CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: October 04, 2022
Expiration: October 03, 2023
Joleen Hubbard, MD:
From the ESMO World Gastrointestinal Cancer conference, I was excited about the data from the MOUNTAINEER trial in HER2-positive metastatic CRC (mCRC). Tucatinib is an oral tyrosine kinase inhibitor of HER2 that is already approved in combination with trastuzumab and capecitabine for patients with previously treated advanced or metastatic HER2-positive breast cancer.1 Approximately 4% of all patients with mCRC have HER2-positive tumors. MOUNTAINEER was a randomized, multicenter, open-label phase II study.2 Patients with mCRC had a RAS wildtype, HER2-positive tumor, which could have been identified by immunohistochemistry (IHC), fluorescent in‑situ hybridization (FISH), or next-generation sequencing (NGS), followed by central confirmation of HER2 positivity. Participants were heavily pretreated with at least 2 lines of therapy. They were stratified by the presence of a left-sided primary tumor into a combination of tucatinib and trastuzumab vs tucatinib-alone. The primary endpoint was a confirmed ORR by blinded independent central review.
Joleen Hubbard, MD:
Patients had primarily an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and the majority (85%-90%) had left colon or rectum primary tumor sites. Most (60%-63%) had metastatic disease at initial diagnosis.
Joleen Hubbard, MD:
The tucatinib plus trastuzumab arm had an ORR of 38%, which is impressive for patients who have been treated with ≥2 lines of therapy. The median time to ORR was 2.1 months and the disease control rate was 60%.
Joleen Hubbard, MD:
Approximately 65% of patients had at least some reduction in tumor size. Several patients are still undergoing treatment.
Joleen Hubbard, MD:
The median PFS time was 8.2 months (95% CI: 4.2-10.3 months) and the median OS time was 24.1 months (95% CI: 20.3-36.7 months).
Joleen Hubbard, MD:
Treatment-emergent adverse events (TEAEs) were consistent with what is anticipated with multikinase inhibitors, including diarrhea, fatigue, and nausea. Tucatinib-related adverse events of grade ≥3 occurred in 8 patients, including alanine aminotransferase increase and diarrhea.
Joleen Hubbard, MD:
The ORR of 38% and median OS of 24 months observed with tucatinib plus trastuzumab are meaningful data for the specific patient population with HER2-positive mCRC who have had ≥2 previous lines of therapy. It is extremely important to remember that the MOUNTAINEER patients had RAS wildtype tumors. I am commonly asked about potential trials for patients with HER2-positive and KRAS-mutant tumors. Those patients are going to be less likely to respond due to the downstream signaling with mutated KRAS.
It is crucial to identify patients with the optimal HER2-positive and RAS wildtype tumor signature and refer them to clinical trials with HER2‑directed therapy because outcomes could substantially be improved compared with the standard of care. I anticipate that tucatinib and trastuzumab is going to become a standard third-line therapy for this patient population. Future trials are evaluating HER2‑directed therapies in earlier lines of treatment. Based on these findings, there is even more reason to ensure patients are tested upfront with either IHC, NGS, or FISH studies to identify patients early on who may benefit from targeted therapies.
Joleen Hubbard, MD:
The next study is an analysis evaluating the impact of BRAFV600E mutations on patients with microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) CRC. Approximately 2% of patients with CRC have MSI-H tumors. This study was a retrospective review of 459 patients with MSI-H/dMMR CRC who had tumor NGS using the same platform; 123 (27%) of the patients had BRAFV600E mutations. The study objective was to assess how BRAFV600E mutations affect the immunologic characteristics and tumor microenvironment (TME) in this patient population.3
Joleen Hubbard, MD:
Among the patients with MSI-H/dMMR CRC containing BRAF mutations, there was a slight predominance for females (69%) and for older patients (median age: 76 years), which is not unexpected.
Joleen Hubbard, MD:
Some differences were observed in cancer stem cell pathways and metabolomic pathways. There was a difference in tumor mutational burden expression, with most being high (95%) in the BRAF wild‑type tumor population compared with 100% in the mutated BRAFV600E arm (P = .008). The PD‑L1 expression level was similar across groups (P = .20).
