Meeting NewsPerspective

Savolitinib, osimertinib combination may benefit certain patients with EGFR-mutated lung cancer

Photo of Lecia Sequist
Lecia V. Sequist

ATLANTA — The combination of savolitinib and osimertinib showed promising clinical activity among patients with EGFR-mutated non-small cell lung cancer resistant to prior EGFR-targeted therapies through MET amplification, according to interim results from two expansion cohorts of the TATTON trial presented at American Association for Cancer Research Annual Meeting.

MET amplification is the second most common driver of acquired resistance to EGFR tyrosine kinase inhibitors — after EGFR T790M — occurring in 5% to 30% of patients with resistance across case series.

“With older EGFR inhibitors like erlotinib [Tarceva; Genentech, Astellas Oncology], MET amplification was the driver of acquired resistance in only 5% to 10% of patients,” Lecia V. Sequist, MD, MPH, thoracic medical oncologist and director of Center for Innovation in Early Cancer Detection at Massachusetts General Hospital Cancer Center, told HemOnc Today. “However, MET amplification makes up a significant proportion of the resistance that occurs with the newest EGFR TKI osimertinib [Tagrisso, AstraZeneca] — up to 25% of resistance to osimertinib is driven by MET. Hence, we need effective treatment strategies for these patients now more than ever.”

Researchers have evaluated other combinations of EGFR- and MET-targeted therapies in these patients, but these attempts failed to improve outcomes.

“Historic studies combining EGFR and MET inhibitors unfortunately did not focus on the most biologically relevant group of patients — EGFR mutation-positive patients who have MET amplification as the driver of acquired resistance,” Sequist said. “TATTON is the first study to examine such a combination in this specific population.”

Sequist and colleagues evaluated new TKIs with greater specificity: savolitinib (HMPL-504/AZD6094; AstraZeneca, Chi-Med) an oral, potent and highly selective MET TKI, and osimertinib.

First cohort

This updated interim analysis from the expansion phase of the TATTON trial includes a cohort of 46 patients (median age, 59 years; range, 41-92; 67% women; 80% Asian) with EGFR-mutated, T790M-negative, MET-amplified NSCLC that progressed on a prior first- or second-generation EGFR TKI. Most patients (67%) received one prior therapy.

Researchers enrolled patients based on local testing for MET-positive status by next-generation sequencing or fluorescence in situ hybridization (MET gene copy 5 or MET/CEP7 ratio 2) or immunohistochemistry (+3 in 50% of tumor cells).

Patients received 80 mg osimertinib plus 600 mg savolitinib daily.

Safety and tolerability served as the primary endpoints. Secondary endpoints included assessment of antitumor activity.

At the time of data cutoff in February 2018, researchers reported a 52% objective response rate, which included 24 patients with partial responses confirmed after 4 weeks.

Median time to response was 43 days (range, 40-43), and median duration of response was 7.1 months.

The most common all-cause adverse events included nausea (37%), diarrhea (30%), fatigue (28%), decreased appetite (28%), pyrexia (26%) and vomiting (22%).

Ninety-one percent of patients experienced a treatment-related adverse event, 43% of which were grade 3 or worse.

Thirty-seven percent of patients experienced serious adverse events and 35% of patients discontinued study treatment due to an adverse event.

Two patients died due to an adverse event, including one patient with possibly savolitinib-related acute kidney injury, and one patient with pneumonia deemed unrelated to study treatment.

Overall, the regimen appears tolerable, although the addition of savolitinib did increase toxicity that caused some patients to discontinue treatment, Sequist said in a press release.

Also, the fatal kidney failure was difficult to evaluate in relation to study treatment, she said.

“Our understanding of the adverse event profile of the osimertinib-savolitinib combination, and how to manage the adverse events, is improving,” she added.

Second cohort

Researchers also evaluated data from a second cohort of 48 patients (median age, 59 years; range, 28-82; 56% men; 77% Asian) with EGFR-mutated NSCLC and acquired resistance driven by MET amplification after receiving osimertinib or another experimental third-generation EGFR TKI. Twenty-seven percent of patients had received three prior treatments, and another 27% received three or more prior treatments, showing how heavily pretreated this cohort was, Sequist said during a press conference.

Because osimertinib received FDA approval for the first-line treatment of patients with EGFR-mutated NSCLC after the initiation of the TATTON trial, only this subset of patients had received prior first-line treatment with osimertinib.

