Patients with solid tumors harboring class I 

, have gained substantial clinical benefit from first-generation BRAF inhibitors. However, currently approved BRAF inhibitors have not been proven as effective in patients with class II or class III 

 alterations, which account for approximately 34% of 

 mutations are observed in up to 8% of patients with cancerand are known to behave differently across tumor types.

 For example, approximately 50% of patients with melanoma harbor a class I 

V600 mutation, whereas approximately 50% to 80% of 

 mutations in non–small cell lung cancer (NSCLC) and 22% to 30% in colorectal cancer are class II or class III.3 Because of the increasing use of next-generation sequencing in clinical oncology practice, 

 mutations beyond V600 are being identified at a greater rate. However, patients with diseases harboring these alterations lack approved treatment options for targeting them.

Three BRAF-targeted therapies are approved by the FDA, each of which is engineered to target class I alterations:vemurafenib (Zelboraf), dabrafenib (Tafinlar), and encorafenib (Braftovi). All 3 agents are approved in combination with MEK inhibitors for patients with 

 Vemurafenib and dabrafenib are also approved as a single-agent therapy for patients with 

 V600–positive unresectable or metastatic melanoma.

 There are no approved systemic therapies targeting class II or class III 

 as a driving genomic abnormality is very well recognized in the oncology community,” Cesar Augusto Perez, MD, said in an interview with 

. “Initial success [with BRAF inhibitors] has been seen in patients with 

 mutations with melanoma, NSCLC, and colorectal cancer. But we [must] acknowledge that in many of the diseases where we see a 

V600 mutation for which the current drugs have been found to be effective,” added Perez, who is director of drug development at Florida Cancer Specialists & Research Institute.

“As an oncologist, when you get a next-generation sequencing report and you see a 

 mutation, there is some excitement initially because you always want to offer something that is effective for your patient,” Perez said. “But right after that when you see it is a non-V600 or a class II or class III, then the general [reaction] is disappointment because we know that for class II, class III mutations [agents such as] dabrafenib are not going to work for this population.”

Investigators hope to address the need for additional treatment options for patients with class II or class III 

-altered disease with KIN-2787, a next-generation, orally available, potent, and selective small molecule inhibitor. The pan-RAF inhibitor is specifically designed to inhibit class II and class III BRAF dimers while still inhibiting class I monomers. Investigators will evaluate the agent in the phase 1/1b KN-8701 trial (NCT04913285) of adult patients with solid tumors harboring class I, class II, or class III 

In vitro and in vivo activity with KIN-2787 laid the foundation for investigators to pursue the agent as a viable option. Specifically, KIN-2787 had activity against human cancers driven by class I, class II, and class III 

 mutations and treatment with the agent led to time-dependent and exposure-dependent inhibition of MEK-ERK phosphorylation. This activity was accompanied by suppression of MAPK transcriptional targets at the RNA and protein level. Investigators also evaluated the dosing tumor response in the human cancer models and reported that twice-daily oral dosing was found to be well tolerated and had prolonged target coverage/inhibition with a trend in the direction of more frequent and deeper tumor responses in vivo.

“The interesting thing about [KN-2787] is that it was developed also to try to target the other 2 classes of 

mutations,” Perez said. “That was not the case for the drugs that we have available on the market. They were always developed to try to target the class I mutation. I think it is important that we have been able to classify these mutations and recognize the mechanisms of how they promote proliferation and survival. We can now actually target these mutations and one of the most exciting things is that after we classified and understood how the class II and class III mutations can promote survival, we were able to develop drugs to target [them].”

The pan-RAF approach in the development of KIN-2787 optimized the agent’s ability to cover the heterogenous nature of class II and III alteration as well as narrow the concentration levels at which paradoxical activation occurs, such as in BRAF-BRAF or BRAF-CRAF conformations.

 Perez added that distinguishing factors in genomic abnormalities of BRAF are displayed in several diseases and that although these mutated cancers may represent only 1% to 2% of cancer cases, it is important to develop drugs to address this patient population. Despite uncertainty as to how effective pan-RAF inhibitors will be against any of the classes in clinical practice, investigators hope initiation of trials such as KN-8701 will shed some light on their role for patients with these mutations.

