Marijke Vroomen Durning, RN

Could SHP2, which plays a role in both tumor and immune cell signaling, be the next target of effective treatments for patients whose cancer does not respond to traditional therapies or relapses?

 SHP2 (SRC homology region 2–containing protein tyrosine phosphatase 2), encoded by the 

 gene, is generating continued interest in oncology research. Agents that inhibit 

 attack cancer cells in a way that is distinct from other therapies, and data showing the potential efficacy of such therapies, are fueling more research.

 oncogene in 1964 produced great excitement in the cancer research community.

 It led to a race to determine the oncogene’s cellular role and how to possibly exploit it for therapeutic purposes. Activating mutations in a RAS homologue, 

, are found in almost 20% of patients with cancer, particularly pancreatic, colon, and non–small cell lung cancers. KRAS inhibitors have been demonstrated to be effective in treating such malignancies. Unfortunately, optimizing KRAS inhibitors has proved challenging. Many cancer cells develop adaptive resistance to these agents by increasing expression of upstream receptor tyrosine kinases (RTKs) or their ligands, which makes finding effective treatments even more difficult.

, an oncogenic tyrosine phosphatase involved in signal transduction downstream of several RTKs, has been associated with several types of cancer. These include leukemia and breast, gastric, laryngeal, liver, lung, and oral cancers, as well as other diseases.

 is necessary for full activation of the MAPK pathway. If clinicians could suppress SHP2 activity, that would inhibit RAS/MAPK signaling and the tumor cell survival and proliferation that it promotes.

SHP2 has also been considered “undruggable,” a protein that oncologists found impossible to target with drugs5—until now. As a phosphatase, SHP2 represents an unusual therapeutic target.

“SHP2 is an interesting molecule. Primarily what we use now in therapeutics are inhibitors of proteins called kinases, and kinases add modifications to other proteins that drive signaling pathways required for tumor cells to proliferate,” explained Michael K. Wendt, PhD, an associate professor of medicinal chemistry and molecular pharmacology at Purdue Center for Cancer Research in West Lafayette, Indiana, in an interview with T

“We have been working—myself, as an example—over 30 years in medical oncology, trying to break the code for lung cancer,” said Ravi Salgia, MD, PhD, in an interview with Targeted Therapies in Oncology. Salgia is a professor in the Department of Medical Oncology and Therapeutics Research and Arthur & Rosalie Kaplan Chair in Medical Oncology at City of Hope, a comprehensive cancer center near Los Angeles, California. “We’ve made huge strides, for example, in [treating cancers with mutations in] 

. But with RAS we were never able to make a big impact.”

Results of recent studies investigating SHP2 may change that. Findings from recent phase 1 trials presented at the American Association for Cancer Research (AACR) Annual Meeting 2021, held April 10 to 15 and May 17 to 21, suggest that some SHP2 inhibitors have the potential to be developed into anticancer agents.

In an article in Scientific Reports in January 2021, investigators from the Novartis Institutes for BioMedical Research reviewed findings from their preclinical SHP2 blockade experiments.1 They found that inhibition of SHP2 enhanced the immune-mediated killing of cancer cells by boosting tumor-intrinsic IFNγ signaling, which, in turn, resulted in “…enhanced chemoattractant cytokine release and cytotoxic T-cell recruitment, as well as increased expression of MHC class I and PD-L1 on the cancer cell surface.”

Investigators in China are developing ETS-001, a highly potent allosteric SHP2 inhibitor that has potential for treating RAS/MAPK–driven cancers.6 They found that using ETS-001 as a single agent dramatically inhibited the growth of cancer cells, both in vitro and in vivo tumor models with mutations in 

 or in components of the nucleotide cycling–dependent KRAS pathway. “Besides, as the effectiveness of RAS pathway inhibitors [is] ultimately limited by rapid emergence of drug resistance via multiple mechanisms, including bypass activation of alternative RTKs, SHP2 inhibition has the potential to overcome the resistance as [part of] combinational strategies associated with various RAS pathway–targeted therapies,” the authors wrote. “We show that ETS-001 exhibited strong synergistic effect with EGFR-tyrosine kinase inhibitors (osimertinib [Tagrisso]), 

 G12Ci [AMG510], or CDK4/6i (ribociclib [Kisqali]) in appropriate cancer models in vitro and in vivo.”

