Studies Explore Targeted Therapies in Lung Cancer

Studies Explore Targeted Therapies in Lung Cancer

In the June 4 Clinical Science Symposium “Old Targets, New Drugs: HER2 and MET,” researchers presented results of four studies evaluating new approaches to targeted therapies for patients with lung cancer, including metastatic non–small cell lung cancer (NSCLC). For these less common genetic alterations, researchers emphasized the importance of collaboration to continue progress.

T-DM1 in HER2-Overexpressing NSCLC

Dr. Tom Stinchcombe, speaks during the Education Session “Old Targets, New Drugs: HER2 and MET.”
Thomas Stinchcombe, MD, of Duke University, presented results of a phase II trial evaluating T-DM1 in patients with HER2 immunohistochemistry (IHC) 2+/3+ metastatic NSCLC previously treated with chemotherapy (Abstract 8509).

He explained that alterations in HER2, including overexpression and gene amplifications and mutations, have been detected in a subset of patients with NSCLC. In contrast to breast cancer, HER2 amplification in NSCLC does not always correlate with HER2 overexpression. However, HER2 overexpression is associated with poor prognosis. In general, HER2 amplifications and mutations are mutually exclusive in NSCLC.

The frequency of HER2 alterations in NSCLC varies based on the tools and criteria used for assessment; up to 6% of patients exhibit IHC 3+ overexpression, or gene amplification or mutations.

Dr. Stinchcombe noted that the low frequency of HER alterations, as well as the need to separate out HER2 overexpression and gene amplification and mutations, has made it more challenging to select the patients most likely to benefit from HER2-targeted therapy.

Of the 393 patients screened in this phase II trial, 40 patients tested HER2-positive: 20 patients with IHC 2+ and 20 patients with IHC 3+. Patients entered into two cohorts based on IHC 2+ or 3+ and received T-DM1 at the standard dose of 3.6 mg/kg every 3 weeks.

After a median follow-up of 16 months, the overall response rate (ORR) was 0% among patients testing IHC 2+ and 20% among those testing IHC 3+. Dr. Stinchcombe noted that most responses occurred rapidly, although some slower responses were observed. The median treatment duration was short at 1.4 to 2.1 months. The median progression-free survival (PFS) was 2.6 months, and median overall survival (OS) was 12.2 months. The researchers reported no new safety signals.

An exploratory biomarker analysis suggested that responses may be more likely in patients with both HER2 IHC 3+ and HER amplification by next-generation sequencing. Of five patients meeting these criteria, two had objective responses to T-DM1. Dr. Stinchcombe concluded that additional research is needed to identify the patients mostly likely to benefit from T-DM1.

T-DM1 in HER2-Mutated Lung Cancer

Dr. Bob T. Li speaks during the Education Session “Old Targets, New Drugs: HER2 and MET.”
Bob T. Li, MD, MPH, FRACP, of Memorial Sloan Kettering Cancer Center, reported partial results from a phase II basket trial of T-DM1 in patients with HER2-amplified or mutant advanced solid tumor cancers (Abstract 8510). The study enrolled patients with any HER2-amplified cancer; HER2-mutated lung cancers were also eligible and were assessed separately.

The current analysis focused specifically on the population with HER2 mutations; this included 18 patients who had received a median of two prior lines of therapy. The majority of patients (72%) were female and 39% were never-smokers. In this cohort, T-DM1 administered at the standard dose was associated with an ORR of 44% and a median PFS of 4 months. The median response duration was 5 months, though Dr. Li noted that some responses did not occur until 3 to 4 months into treatment.

Although 50% of patients who experience a response had received prior HER2-targeted therapy, there was no association between prior anti-HER2 therapy and response. Safety outcomes were as expected, aside from a higher rate of infusion reactions that were manageable.

Dr. Leena Gandhi speaks during the Education Session “Old Targets, New Drugs: HER2 and MET.”
Correlative studies suggested that high levels of HER2 protein expression were not required for responses. Dr. Li concluded, “These patients do not have an approved targeted therapy; a confirmatory multicenter study of T-DM1 is warranted.”

However, discussant Leena Gandhi, MD, PhD, of the NYU Langone Medical Center and the Laura and Isaac Perlmutter Cancer Center, commented that “for a targeted therapy of any kind, we need a durable PFS benefit and we don’t see that here.” She added that results are awaited from the HER2-amplified cohort of the basket trial.

MET Inhibitors in MET-Mutated NSCLC

Dr. Mark M. Awad speaks during the Education Session “Old Targets, New Drugs: HER2 and MET.”
Mark M. Awad, MD, PhD, of the Dana-Farber Cancer Institute, presented a retrospective analysis on the effect of MET inhibitors on survival in patients with MET exon 14–mutated NSCLC (Abstract 8511). Mutations in MET exon 14 are detectable in 3% of NSCLCs. Although case reports and small series have shown activity with MET inhibitors in these patients, Dr. Awad noted that it may be difficult to demonstrate a survival benefit in a randomized prospective trial because of the widespread availability of crizotinib, planned crossovers, and post-progression treatment.