The KN-8701 multicenter study will evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of KIN-2787 in approximately 115 adult patients with 

-mutated advanced or metastatic solid tumors (

 The study will be divided into dose escalation and dose expansion portions. The dose escalation group will consist of patients withsolid tumors harboring class I, class II, or class III 

 alterations and will determine therecommended phase 2 dose (RP2D). The RP2D will then be evaluated in patients with NSCLC, melanoma, and other solid tumors harboring class II or class III 

 alterations in the dose expansion segment. KIN-2787 will be administered orally twice daily in 28-day cycles in both phases.

 alteration will be confirmed by previous genomic analysis of tumor tissue or circulating tumor DNA. Patients must have received prior standard therapy appropriate for the tumor type and disease stage or be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. An ECOG performance status of 2 or less, adequate organ function, and the ability to swallow, retain, and absorb oral medications are also required.

“Patients with class I mutations who have been previously treated with an approved BRAF inhibitor—for example, patients with melanoma who have had disease progression—will [be included in the trial],” Perez explained. If patients have previously received BRAF-directed, MEK-directed, or MAPK-directed inhibitor therapy for tumor types and indications not approved by the FDA, they will not be able to participate. Further, those with known active brain metastases from nonbrain tumors will be excluded from the trial, along with those who are seropositive for hepatitis B or hepatitis C.

The primary end points of the trial are the incidence of dose-limiting toxicities, treatment-emergent adverse events, treatment-related adverse events, and incidence of clinically significant changes in vital signs, physical examinations, electrocardiograms, and clinical laboratory tests. In the dose expansion portion, primary outcome measures include objective response rate, disease control rate, duration of overall response, and duration of stable disease. Secondary end points of the study consist of maximum observed plasma concentration (Cmax) of KIN-2787, time to achieve Cmax, and area under the plasma concentration-time curve.

Perez noted that any signaling on activity patients with class I, class II, or class III 

 genomic abnormalities will also be monitored. The first patient in the study was dosed in August 2021. The study is estimated to be completed in June 2024.

In January 2022, investigators expanded the KN-8701 trial to include a dose-escalation cohort of patients with 

-mutant melanoma who will receive KIN-2787 in combination with binimetinib (Mektovi). “Patients with 

 mutations are another population with a high unmet need in metastatic melanoma,” Meredith McKean, MD, MPH, said in an interview. “There are a couple of different targeted therapies under development, but the fact is that there are no approved therapies for these patients and data show that [this population] has worse outcomes than patients without 

 mutations.” McKean is the associate director of melanoma and skin cancer research at Sarah Cannon Research Institute in Nashville, Tennessee.

 occur in approximately 25% of melanomas with signaling shown to be highly CRAF-dependent.

 Data from a phase 1 study (NCT03284502) showed that treatment using a pan-RAF inhibitor in combination with a MEK inhibitor elicited a partial response rate of 26.3% among 19 patients, with 41.2% achieving stable disease.

Investigators leveraged these findings as rationale to combine KIN-2787 administered at the clinical dosing strategy (10 mg/kg twice daily) with binimetinib (3 mg/kg twice daily) in patients with 

-mutant melanoma. The 2 agents had a synergistic effect with meaningful tumor reductions compared with monotherapy. Specifically, preclinical findings demonstrated a 122% tumor growth inhibition with the combination.

The dose expansion cohort will evaluate up to 36 patients with 

-mutant melanoma. “There is a lot of excitement about opportunities in this trial and trying to find new avenues of treatment for these patients,” McKean said. “[We need to] highlight the importance of molecular profiling. The days of testing for 

 V600 mutations are over and we really should be doing full, comprehensive profiling for all patients with metastatic melanoma to make sure that we are identifying other actionable driver mutations and [to help us] identify clinical trial opportunities for these mutations.”

Franovic A, Miller N, Severson P, et al. The next-generation pan-RAF inhibitor, KIN-2787, is active in class II and class III BRAF mutant models. 

. 2021;39(suppl 15):3116. doi:10.1200/JCO.2021.39.15_suppl.3116

Halle BR, Johnson DB. Defining and targeting BRAF mutations in solid tumors

. 2021;22(4):30. doi:10.1007/s11864-021-00827-2

Dankner M, Rose AAN, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. 

