Cogent Biosciences: Bezuclastinib's Potential In Treating Gastrointestinal Stromal Tumors

Introduction

Cogent Biosciences (NASDAQ:COGT) is a biotechnology company that aims to develop innovative solutions for complex medical conditions. One of its key areas of focus is Gastrointestinal Stromal Tumors [GIST]. The company is developing a promising drug called bezuclastinib (formerly, PLX9486) that targets exon 17 mutations found in the KIT receptor tyrosine kinase, including KIT D816V. The drug is currently undergoing a Phase 3 clinical trial in combination with sunitinib for patients with locally advanced, unresectable, or metastatic GIST who have previously received imatinib.

In this article, we will focus on the potential of bezuclastinib in treating GIST.

Financials

Before starting, let's review Cogent's financials. As of September 30, 2022, Cogent had $289.1 million in cash, cash equivalents, and marketable securities, compared to $325.6 million as of June 30, 2022, which should provide a cash runway until 2025 according to the company. During Q3 2022, Cogent incurred $8.6 million in one-time cash payments for a newly-constructed Research Lab. R&D expenses were $29.9 million, a $15.1 million increase from Q3 2021, due to clinical trials and expanding the research team. G&A expenses were $6.9 million, a $1.9 million increase from Q3 2021, due to non-cash stock compensation. The net loss for Q3 2022 was $35.1 million, compared to a net loss of $19.1 million for Q3 2021.

The Challenge of Imatinib Resistance in Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors [GISTs] are a form of cancer that arises from a specific type of cells called interstitial cells of Cajal [ICC] located in the gastrointestinal tract. The majority of GISTs contain mutations in the c-Kit gene, which codes for a protein known as KIT, responsible for regulating cell growth, survival, differentiation, and proliferation. When mutated, KIT protein becomes overactive, leading to the uncontrolled growth and division of cells, eventually causing GIST.

Imatinib mesylate (Gleevec) is a drug that can inhibit the activity of KIT protein, making it the preferred first-line treatment for GISTs. Imatinib attaches to the ATP-binding site of the KIT protein and blocks its kinase activity, ultimately leading to the inhibition of downstream signaling pathways and apoptosis in cancer cells. However, many GISTs become resistant to imatinib because of secondary mutations in the c-Kit gene or the activation of alternative downstream signaling pathways.

The Process of Diagnosing and Treating Gastrointestinal Stromal Tumors

To effectively treat GIST, an accurate diagnosis is crucial. This involves imaging and biopsy tests to determine the size, location, quantity, and specific KIT or PDGFRA gene mutations present. The majority of GIST cases (80%) are caused by overexpression of the tyrosine kinase receptor KIT, with ~10% caused by exon 9 mutations, ~65% by exon 11 mutations, and 1% each for exon 13 and 17 mutations. Approximately 5% of cases involve overexpression of PDGFRA, while 15% are classified as "wild type." Surgical removal of tumors is the first treatment option for GIST cases, particularly when the tumors are small and localized.

However, if the tumors are advanced and cannot be surgically removed, or to prevent recurrence, tyrosine kinase inhibitors [TKIs] like imatinib are typically prescribed. These drugs target the gene mutations (KIT or PDGFRA) responsible for GIST growth. It is important to note that there are two types of KIT inhibitors: type 1 and type 2. Type 1 inhibitors, like imatinib, target the ATP-binding pocket of KIT, while type 2 inhibitors, such as sunitinib, target the activation loop (A-loop) of KIT. In cases where a patient has the PDGFRA exon 18 D842V mutation, which is the most common cause of PDGFRA overexpression, and is experiencing rapidly progressive disease or symptoms, treatment with avapritinib is recommended over other TKIs. Avapritinib is a type 1 KIT inhibitor that is specifically designed to target this mutation. Overall, the choice of TKI depends on the specific mutations present and the stage of the disease, and should be made in consultation with a healthcare provider.

Treatment recommendation for advanced unresectable GIST:

If GIST progression is not controlled with imatinib, increasing the dose of imatinib or using another TKI like sunitinib may be considered as a second-line treatment. For third-line treatment, in cases where imatinib and sunitinib have failed, regorafenib is recommended. Ripretinib is FDA-approved for fourth-line GIST (historically associated with a 6.3-month median PFS) .

Challenges and Limitations in the Treatment of GIST

The treatment of GIST is limited by drug resistance, significant side effects, an advanced stage of the disease, high treatment costs, and a lack of standardization. Despite imatinib being the first-line treatment, patients with metastatic or inoperable GIST eventually acquire resistance in most cases. Furthermore, chemotherapy and targeted therapies can cause adverse side effects, while the advanced stage of the disease can limit treatment options. Moreover, targeted therapies for GIST can be expensive, making them inaccessible to some patients. The lack of standardization in the management and treatment of GIST is also a challenge, given the complex genetic nature of GIST and the varying treatments available. Bezuclastinib needs to overcome some of these limitations to become relevant in the treatment of GIST.

Targeting Rare Mutations in GISTs: The Potential of Bezuclastinib and Combination Therapy

Mutations in exon 17 and 18 of the KIT gene are rare in GISTs, accounting for only about 2-3% of all KIT mutations. However, these mutations are associated with aggressive disease and a poor response to available targeted therapies like imatinib and sunitinib. Therefore, there is a need for new therapies that can target these mutations and improve outcomes for patients with exon 17/18 mutated GISTs.