“The newly opened phase 2 SAVANNAH study will further explore the combination of osimertinib plus savolitinib in patients whose disease has progressed on osimertinib and is MET positive,” Sequist said in the press release.

In this cohort, ORR was 25% with 12 partial responses. Median time to response was 46 days (range, 43-51) and median duration of response was 9.7 months.

The most common all cause-adverse events in this cohort were nausea (52%), vomiting (38%), diarrhea (27%), fatigue (25%), decreased appetite (23%) and pyrexia (21%).

Ninety percent of patients experienced treatment-related adverse events, 23% of which were grade 3 or worse.

Twenty-nine percent of patients experienced a serious adverse event; 21% of patients discontinued savolitinib and 10% discontinued osimertinib due to an adverse event.

Two deaths occurred, both of which were deemed unrelated to the study treatment.

“It has been very satisfying to see that preclinical findings generated over 10 years ago suggesting this concept could work have finally been able to be proven clinically,” Sequist told HemOnc Today. “A certain level of acceptance about the importance of repeat biopsies was needed before this type of trial design could successfully be implemented. I was also pleasantly surprised to see that the side effect profile was manageable for most patients over an extended duration of therapy.”

Moving forward, researchers hope to evaluate this combination in earlier lines of treatment.

“One of the important future steps is to look at this combination at the time of diagnosis to see if frontline therapy can be made even more effective by trying to thwart a key mechanism of resistance from day 1,” Sequist said. – by Alexandra Todak

References:

The following were presented at AACR Annual Meeting; March 29-April 3, 2019; Atlanta:

Sequist LV, et al. Abstract CT033.

Yu H, et al. Abstract CT032.

Disclosures: AstraZeneca funded this study. Sequist reports consultant roles with AstraZeneca, Blueprint Medicine, Genentech and Merrimack Pharmaceuticals, and honoraria from AstraZeneca. She also reports research funding paid to her institution from AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Merrimack Pharmaceuticals, Novartis and LOXO Oncology. Please see the abstracts for all other authors’ relevant financial disclosures.

Photo of Lecia Sequist
Lecia V. Sequist

ATLANTA — The combination of savolitinib and osimertinib showed promising clinical activity among patients with EGFR-mutated non-small cell lung cancer resistant to prior EGFR-targeted therapies through MET amplification, according to interim results from two expansion cohorts of the TATTON trial presented at American Association for Cancer Research Annual Meeting.

MET amplification is the second most common driver of acquired resistance to EGFR tyrosine kinase inhibitors — after EGFR T790M — occurring in 5% to 30% of patients with resistance across case series.

“With older EGFR inhibitors like erlotinib [Tarceva; Genentech, Astellas Oncology], MET amplification was the driver of acquired resistance in only 5% to 10% of patients,” Lecia V. Sequist, MD, MPH, thoracic medical oncologist and director of Center for Innovation in Early Cancer Detection at Massachusetts General Hospital Cancer Center, told HemOnc Today. “However, MET amplification makes up a significant proportion of the resistance that occurs with the newest EGFR TKI osimertinib [Tagrisso, AstraZeneca] — up to 25% of resistance to osimertinib is driven by MET. Hence, we need effective treatment strategies for these patients now more than ever.”

Researchers have evaluated other combinations of EGFR- and MET-targeted therapies in these patients, but these attempts failed to improve outcomes.

“Historic studies combining EGFR and MET inhibitors unfortunately did not focus on the most biologically relevant group of patients — EGFR mutation-positive patients who have MET amplification as the driver of acquired resistance,” Sequist said. “TATTON is the first study to examine such a combination in this specific population.”

Sequist and colleagues evaluated new TKIs with greater specificity: savolitinib (HMPL-504/AZD6094; AstraZeneca, Chi-Med) an oral, potent and highly selective MET TKI, and osimertinib.

First cohort

This updated interim analysis from the expansion phase of the TATTON trial includes a cohort of 46 patients (median age, 59 years; range, 41-92; 67% women; 80% Asian) with EGFR-mutated, T790M-negative, MET-amplified NSCLC that progressed on a prior first- or second-generation EGFR TKI. Most patients (67%) received one prior therapy.

Researchers enrolled patients based on local testing for MET-positive status by next-generation sequencing or fluorescence in situ hybridization (MET gene copy 5 or MET/CEP7 ratio 2) or immunohistochemistry (+3 in 50% of tumor cells).

Patients received 80 mg osimertinib plus 600 mg savolitinib daily.

Safety and tolerability served as the primary endpoints. Secondary endpoints included assessment of antitumor activity.