. 2018;37(24):3183-3199. doi:10.1038/s41388-018-0171-x

Zelboraf. Prescribing information. Genentech; 2020. Accessed February 7, 2022. bit.ly/3Jgugkp

Tafinlar. Prescribing information. Novartis; 2021. Accessed February 7, 2022. bit.ly/3B6myGH

Braftovi. Prescribing information. Array BioPharma, Inc; 2020. Accessed February 7, 2022. bit.ly/3B6JYve

Cotellic. Prescribing information. Genentech, Inc; 2018. Accessed February 7, 2022. bit.ly/34FGrIi

Investor presentation. Kinnate Biopharma Inc. Accessed February 7, 2022. 

https://investors.kinnate.com/static-files/eeb5e193-3a14-4133-9d56-c0145dca699b

A study to evaluate KIN-2787 in participants with BRAF and/or NRAS mutation positive solid tumors. ClinicalTrials.gov. Updated January 28, 2022. Accessed February 7, 2022. 

https://www.clinicaltrials.gov/ct2/show/NCT04913285

Kinnate Biopharma Inc. reports second quarter 2021 financial results. News release. Kinnate BioPharma Inc. August 16, 2021. Accessed February 8, 2022. bit.ly/3oxGa10

Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. 

. 2010;140(2):209-221. doi:10.1016/j.cell.2009.12.040

Guo W, Wang H, Li C. Signal pathways of melanoma and targeted therapy. 

. 2021;6(1):424. doi:10.1038/s41392-021-00827-6

Kim TW, Lee J, Kim TM, et al. A phase Ib trial of belvarafenib in combination with cobimetinib in patients (pts) with RAS- or RAF- mutated (m) solid tumors: updated safety data and indication-specific efficacy results. 

. 2021;32(suppl 5):S595. doi:10.1016/j.annonc.2021.08.1051

Articles

Investigators hope to address the need for additional treatment options for patients with class II or class III BRAF-altered disease with KIN-2787, a next-generation, orally available, potent, and selective small molecule inhibitor.

KIN-2787 Looks to Fill Unmet Need in Class II/III BRAF-Altered Solid Tumors

Meredith McKean, MD, MPH, associate director, Melanoma and Skin Cancer Research Program, Sarah Cannon Research Institute of Tennessee Oncology, discusses the importance of molecular profiling in melanoma.

The role of molecular testing has grown beyond only looking for 

 V600E mutations, so clinicians should be ordering full comprehensive profiling for all patients with metastatic melanoma, McKean says. This is to ensure the identification of driver mutations, as well as to understand what clinical trials may be available for patients harboring mutations other than 

Moreover, the field is generating excitement surrounding clinical trial opportunities to develop new avenues of treatment for patients with metastatic melanoma, McKean concludes.

Videos

Meredith McKean, MD, MPH, discusses the importance of molecular profiling in melanoma. 

Dr. McKean on the Importance of Molecular Profiling in Metastatic Melanoma 

The field of metastatic melanoma is continuing to develop novel targeted therapies that will further personalize treatment options to individuals based on the molecular characteristics of their disease, said Meredith McKean, MD, MPH, who highlighted that these developments further underscore the importance of broad molecular testing with next-generation sequencing (NGS).

“In oncology, we are continuing to evolve toward more personalization. That is in correlation with clinical trials that provide more opportunities for our patients. Trying to match the right patient to the right drug is really what we should be doing in oncology,” McKean said.

To that end, the ongoing phase 1 KN-8701 trial (NCT04913285) is evaluating KIN-2787, a novel small molecule pan-RAF inhibitor in patients with 

-mutated solid tumors, including melanoma and non–small cell lung cancer.1

Notably, patients with known class I, class II, or class III 

 mutations are eligible for enrollment, which distinguishes the trial from others that include only patients with typical class I mutations like 

, McKean, associate director of the Melanoma and Skin Cancer Research Program at Sarah Cannon Research Institute of Tennessee Oncology, discussed how the presence of atypical 

 mutations affects treatment selection in patients with metastatic melanoma, highlighted the ongoing KN-8701 trial, and explained why developments in this space further solidify the importance of broad molecular profiling.