The investigators concluded that their findings provided preclinical evidence that ETS001 may effectively treat 

–altered tumors either alone or in combination with other targeted therapies.

According to a second presentation at the conference, RMC-4630 is a potent, selective, orally bioavailable allosteric SHP2 inhibitor.

The investigators noted that preclinically, inhibition of SHP2 reduced tumor growth not only by suppressing 

 signaling but also by transforming the tumor immune microenvironment.

“SHP2 actually acts in the opposite fashion of kinases. Kinases add phosphate groups to proteins, but the P part of the SHP2 acronym stands for phosphatase. These molecules remove phosphate groups from proteins,” Wendt said. “And interestingly, however, SHP2 is still somehow required for these proliferation pathways to take place. [The reason for this is] not completely understood.”

Determining the kind of signal can be hard, as can identifying which toxicities may occur with a novel SHP2 inhibitor, said Salgia. “You need to do phase 2 studies, phase 3 studies, to be able to say if it is going to play an important role in our therapeutic armamentarium… especially [in patients] with KRAS [mutations].” He pointed out that investigators must also evaluate whether a new agent would be used as monotherapy or as part of a combination, as well as how to approach the development of resistance.

 mutation has the potential for treatment with SHP2 inhibition; this has created buzz among investigators. “We know, for example, colon cancer has KRAS mutations,” Salgia explained. “We know that pancreatic cancer has 

 mutations. Other cancers do as well. But not all mutations are created equal, and not all cancers are created equal,” he cautioned. For example, both small cell lung cancer and colon cancer can be treated with topoisomerase inhibitors, but they have different levels of sensitivity to specific agents. Both irinotecan and topotecan can be efective in treating small cell lung cancer, but only irinotecan is effective in treating colon cancer.

Some concern also exists about potential problems with SHP2 inhibition. According to a review published earlier this year, there is evidence that the 

 gene synergistically inhibit liver tumor formation in mice. Therefore, to treat solid tumors such as liver cancer, SHP2 inhibitors should be used with caution as they could also activate STAT3, an important cancer- promoting factor. “Thus, the phosphorylation level of STAT3 should be paid close attention to when trying to treat related solid tumors with SHP2 inhibitors,” the authors wrote.

SHP2 inhibitors hold tremendous potential; however, whether this potential will be realized remains to be seen, particularly given that the cellular function of 

 is very different from that of most cancer therapy targets.

“SHP2 is a phosphatase, and an inhibitor of a phosphatase has never made it this far [in targeted cancer therapy development],” Wendt said. “It’s new ground in terms of the effects we’re seeing, and preclinical experiments are just the tip of the iceberg. [The efficacy of these agents] could actually get better in clinical experiments. Another exciting thing around SHP2 is there are studies coming out now showing that in addition to [reducing] cancer cell proliferation, SHP2 inhibition can also aid in the ability of the immune system to sense cancer cells and eliminate them.”

One of the biggest drawbacks, according to Wendt, is that it is not yet known how to identify which patients would have the best response to this new type of therapy. “I think over the next couple of years, if SHP2 inhibitors continue to develop clinically, a crucial aspect is what do we [test in] patient biopsies to identify [who] might best respond to an SHP2 inhibitor?”

Several clinical trials are planned for the future. Phase 1 and 2a trials are currently recruiting patients with advanced solid tumors to test potential treatments (TABLE).

Although there is always hope that the trial will provide an effective treatment for the participant, patients often enroll in trials to help research progress, which in turn may help others with cancer years later. If community oncologists encourage their patients to participate in clinical trials, the patients become involved in the process.

Salgia said that oncologists are always optimistic about their patients’ future, although 

-directed treatments are still a long way from being commercially available. “What I tell our patients is, you have this current therapy and our goal is to get you to the next level. And suppose you have a recurrence or resistance, then by that time, we may have more therapies available.”