Joleen Hubbard, MD:
Several oncogenic comutations that had higher expression in the BRAFV600E-mutant tumor population included MSH6, B2M, ATM, TP53, and MSH2, which was not unexpected.
Joleen Hubbard, MD:
With respect to the TME, natural killer cell infiltration was higher in the BRAFV600E-mutant tumor population (P <.001.) There were no differences in the proportions of CD4-positive and CD8-positive T-cells (P <.50.) The BRAFV600E-mutant tumor population had an upregulation of metabolomic pathways including cyclin-dependent cell signaling, glycerophospholipid metabolism, galactose metabolism, and nucleotide metabolism.
Joleen Hubbard, MD:
Approximately one quarter of the population with MSI-H/dMMR CRC (23.7%) had a tumor with a KRAS mutation; this population had lower neoantigen burden with a score of 12 compared with the score of 16 observed with wild-type KRAS (P <.001).
Joleen Hubbard, MD
What I conclude from this study is that patients with MSI-H/dMMR CRC containing BRAF mutations have just as much of a chance to respond to immunotherapy as patients with BRAF wild‑type tumors. The patient population with KRAS‑mutant tumors had a slightly lower tumor antigen burden compared with the KRAS wild‑type, but I would still consider trying immune checkpoint inhibitors in the KRAS‑mutant tumor patient population. Overall, if patients have MSI-H/dMMR CRC they could benefit whether tumors are BRAF mutant, BRAF wild‑type, or KRAS mutant.
Joleen Hubbard, MD:
The next study is a combination study of 2 immune checkpoint inhibitors. It was a phase I first in-human trial evaluation of botensilimab plus balstilimab in 195 patients with treatment-refractory solid tumors.4 Botensilimab is an Fc‑enhanced CTLA4 antibody that potentially attunes the activity of other agents that target T-cell–associated antigens.5 Balstilimab is a PD‑1 inhibitor that has previously been evaluated in combination with a different CTLA4 antibody in cervical cancer.6 This report focuses on data with botensilimab and balstilimab for up to 2 years in 41 patients with heavily pretreated, microsatellite‑stable (MSS) mCRC. The primary endpoints included ORR and safety.4
Joleen Hubbard, MD:
The 41 patients in this study had a median age of 57 years, were predominantly women (59%), and had received a median of 4 previous lines of therapy, with 34% having been exposed to previous immunotherapy. More than one half (51%) of patients had tumors with RAS mutations.
Joleen Hubbard, MD:
After a median follow-up of 5.8 months, there was a 24% ORR, which is very meaningful for this patient population. At the time of reporting, 8 of the 10 responses were still ongoing and 3 of those were longer than 1 year. Patients without liver metastases had a higher ORR of 42%, which was an exploratory finding. The median DoR was not reached.
Joleen Hubbard, MD:
There were no new safety signals. The grade 3 immune-related adverse event rate was 17%, which appeared consistent with what has been observed in some other studies of immune checkpoint inhibitors in mCRC.
Joleen Hubbard, MD:
In patients with MSS mCRC, previous trials with immune checkpoint inhibitors have not demonstrated clinically significant responses,7 which emphasizes the relevance of the 24% ORR observed in this trial. An exploratory analysis demonstrated an ORR of 42% in patients without liver metastases, which reminded me of a phase I/Ib study with regorafenib and nivolumab. In that study, patients with refractory mismatch repair–proficient mCRC received regorafenib and nivolumab to determine the dose-limiting toxicity and maximum tolerated dose, with secondary outcomes of PFS and OS.8 Patients in that trial with metastatic disease not involving the liver had an improved median PFS (8.9 months) and median OS (not reached) compared with those who had liver metastases (median PFS: 2.3 months; median OS: 9.7 months).8
The results from both trials were interesting and warrant further exploration in this patient population. It is still not clear how best to produce a response to immunotherapy in a patient with microsatellite-stable disease, and it would be fantastic if this were the future way to do that.
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