:What are some of the unmet needs for systemic therapies for patients with class II and III 

: We have 3 different effective combination therapies for patients with classic 

 V600E mutations, but there is a number of other patients with atypical 

 mutations. Although there have been case reports and some examples of patients who may have some sensitivity to these classic BRAF/MEK inhibitor combinations, for the most part, these inhibitors are not very effective for patients with atypical mutations. Therefore, there is currently no FDA-approved treatment options for these patients and no standard-of-care targeted therapies.

 mutation is identified, how does that affect how you approach treatment selection?

For standard of care, these patients are traditionally treated with immunotherapy. Then we start looking at clinical trials because there are so many options available. There are atypical BRAF inhibitors that have different binding [to 

] at high affinity and those that are more specific to these atypical mutations.

Several clinical trials are looking at different MEK inhibitors and ERK inhibitors that are trying to block just downstream of these active mutations.

What ongoing research has caught your eye in this space?

Several molecules are in development in phase 1 and 2 trials. The most important thing to know is that there are trial options out there. These patients and their providers should be seeking out these opportunities because there are molecules in development. Several different companies are [developing these] molecules. It will be exciting to see some of the results.

One such molecule is KIN-2787, which is now under study in the KN-8701 trial. The trial was expanded to include patients with 

-mutated melanoma. What could that mean for those patients?

 mutations are another population with a high unmet need in metastatic melanoma. There are a couple different inhibitors and targeted therapies under development, but no therapies are approved for these patients. Some data have shown that these patients have worse outcomes compared with patients without 

 mutations. Therefore, it is an important population for which we are looking to develop treatment options. [KIN-2787] is important because it may have some activity in targeting that patient population.

What do these advances signify regarding the importance of broad molecular profiling in patients with metastatic melanoma?

Number 1, for any oncologists or patients, is the importance of molecular profiling. The days of just looking for 

 V600E mutations are over. We should be doing full comprehensive profiling for all our patients with metastatic melanoma to make sure we are identifying their driver mutations and available clinical trials for those with non–

 mutations, or other mutations that might be seen on profiling. That is an important takeaway.

There is a lot of excitement about these clinical trial opportunities and trying to find new avenues of treatment for these patients.

What does the increasing emphasis on broad molecular testing mean for pathologists?

Our pathologists can have a difficult job because patients may have different resections of cutaneous tumors and in-transit metastases so they may not know where that patient is in their journey. It’s important for pathologists to [perform full molecular profiling]. [Pathologists should be] looking for mutations beyond just 

, which was the standard 3-gene panel test that had previously been done [in melanoma]. It’s important to recognize that it is worth checking with clinicians and asking: Has full profiling been completed? [It’s important to at least] have those results for the 

 mutations in that they could be game changers to open clinical trial opportunities for these patients.

A study to evaluate KIN-2787 in participants with BRAF and/or NRAS mutation positive solid tumors. Clinicaltrials.gov. Updated January 28, 2022. Accessed February 2, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04913285

Meredith McKean, MD, MPH, discusses how the presence of atypical BRAF mutations affects treatment selection in patients with metastatic melanoma, highlighted the ongoing KN-8701 trial, and explained why developments in this space further solidify the importance of broad molecular profiling.

Personalized Medicine Approaches Continue to Gain Steam in BRAF/NRAS+ Metastatic Melanoma

Developing BRAF inhibitors for patients with atypical class II and III mutations has become an exciting area of research, explained Shumei Kato, MD, who added that although pan-RAF and ERK inhibitors are currently under study as single agents in this population, investigation into co-alterations for potential combination approaches is already under way.

 mutations] seem to be ideal targets, especially in targeting RAF itself or downstream [signals] like MEK and ERK,” Kato said. “There are a lot of clinical trials that have been focusing on these atypical forms of 

“I’m hoping we will see some good outcomes even with single-agent approaches, but if [that is not successful], perhaps the next step will be to consider some flexible combination approach. We will see how that goes,” Kato added.

, Kato, a medical oncologist and assistant professor of medicine in the Department of Medicine at the University of California San Diego (UCSD) Health, discussed the rationale to target class II and III 

 mutations in solid tumors, the benefit of next-generation sequencing (NGS) testing, and ongoing clinical trials gathering data on this research.