1. Wang Y, Mohseni M, Grauel A, et al. SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms. Sci Rep. 2021;11(1):1399. doi:10.1038/s41598-021-80999-x 

2. Weiss RA. A perspective on the early days of RAS research. 

v. 2020;39(4):1023-1028. doi:10.1007/s10555-020-09919-1 

3. Mukhopadhyay S, Fedele C, Neel BG. SHP(ing) out oncogenic KRAS towards therapeutics. National Cancer Institute. April 15, 2021. Accessed April 30, 2021. https://www.cancer.gov/research/key-initiatives/ras/ ras-central/blog/2021/neel-shp2-inhibitors 

4. Zhang J, Zhang F, Niu R. Functions of Shp2 in cancer. 

. 2015;19(9):2075-2083. doi:10.1111/jcmm.12618 

5. Song Z, Wang M, Ge Y, et al. Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies. 

. 2021;11(1):13-29. doi: 10.1016/j.apsb.2020.07.010 

6. Xia X, Du L, Zhuge H, et al. Discovery of ETS-001, a highly potent allosteric SHP2 inhibitor to treat RTK/RAS-driven cancers. Presented at: AACR Annual Meeting 2021; April 10-15 and May 17-21, 2021; Virtual. Accessed May 14, 2021. https://bit.ly/3vbw1bJ 

7. Nichols RJ, Haderk F, Stahlhut C, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. 

 2018;20(9):1064-1073. doi:10.1038/s41556-0180169-1 

8. Quintana E, Schulze CJ, Myers DR, et al. Allosteric inhibition of SHP2 stimulates antitumor immunity by transforming the immunosuppressive environment. 

. 2020;80(13):2889-2902. doi:10.1158/00085472.CAN-19-3038

9. Luo X, Liao R, Hanley KL, et al. Dual Shp2 and Pten deficiencies promote non-alcoholic steatohepatitis and genesis of liver tumor-initiating cells.

. 2016;17(11):2979-2993. doi:10.1016/j.celrep.2016.11.048 

10. Chen AY, Haura E, Pacheco J, et al. Modulation of innate and adaptive immunity in blood and tumor of patients receiving the SHP2 inhibitor RMC4630. Presented at: AACR Annual Meeting 2021; April 10-15 and May 1721, 2021; Virtual. Accessed May 10, 2021. https://bit.ly/3u8r4iO

Articles

Agents that inhibit SHP2 attack cancer cells in a way that is distinct from other therapies, and data showing the potential efficacy of such therapies, are fueling more research.

SHP2 Inhibitors Open the Door to Treat KRAS-Mutant Cancers

The pandemic brought about by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has put some aspects of life on hold for over a year now. However, for people living with serious and potentially fatal illnesses, putting life on hold is not an option.

We’re dealing with life and death situations,” said Mark K. Kyei, MD, a medical oncologist at Cleveland Clinic in Ohio, during an interview with 

. “We still need to deliver care for patients and we can’t just compromise because of the pandemic.”

As physicians across all specialties scrambled to find ways to deliver care, oncologists had to balance keeping patients safe from infection with delivering care that frequently has toxic treatments.

“As an infectious disease physician, my team and I were constantly learning, adapting, and implementing protocols based on new science and new evidence—basically everything,” Monika Shah, MD, an infectious disease specialist at Memorial Sloan Kettering Cancer Center in New York, New York, said in an email. “We were in constant motion, especially when there was much uncertainty and real fear, not only from our patients but also our work force.”

Continuing Care Through Virtual and Telehealth Appointments

One could argue that some form of telehealth has existed since patients could speak with their doctor by phone, but systems that deliver effective and consistent care by phone or video are only decades old.

According to a report published by the World Health Organization (WHO) in 2010, “Some predict that telemedicine will profoundly transform the delivery of health services in the industrialized world by migrating health care delivery away from hospitals and clinics into homes.”

But despite its convenience, telemedicine did not become as popular as many people had hoped—until now. Not only did patients and physicians begin to ask for distance visits once they understood the severity of SARS-CoV-2, but the US Congress passed an act in March 2020 allowing providers to bill Medicare for telehealth appointments during the pandemic.

The American Society of Clinical Oncology (ASCO) issued a comprehensive guide to cancer care delivery, updated in December 2020, recommending that clinicians identify patients for whom distance medical appointments would be appropriate, such as those not needing in-person examinations or in-person diagnostics.

“I switched about 50% of my follow-up patients to either telephone visits or video visits,” said Huynh Cao, MD, a medical oncologist at Loma Linda University Health in California. “These were mostly patients who were in remission, though. Patients undergoing treatment that required visits to the clinic could benefit from a hybrid version, however, using phone or video for meetings between active treatments.”