At the time of data cutoff in February 2018, researchers reported a 52% objective response rate, which included 24 patients with partial responses confirmed after 4 weeks.

PAGE BREAK

Median time to response was 43 days (range, 40-43), and median duration of response was 7.1 months.

The most common all-cause adverse events included nausea (37%), diarrhea (30%), fatigue (28%), decreased appetite (28%), pyrexia (26%) and vomiting (22%).

Ninety-one percent of patients experienced a treatment-related adverse event, 43% of which were grade 3 or worse.

Thirty-seven percent of patients experienced serious adverse events and 35% of patients discontinued study treatment due to an adverse event.

Two patients died due to an adverse event, including one patient with possibly savolitinib-related acute kidney injury, and one patient with pneumonia deemed unrelated to study treatment.

Overall, the regimen appears tolerable, although the addition of savolitinib did increase toxicity that caused some patients to discontinue treatment, Sequist said in a press release.

Also, the fatal kidney failure was difficult to evaluate in relation to study treatment, she said.

“Our understanding of the adverse event profile of the osimertinib-savolitinib combination, and how to manage the adverse events, is improving,” she added.

Second cohort

Researchers also evaluated data from a second cohort of 48 patients (median age, 59 years; range, 28-82; 56% men; 77% Asian) with EGFR-mutated NSCLC and acquired resistance driven by MET amplification after receiving osimertinib or another experimental third-generation EGFR TKI. Twenty-seven percent of patients had received three prior treatments, and another 27% received three or more prior treatments, showing how heavily pretreated this cohort was, Sequist said during a press conference.

Because osimertinib received FDA approval for the first-line treatment of patients with EGFR-mutated NSCLC after the initiation of the TATTON trial, only this subset of patients had received prior first-line treatment with osimertinib.

“The newly opened phase 2 SAVANNAH study will further explore the combination of osimertinib plus savolitinib in patients whose disease has progressed on osimertinib and is MET positive,” Sequist said in the press release.

In this cohort, ORR was 25% with 12 partial responses. Median time to response was 46 days (range, 43-51) and median duration of response was 9.7 months.

The most common all cause-adverse events in this cohort were nausea (52%), vomiting (38%), diarrhea (27%), fatigue (25%), decreased appetite (23%) and pyrexia (21%).

Ninety percent of patients experienced treatment-related adverse events, 23% of which were grade 3 or worse.

Twenty-nine percent of patients experienced a serious adverse event; 21% of patients discontinued savolitinib and 10% discontinued osimertinib due to an adverse event.

PAGE BREAK

Two deaths occurred, both of which were deemed unrelated to the study treatment.

“It has been very satisfying to see that preclinical findings generated over 10 years ago suggesting this concept could work have finally been able to be proven clinically,” Sequist told HemOnc Today. “A certain level of acceptance about the importance of repeat biopsies was needed before this type of trial design could successfully be implemented. I was also pleasantly surprised to see that the side effect profile was manageable for most patients over an extended duration of therapy.”

Moving forward, researchers hope to evaluate this combination in earlier lines of treatment.

“One of the important future steps is to look at this combination at the time of diagnosis to see if frontline therapy can be made even more effective by trying to thwart a key mechanism of resistance from day 1,” Sequist said. – by Alexandra Todak

References:

The following were presented at AACR Annual Meeting; March 29-April 3, 2019; Atlanta:

Sequist LV, et al. Abstract CT033.

Yu H, et al. Abstract CT032.

Disclosures: AstraZeneca funded this study. Sequist reports consultant roles with AstraZeneca, Blueprint Medicine, Genentech and Merrimack Pharmaceuticals, and honoraria from AstraZeneca. She also reports research funding paid to her institution from AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Merrimack Pharmaceuticals, Novartis and LOXO Oncology. Please see the abstracts for all other authors’ relevant financial disclosures.

    Perspective
    Hossein Borghaei

    Hossein Borghaei

    MET pathway activation is an important bypass mechanism for tumors with EGFR mutation. Activation of this pathway can lead to tumor progression despite treatment with the usual EGFR TKIs. These two studies indicate that the two drug combinations are effective in controlling tumor progression with reasonable response rates and PFS. The combination was effective regardless of the prior EGFR TKI use. If confirmed, this would represent a new standard of care for this population.

    • Hossein Borghaei, DO, MS
    • Fox Chase Cancer Center

    Disclosures: Borghaei reports no relevant financial disclosures.

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