: Why should class II and III BRAF mutations be evaluated for potential actionability in oncology?

: [With] larger panels, like NGS, we are identifying more genes that are theoretically actionable, such as atypical 

 V600E mutations are found in a small percentage of] cancer types. There is a lot of interest when it comes to targeting those mutations. 

 mutations are classified into 3 different classes. Class I [mutations] are more typical like V600E mutations. Initially, [these mutations were] targeted among patients with melanoma, but now we are seeing more applications in different histologies like lung cancer, colon cancer, or other rare tumor types like Erdheim-Chester disease. Now, [class I mutations] are more targetable with a typical BRAF or MEK inhibitor, although for colon cancer, we need to add an EGFR inhibitor. 

The more we use NGS, [the more] we are identifying the atypical class II and III 

 mutations can lead to increased dimerization of BRAF, which can lead to downstream MEK/ERK [signaling] and progressive cancer. Class III mutations are inactivated, so theoretically, they are not going to be ideal targets. However, interestingly, when BRAF is inactivated, c-RAF will be recruited, which can ultimately lead to the downstream signaling activation of MEK and ERK. 

You published a paper in Nature Communications regarding the real-world benefit of molecular tumor boards in matching patients with alterations to specific targeted therapies. Could you provide some insight into the purpose of the paper and what the results demonstrated?

Thank you for asking about our molecular tumor board experience at UCSD. Razelle Kurzrock, MD, of UCSD Moores Cancer Center, initially developed the molecular tumor board at UCSD. The initial idea was to try to guide the physician who may not be familiar with complex molecular pathways. That has evolved with more evidence when it comes to matched targeted therapy approaches. However, we also noticed with our experience that single-agent approaches may not be enough for the patient. We know that when we do molecular profiling on solid tumors, patients on average will come in with 3 or 4 alterations [identified] by a large NGS panel. However, most of our clinical trials are focusing on [targeting] 1 gene at a time. That could, of course, work, as we have seen with 

 mutations in melanoma. We also know though that single-agent targeted approaches have some limitations with early progression. 

Therefore, we created a protocol where we could capture the data if we were to treat the patient with a combination approach based on the patient’s unique molecular profile.

In short, what we have found is that if we can target more alterations with different drugs or combinations of drugs based on each patient’s molecular profiling, patients may do better. For example, let’s say a patient comes in with gene A, B, or C. If we can correlate those genes with drug A, B, or C, we believe patients will have better clinical outcomes. That is what we have seen from our molecular tumor board experience.

Do you anticipate that experience can be extrapolated to the patient population harboring atypical BRAF mutations as well?

-mutated population, [we are evaluating] single-agent approaches with pan-RAF inhibitors or ERK inhibitors. However, those patients most likely will have other co-alterations that could be co-targeted. We will see how the results go with single-agent approaches. If that is sufficient, that will be great, but if we are seeing similar mutations as we see in [patients who receive] other single-agent targeted therapy approaches, perhaps the next step will be to combine medications based on the patient’s molecular profiling.

There is a lot of difficulty [in doing that] though because it is more complex than we think. Let’s say we have 100 patients with colon cancer. If we do the large panel of NGS, even though they come in with similar histologies or microscopic findings, every patient will have different alteration patterns. They may have common mutations from patient to patient, but when it comes to the big picture, they are all different, like malignant snowflakes. That means we may have to come up with some customized approach based on each patient’s molecular profiling. That will be the next [phase of research].

What research is ongoing in this space with pan-RAF inhibitors and ERK inhibitors?

We do have FDA-approved medications with different MEK inhibitors, especially for melanoma. However, there are more potent RAF inhibitors or even [medications] targeting downstream ERK [in development]. It is worth trying [to develop these] for patients.

How do these agents distinguish themselves from traditional BRAF inhibitors? Given the differences in their mechanism of action, are there anticipated differences in toxicities?

