ctDNA Identifies Acquired Resistance Mechanisms to Savolitinib in MET+ Gastric Cancer

April 21, 2020
Brittany Cote

The use of circulating tumor DNA via baseline tumor tissue or rebiopsy led to the identification of several MET mutations previously unidentified upon progression on savolitinib in patients with gastric cancer, as well as MET amplifications as drivers of resistance to the agent during monotherapy treatment of those with MET-amplified disease.

Melanie M. Frigault, PhD

The use of circulating tumor DNA (ctDNA) via baseline tumor tissue or rebiopsy led to the identification of several MET mutations previously unidentified upon progression on savolitinib in patients with gastric cancer, as well as MET amplifications as drivers of resistance to the agent during monotherapy treatment of those with MET-amplified disease, according to an article published by the JCO Precision Oncology.1

For this analysis, investigators used a next-generation sequencing (NGS) 100-gene panel and identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when a patient with MET-amplified gastric cancer develops resistance to savolitinib.

“ctDNA is a powerful tool for identifying potential genomic aberrations that emerge during therapy to confer resistance to targeted therapies,” wrote lead author Melanie M. Frigault, PhD, of AstraZeneca, and co-investigators. “In gastric cancer, ctDNA monitoring of shedding tumors may have clinical utility and provide dynamic assessments that are challenging to conduct by rebiopsy.”

As part of the gastric cancer—specific umbrella trial, the VIKTORY trial, investigators enrolled patients with MET-amplified disease into 2 separate trials: a phase 2 trial of savolitinib monotherapy in patients with MET-amplified advanced gastric adenocarcinoma as a third-line treatment (NCT02449551) and a phase 1b/2 trial of savolitinib in combination with docetaxel in the same patient population as second-line treatment (NCT02447406).2,3

Data from the phase 1 trial of savolitinib plus docetaxel in patients with MET-amplified gastric cancer revealed promising antitumor activity; notably, the approach resulted in durable responses that persisted for 297 days. These data have yet to be officially published, but in this analysis, the investigators reported the first 3 consecutive patients with MET amplification who were given savolitinib monotherapy in either the second- or third-line setting.

Patients were screened for the presence of MET amplification via tumor sequencing as part of the VIKTORY trial and were confirmed wild-type for MET. A total of 715 patients were screened with genomic sequencing in the VIKTORY trial and the incidence of MET amplification was reported to be 3.5%. In this study, investigators sought to evaluate the feasibility of using a 100-gene panel in patients with MET-amplified disease from baseline until disease progression using both matched biopsies and ctDNA.

The first patient was a 35-year-old male who was diagnosed with metastatic gastric cancer at presentation; he was microsatellite stable, had HER2-negative disease, and experienced rapid disease progression after 5 cycles of capecitabine plus oxaliplatin. The pathologic findings showed tubular adenocarcinoma, poorly differentiated, and a MET/CEP7 ratio of 10. At baseline, prior to savolitinib treatment, the patient’s ctDNA showed TP53 P190L at 44%, MET 3.0 copy number, and MYC 5.6 copy number.

The patient experienced a dramatic response to 2 cycles of savolitinib, which was concordant with a 7% decrease in allele frequency of TP53 P190L, MET 1.4 copy number, and MYC 3.4 copy number in the ctDNA. The tumor size was also reduced by 68.5% compared with the size at baseline. Moreover, despite the fact that the patient maintained a radiologic and clinical partial response (PR) to the MET inhibitor, investigators observed newly detected low frequencies of MET D1228H, MET D1228N, MET D1228V, and MET Y1230C at 5%, 5%, 35%, and 3%, respectively.

After 3.5 months of savolitinib treatment, the patient experienced rapid progression and the patient’s ctDNA indicated persistently low copy numbers of MET and MYC compared with those at baseline. However, the allele frequencies of MET D1228H and MET D1228N significantly increased to 31% and 12%, respectively, compared with those in ctDNA collected during the PR. Additionally, the MET D1228V (1%) and MET Y1230C (1%) mutations were also reported at progression.

Notably, MET D1228N is known to be a resistance mutation to crizotinib (Xalkori) in lung cancer; MET Y1230C is associated with crizotinib resistance in non—small cell lung cancer; and MET D1228V has been shown to result in resistance to type 1 MET TKIs in lung cancer. Because the patient’s samples demonstrated decreases in MET and MYC levels versus those at baseline, investigators believe that the MET copy number did not drive resistance in this patient. Additionally, the fact that the patient experienced progression to bone and bone marrow metastases rather than previous lymph nodes suggests the emergence of an aggressive clone that spread to the bone and bone marrow at the time of disease progression.