To attempt to gauge the effects of MET tyrosine-kinase inhibitors (TKIs) on survival in this population, Dr. Awad and colleagues retrospectively evaluated clinical outcomes in 61 patients with MET exon 14–mutated, stage IV NSCLC, including 34 who had not received a MET TKI and 27 patients who had received a MET TKI. The TKIs included crizotinib (administered to 20 patients off-label and four patients on a trial), glesatinib (four patients), and capmatinib (three patients); some patients had received multiple TKIs. The patient population was 57% female and 39% never-smokers; 30% had stage IV disease at diagnosis.

The researchers reported a substantial survival advantage among patients who had received a MET TKI, with a median OS from the date of stage IV diagnosis of 24.6 months compared with 8.1 months in patients who had never received a MET TKI. Findings were similar in the subset of patients who received crizotinib, in whom the median OS was 20.5 months. The median PFS with crizotinib was 7.4 months.

Dr. Patrick C. Ma speaks during the Education Session “Old Targets, New Drugs: HER2 and MET.”
In a subset analysis, the researchers found that patients who had received a MET TKI had also received significantly more lines of systemic therapy in general than those who had not received a MET TKI (p < 0.001). Patients who were treated with a MET TKI were also significantly more likely to have received a PD-1 inhibitor than those not treated with a MET TKI (37% vs. 9%; p = 0.01).

The significance of these findings—whether they reflect a more indolent disease course, differences in treatment decisions, or other patient-related differences—is unknown. In his discussion of the abstract, Patrick C. Ma, MD, MSc, of West Virginia University, thought that the imbalance in the lines of treatment between cohorts raises some concern regarding the analysis.

The researchers concluded that testing for MET exon 14 mutations should be performed up front in all patients with stage IV NSCLC, and prompt initiation of a MET inhibitor should be considered in patients with MET exon 14 mutations.

Response to Immunotherapy in MET-Mutated NSCLC

Dr. Joshua K. Sabari speaks during the Education Session “Old Targets, New Drugs: HER2 and MET.”
Joshua K. Sabari, MD, of Memorial Sloan Kettering Cancer Center, presented results of a retrospective study evaluating tumor characteristics and therapeutic outcomes in 81 patients with MET exon 14–altered NSCLC (Abstract 8512). The investigators were specifically interested in responses to immune checkpoint inhibitors and the relevance of PD-L1 expression in these patients.

Of the 81 patients in the analysis, PD-L1 expression by IHC was performed on 54 specimens (67%). Nearly half of samples (46%) tested PD-L1–high, defined as at least 50% of cells expressing PD-L1. Another 19% had PD-L1 expression between 1% and 49%, and the remaining 35% were PD-L1–negative. No significant associations were found between PD-L1 expression and any clinical or molecular features.

Dr. Sabari noted that tumor mutational burden, which reflects the number of nonsynonymous somatic mutations present per megabase of genome, has been identified as a potential biomarker of response to immunotherapy. He and his colleagues compared tumor mutational burden in 78 patients with MET exon 14-altered NSCLC against a large set of 1,769 NSCLC cases sequenced on the same platform at their institution.

They found that tumor mutational burden was significantly lower in patients with MET exon 14 alterations compared with the general NSCLC population, with a median of 3.8 mutations per megabase and 5.7 mutations per megabase, respectively (p = 0.0006). Researchers found no significant association between PD-L1 expression and total tumor burden.

A total of 15 patients with MET exon 14–altered NSCLC received an immune checkpoint inhibitor and were evaluable for response. Fourteen patients had received a PD-1– or PD-L1–targeting single agent, and the remaining patient had received a PD-1–targeting and CTLA-4–targeting combination therapy. A total of six patients had not received any prior therapy.

In this cohort, responses to immunotherapy were poor, with an ORR of only 6.7%. PD-L1 expression did not appear to predict responses to immunotherapy in this cohort, and no responses were observed among the six patients with high PD-L1 expression. Tumor mutational burden was also not predictive of response to immunotherapy; no responses were observed in patients with high tumor mutation burden.

In his discussion, Dr. Ma said that responses to immunotherapy in patients with MET exon 14–altered NSCLC appear to be very poor, even in patients with high PD-L1 expression. He also emphasized the importance of prompt initiation with a MET inhibitor in these patients. However, Dr. Ma also said that additional research is “urgently needed” regarding the interplay between MET exon 14 alterations and the immune checkpoint pathway.

“In my mind,” he concluded, “[MET exon 14] should not be excluded at this time for immune-oncology therapy just yet.”  

–Melinda Tanzola, PhD