There are a couple questions: What is the difference between typical BRAF inhibitors in terms of toxicity. I don’t know in depth; however, for typical BRAF V600E inhibitors like vemurafenib [Zelboraf], [the agent] is only targeting that specific mutation. So, it won’t work for different mutations [like atypical 

 mutations]. [KIN-2787], which is under investigation in an ongoing clinical trial, [may] inhibit different 

Additionally, regarding ERK inhibitors, we don’t have a lot of clinical data, though there are promising preclinical data using ERK inhibitors for patients with typical 

 mutations. The clinical side has still not matured, so it is worth investigating. 

When it comes to the toxicity profiles, I will assume it will be very similar to the BRAF or MEK inhibitors we already have. [Toxicities will likely include] rash, diarrhea, and so on. Those will be the common toxicities, but we will have more data in the future.

Are these atypical BRAF mutations being automatically tested for on broad NGS panels or do clinicians have to specifically ask for those alterations to be tested?

My understanding is that most main NGS [panels] will automatically catch those mutations. The major laboratories will [identify] them and if it is not reported, the patient is [deemed] negative.

Is there any inclination yet as to the likelihood of co-mutations presenting in patients with atypical BRAF mutations, or is it too early to tell?

There are a lot of publicly accessible data. Also, at UCSD, we have our internal data. I haven’t had a chance to investigate atypical 

 mutations, specifically. However, for example, we have investigated patients with 

 mutations, which is upstream of BRAF. These are publicly accessible data. We found that 90% of patients will have some kind of co-alteration alone with 

 mutations. The most common [co-alterations] were PI3K pathway alterations, cell cycle alterations, and 

-mutated patients had interesting co-alterations in other TKI pathways. I assume that even for the atypical 

-mutated patients, they will have different types of co-alterations very frequently.

Are there active clinical trials at UCSD you’d like to highlight in this realm?

[At UCSD], we have 2 active trials looking at [agents for] atypical 

 mutations. One is a pan-RAF inhibitor, and the other is an ERK inhibitor. We are trying to open a couple more similar but different [studies] looking at different populations. There is a high interest in this patient population. 

Developing BRAF inhibitors for patients with atypical class II and III mutations has become an exciting area of research.

Investigation Into the Actionability of Atypical BRAF Mutations Continues in Solid Tumors

Shumei Kato, MD, medical oncologist, assistant professor of medicine, University of California San Diego Health, discusses the characterization of 

 mutations have been classified into 3 different classes, Kato says. Class I mutations comprise more typical alterations that were initially targeted among patients with melanoma; however, they are now seen more often in different tumor types, such as lung and colon cancers, Kato explains. Moreover, it is thought that class I mutations are nowmore targetable with 

 inhibitors, Kato says. However, patients with colon cancer also require EGFR inhibitors, Kato adds.

The more often that next-generation sequencing is done, the more frequently atypical, class II and III 

 mutations will be identified, Kato continues. Overall, class II 

 mutations can lead to the increased dimerization of BRAF, leading to downstream MEK/ERK signaling and cancer progression. Additionally, class III mutations are inactivated, so they are theoretically not ideal targets for BRAF inhibitors, Kato concludes.

Shumei Kato, MD, discusses the characterization of BRAF mutations in oncology. 

Dr. Kato on the Characterization of BRAF Mutations in Oncology 

Cesar Augusto Perez, MD, medical oncologist, director, Drug Development, Florida Cancer Specialists & Research Institute, Sarah Cannon Research Institute, discusses the potential utility of KIN-2787 in 

KIN-2787 is an investigational, next-generation, pan-RAF inhibitor being evaluated for patients with solid tumors harboring class I, II, and III 

 mutations, Perez explains. The agent was specifically developed to target class II and III mutations, which is an area of significant unmet need in patients with 

KIN-2787 is being evaluated in an ongoing phase 1 trial (NCT04913285) for adult patients with 

-mutated solid tumors, including non–small cell lung cancer and melanoma, Perez says. This drug is unique because most available agents for patients with 

-mutated diseases were designed to target class I mutations. As such, the results of this study will be intriguing as KIN-2787 could have clinical utility across 

 mutation–positive subgroups, Perez concludes. 

Cesar Augusto Perez, MD, discusses the potential utility of KIN-2787 in BRAF-mutated solid tumors. 

Dr. Perez on the Potential Utility of KIN-2787 in BRAF-Mutated Solid Tumors 