These virtual visits are necessary, but not always ideal. “There’s such a dramatic contrast between in-person and virtual visits,” Kyei said. “I generally prefer to see my patients in the office, talking to them, picking up cues.”

Patients undergoing cancer treatment often need the support of a friend or family member. Oncologists usually encourage patients with a new diagnosis to bring at least 1 person with them for their first visit. But with most facilities banning companions except for hands-on caregivers, this has become particularly challenging for both patient and clinician.

The oncologists at Cleveland Clinic had the policy modified slightly. “In our department, we allowed 1 person, a caregiver or first-degree relative, to accompany [the patient], especially for a new consult,” said Kyei. “Having someone else there, even if that person joins via phone, can help [them] collaborate and corroborate the information, and remember things that we spoke about.”

He also believes that having this extra person is important for patients at follow-up appointments because when they return they often don’t remember what they were told during previous visits. This means that much time is spent reviewing the information.

To address the visitor restrictions at Cancer Treatment Centers of America (CTCA), Ankur Parikh, DO, director of CTCA’s Precision Medicine Program in Philadelphia, Pennsylvania, suggested his patients bring a device to their appointments so they could include a family member or friend through FaceTime or a similar app. And if the patients didn’t have a device, Parikh said that CTCA would help them with a tablet.

“At least they could be part of the conversation and that helps a little bit, although it doesn’t replace having a loved one with you in person.”

Patients must trust their health care teams, particularly while undergoing treatment for a disease such as cancer.

Luckily, I had established relationships with most of my patients [before the pandemic],” said Parikh. This allowed him to have real conversations with his patients, asking about children or work when appropriate, because that connection had been made. But the situation is different with new patients. “To start with a new patient via telemedicine, you don’t get the full story,” he explained. “What you get are screenshots. You don’t always see the patient as you would [in the office].”

In addition, not all patients can participate in virtual visits.4 They may not have a private area to maintain their confidentiality, or they may not have devices or a reliable service for a good connection. This is particularly concerning in certain populations, such as those who are not financially stable or are home insecure.

In April last year, the CMS issued recommendations regarding treatment priorities for low-, intermediate-, and high-acuity treatments or services.5 However, according to news reports, procedures were still being canceled, including surgeries to remove tumors or more definitive testing.6 Although these are not elective procedures, they were considered nonurgent.

Kyei explained that Cleveland Clinic has a 30-day time-to-treat policy, which they are working on maintaining, but the pandemic has caused some variability. “There were instances where initiating treatment took more time,” he said, “especially for patients who required additional procedures before starting treatment, as nonurgent procedures were temporarily suspended.”

Parikh’s experience was different, as scheduled surgeries at CTCA continued for the most part. “We ended up seeing a lot of patients from outside that probably wouldn’t have come to us in the beginning because they’d have [had] their potential curative surgery locally,” he explained.

Quarantine and Fear Affect In-Person Visits

The slowdown of cancer care is not wholly the result of facilities cutting back on in-person visits or performing fewer procedures. It can be due to the patients themselves being unwilling or unable to see a doctor in person.

, 46.35% of the centers providing cancer care reported that more than 10% of their patients had missed at least 1 session.

Obviously, patients who developed coronavirus disease 2019 (COVID-19) could not attend their appointments, but there were also those who may have been exposed to someone with symptoms and had to wait for test results, explained Parikh. This would mean another 2 weeks before they could come in to the hospital or clinic, adding to the delay in care. And, the more possible exposures, the more delays.

Then there is the issue of seeing patients who received a diagnosis later than they might have done before the pandemic. Those who experience concerning symptoms may decide to wait out of fear of subjecting themselves to infection. “We noticed that people put off screening tests because of the virus,” said Kyei. “When some people had symptoms, they delayed because they wanted to wait until things got better, and things never really got better. They ended up presenting with late symptoms, advanced disease.

“We are trying to find other means and ways to prevent this because COVID-19, the impact, has the potential of basically undoing all the progress [in screening] we’ve been able to [make] in the past,” he added.

Although limited to colon cancer, one possible step to mitigate this concern is to increase the availability and use of the noninvasive fecal immunohistochemical (FIT) test, which looks for occult blood. “But if that test is positive, you will still need a colonoscopy, which brings you back to square one,” Kyei noted.

