab plus tremelimumab plus EP against EP alone. This arm will continue to the final analysis and was not reported at the 2019 WCLC.
In CASPIAN, 265 patients received durvalumab + EP; 266 received EP alone. With regard to baseline demographics, both cohorts were similar; about 70% male, with similar median age (62-63 years) and stage, smoking status, and similar baseline incidence of brain or CNS metastases. Median follow-up at the time of the analysis was 14.2 months.
The median survival for the durvalumab + EP arm was 13.0 months vs. 10.3 months for EP alone. At 12 months, 53.7% of patients who received the combination were alive vs. 39.8% of patients who received EP. At 18 months, survival had dropped to 33.9% for patients who received the combination and 24.7% for EP alone. The hazard ratio favoring the combination was 0.73 (p = 0.0047).
“Survival benefit was very consistent across all subgroups, including those with brain metastases,” Dr. Pas-Araz said. “We saw no major differences in safety or adverse events between the two arms.” The CASPIAN results are very similar to the earlier IMpower133 trial of atezolizumab plus etoposide and carboplatin (EC) versus EC alone, where the addition of a PD-L1 inhibitor to standard chemotherapy led to a significant improvement in survival, noted discussant Myung-Ju Ahn, MD, Samsung Medical Center, Seoul Korea.
“Durvalumab plus EP is a new standard in extensive-stage SCLC,” Dr. Ahn said. “CASPIAN confirmed the role of checkpoint inhibition in extensive-stage SCLC.” ✦