“Our data suggest that, rather than MET amplifications, MET mutations drove the rapid progression observed in this patient,” the investigators wrote.

The second patient was a 74-year-old female who was diagnosed with gastric cancer and extensive liver metastases at presentation; she was enrolled in the VIKTORY trial at the time of diagnosis. Notably, her disease rapidly progressed to liver and peritoneal seeding following the first cycle of first-line titanium silicate-1 chemotherapy. After MET amplification was identified, she was enrolled in the savolitinib monotherapy arm as a second-line treatment. Specifically, the patient had tubular adenocarcinoma that was poorly differentiated, microsatellite stable, and HER2 negative. ctDNA showed no MET amplification when the patient achieved a PR with savolitinib.

Following 4 cycles of savolitinib, the MET copy number was 2.7, showed a slight increase from diploid, and ctDNA detected the emergence of a TP53 G245D (2%) variant. The tumor size was reduced by 83.5% compared with the size at baseline, and after 6 months of treatment with savolitinib, the patient developed radiologic progression.

“Interestingly, in contrast to the newly emerging mutations conferring resistance to savolitinib in patient 1, the second patient developed a high level of MET amplification of 13 copies and CDK6 copy number of 3.9 at progression,” the investigators noted.

Additionally, high concordance was noted between the ctDNA and tumor tissue DNA with a re-increase in MET amplification and CDK6 amplification that had not been identified at the time of PR. The ctDNA sample at progression indicated that the TP53 G245D substitution containing the clone had increased from a 2% allele fraction to a 22% allele fraction; this was confirmed in the progression rebiopsy where the same TP53 G245D substitution that was not detected in normal DNA was found to have increased to an 82% allele fraction.

The third patient was a 31-year-old female who had underwent a total gastrectomy for her disease in 2013. The pathologic diagnosis of the surgical specimen was pT4N3M0. The patient had poorly differentiated tubular adenocarcinoma, was microsatellite stable, and had HER2-negative disease. The patient developed recurrent metastases to both ovaries 18 months after postoperative chemoradiation therapy. Following a bilateral oophorectomy, the patient received 6 cycles of a postoperative capecitabine plus cisplatin regimen. Ten months later, the patient developed a peritoneal seeding mass.

Despite the fact that this patient’s tumor tissue sequencing failed, her tumor at the time of oophorectomy showed MET IHC 3+ and MET amplification by FISH (MET/SEP7 ratio, 5.6). The tumor was found to have decreased in volume during savolitinib therapy and the patient achieved a PR for 6 months. Genomic sequencing of the ctDNA sample suggested that this patient had a nonshedding tumor. Furthermore, no sequencing variants were detected from the 100-gene panel, including MET amplification, mutation, or other genomic aberrations.

“This is a preliminary report of the first 3 patients with MET-amplified gastric cancer who were enrolled in a phase 2 savolitinib monotherapy study,” the investigators concluded. “The efficacy of the trial will be reported once the trial completes recruitment; here, we focused on the utility of ctDNA sequencing to identify potential resistance mechanisms in gastric cancer after MET inhibition.”

On the basis of this trial, the phase 3 SAVOIR study is currently underway. In the trial, investigators will compare sunitinib (Sutent) with savolitinib in the treatment of patients with MET-amplified papillary renal cell carcinoma.4

References

  1. Frigault MM, Markovets A, Nuttall B, et al. Mechanisms of acquired resistance to savolitinib, a selective MET inhibitor in MET-amplified gastric cancer. JCO Precis. 2020;4:222-232. doi:10.1200/PO.19.00386
  2. Study of AZD6094 (Volitinib) in Advanced Gastric Adenocarcinoma Patients With MET Amplification as a Third-Line Treatment. https://clinicaltrials.gov/ct2/show/NCT02449551?term=NCT02449551&draw=2&rank=1. Updated January 22, 2020. Accessed April 20, 2020.
  3. Phase Ib, Single-arm Study of AZD6094 (Volitinib) in Combination With Docetaxel, in Any Solid Cancer and Sequential Phase II, Single-arm Study of AZD6094 (Volitinib) in Combination With Docetaxel in Advanced Gastric Adenocarcinoma Patients With MET Amplification as a Second Line Treatment. https://clinicaltrials.gov/ct2/show/NCT02447406?term=NCT02447406&draw=2&rank=1. Updated December 30, 2019. Accessed April 20, 2020.
  4. Savolitinib vs. Sunitinib in MET-driven PRCC. https://clinicaltrials.gov/ct2/show/NCT03091192. Updated March 13, 2020. Accessed April 20, 2020.

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