Bezuclastinib is a novel tyrosine kinase inhibitor that specifically targets KIT exon 17/18 mutations. On the other hand, sunitinib targets KIT exon 13/14 mutations which are more prevalent in GISTs. Since bezuclastinib is a highly selective type I TKI with activity against primary KIT mutations (exons 9 and 11) and A-loop mutations (exons 17 and 18), combining these drugs could enhance their effects by targeting a wider range of KIT mutations and blocking abnormal signaling pathways that stimulate tumor growth.

However, combining multiple targeted therapies may increase the risk of toxicity and side effects. Therefore, the potential benefits of this combination therapy must be weighed carefully against its potential risks.

Bezuclastinib and Sunitinib Combination Therapy Shows Promise for GIST Patients with Exon 17/18 Mutations: Results from Phase 1/2 Clinical Trial and Ongoing Phase 3 Trial

A phase 1/2 clinical trial for GIST enrolled 39 patients, with almost 90% having refractory GIST. The trial determined that the optimal dose of bezuclastinib was 1000 mg daily, which could be safely combined with 25 or 37.5 mg daily of sunitinib. The efficacy and benefits varied depending on the bezuclastinib dose, with the best results seen in patients who received the recommended 1000 mg dose (12.1 months median progression-free survival and 80% clinical benefit rate). The company's corporate presentation highlighted a subset of patients who received bezuclastinib + sunitinib and had known exon 17/18 secondary mutations but not exon 13/14, achieving the greatest benefit (16.5 months median PFS).

When bezuclastinib was combined with sunitinib, the adverse event [AE] profile was similar to what would be expected from each drug alone. The highest doses of both drugs (1000 mg/day bezuclastinib and 37.5 mg/day sunitinib, taken continuously) were well tolerated. Common treatment-emergent adverse events [TEAEs] in the combination group were diarrhea, increased aspartate aminotransferase/alanine aminotransferase levels, nausea, and vomiting. The most common TEAEs that were grade 3 or higher included anemia (5 patients, 27.8%), hypophosphatemia (3 patients, 16.7%), diarrhea, fatigue, hypertension, and lymphopenia (each 2 patients, 11.1%). Only one patient had an AE (grade 3 anemia) that met the criteria for dose-limiting toxicities, and it was resolved within 5 days without changing bezuclastinib dosing.

Currently, a phase 3 clinical trial [PEAK] is ongoing to evaluate the safety and efficacy of the combination therapy in previously treated GIST patients. The company plans to disclose updated clinical data from the lead-in phase in the first half of this year.

Bezuclastinib and Sunitinib Combination Therapy Shows Promise for Treating Second-Line GIST with Exon 17/18 Mutations and Third-Line GIST: Analysis of Refractory GIST as a Model for Combinatorial Kinase Inhibitors

The combination of bezuclastinib and sunitinib shows potential for the treatment of second-line GIST with exon 17/18 mutations and later-line GIST if it succeeds in phase 3 trials. Refractory GIST is an ideal model for exploring the combination of complementary kinase inhibitors targeting different conformations of a driver kinase to address clonal heterogeneity in resistance. Tyrosine kinase inhibitor-resistant GISTs harbor mutations in both the ATP-binding pocket and the A-loop, which limit the clinical activity of monotherapy that inhibits only a subset of the mutations. Bezuclastinib is a highly selective type I TKI with activity against primary KIT mutations (exons 9 and 11) and A-loop mutations (exons 17 and 18), and its safety profile makes it a desirable partner in combination with TKIs with complementary KIT mutant inhibition profiles, especially type II inhibitors such as sunitinib, which have activities against ATP-binding pocket mutations (exons 13 and 14). Preliminary data show that the combination of bezuclastinib and sunitinib achieved an improved clinical outcome in patients with GIST with heavily pretreated disease, with a median PFS of 12.1 months for all patients and 11.6 months for patients who previously progressed on sunitinib. The median PFS in a subset of patients with 3 or more prior therapies remains 11 months, which compares favorably with the historical data with ripretinib monotherapy in a similar patient population. Although ripretinib has recently been approved as fourth-line treatment for GIST, the combination of bezuclastinib and sunitinib shows promise as a potential second- or third-line treatment option for GIST patients with specific mutations.

It should be noted that the preliminary data on the combination of bezuclastinib and sunitinib for the treatment of GIST with specific mutations are based on a small sample size, with only 15 patients included in the study. While the results are promising and suggest potential for the combination therapy, larger-scale clinical trials will be needed to confirm these findings and evaluate the safety and efficacy of the treatment in a wider patient population. Additionally, the combination therapy may have potential side effects or drug interactions that have not yet been fully explored, underscoring the need for further research before the treatment can be widely adopted as a standard of care.

Conclusion

For Cogent and its investors, the potential of the combination of bezuclastinib and sunitinib for the treatment of GIST with specific mutations is promising. If the combination therapy succeeds in phase 3 trials and receives FDA approval, it could generate significant revenue for the company. While it is difficult to estimate exact revenue figures, the global market for GIST treatments is expected to reach $1.5 billion by 2026, and Cogent's combination therapy could capture a significant share of this market.

In conclusion, the combination of bezuclastinib and sunitinib has the potential to offer a promising treatment option for GIST patients with specific mutations and in later stages. This presents a valuable opportunity for Cogent and its investors, as the therapy could have a significant impact on the GIST treatment landscape and potentially generate substantial revenue for the company upon successful development and approval. Nonetheless, it is crucial to exercise caution when interpreting the preliminary data, and larger clinical trials are necessary to evaluate the safety and efficacy of the combination therapy. Moreover, the landscape of GIST treatment is evolving swiftly, with numerous other medications currently in clinical development.

For now, COGT stock is a speculative "buy" due to bezuclastinib's potential in the treatment GIST.