Now that vaccines for COVID-19 are rolling out across the country, where do people with cancer stand? Most, it seems, do want the vaccine. Almost 80% of Parikh’s patients have discussed the vaccine, he said. “Most of my patients are just waiting to be able to get it.” But when they will get it is the bigger question.

Priority for receiving COVID-19 vaccines is decided at the state level, with each state having its own regulations. “In New York State, anyone with cancer or a history of cancer is now eligible for the vaccine,” said Shah. But this is not the case in all states. “At Memorial Sloan Kettering, we prioritize our patients under the state framework, and are rolling it out in a further stratified fashion among our patients, by age and active treatment status.” That being said, the program is subject to vaccine supply, which varies from week to week, so the staff do not know more than a week ahead of time how many people they can vaccinate.

It is not possible to read about the vaccines without reading about their potential adverse effects. Many people report soreness at the injection site, fever, chills, even muscle aches. These symptoms could also be signs of an infection something people with cancer are warned about. This could result in confusion if patients aren’t sure what is causing these symptoms— the vaccine or the start of an infection.

“I told [my patients that] if their fever is mild, about 100 °F or below, then maybe it’s the vaccine,” Cao said. “But if you have a high persistent fever, above 101°F, then please do call us or get help, or go to the ED [emergency department], because it could be something serious.”

Shah agreed. “The main point to counsel a patient about is that the fever and chills associated with the vaccine should be self-limited. Anything prolonged or anything associated with other symptoms, like cough, shortness of breath, or dizziness, for example, requires prompt investigation. Physicians may also need to consider the timing around when the vaccine was given and where in the therapy cycle a patient may be in their treatment plan. If a patient’s white blood cell count is low and they develop a fever, patients should be counseled on what they should be doing in terms of seeking care.”

Solid Tumors Vs Blood Cancers—Any Differences During the Pandemic?

Cancer care during the pandemic is not all that different between oncologists who treat solid tumors and those who treat hematologic malignancies, except when aggressive cancers come in. “Hematological patients tend to have, sometimes, more aggressive disease…so you really don’t have the luxury of just waiting versus someone who may have stable disease, with colon cancer, for example,” Parikh said.

The American Society of Hematology has issued guidance for some types of cancer, such as acute myeloid leukemia (AML), for which they wrote: “Because newly diagnosed AML is considered treatment-emergent in most cases, intensive induction chemotherapy should still be offered for eligible patients (

Regardless of the type of cancer, decisions must be made on a case-by-case basis, Cao said. “For a patient with CML [chronic myeloid leukemia] on maintenance therapy, and all the numbers look good and the disease has been stable for a long time, then we have a little more wiggle room and we can hold a treatment as long as possible,” he explained. “But for a patient with AML, newly diagnosed AML, and who had COVID, then you have to make that hard decision to go ahead with the induction, because if you wait a week or 2, that patient doesn’t have that week or 2 to wait.”

Shah added that her team learned and knew that the risk of having a more severe and/or prolonged illness with COVID-19 was greater in their patients with hematologic malignancy. Thus, COVID-19 screening prior to new treatment initiation became an early strategy at Memorial Sloan Kettering. “For example, we would not want to [give a] transplant to someone with new COVID-19,” she wrote in an email.

The research side of oncology was also affected by the pandemic, both in the lab and clinically. Cao, who oversees a translational lab that focuses on AML treatments, has experienced delays in getting supplies, including the mice his team needs.

For clinical trials, recruitment became a lot more difficult. Participants did not want the extra travel and additional blood draws and other assessments these studies require, said Parikh.

“In some places, almost all clinical trial activity ceased as difficult decisions were made about balancing patient access to critical cancer clinical trials and exposure to COVID-19,” Mark Reeves, MD, PhD, director of the Loma Linda University (LLU) Health Cancer Center, said in an email. “Here at LLU Cancer Center, we kept our trials open for accrual, and made these trials available to patients, but with tremendous care to minimize the risk of COVID-19 exposure. Trial accrual was less here than prior to COVID- 19, but it was still fairly brisk, and it certainly did not come to a halt as it did in many places.”

The delays in clinical trials may come back to haunt us in the future. “We’re not recruiting to the degree as we did [pre-pandemic],” Parikh said, “so that is really impacting the results we are going to get. But we also have to be a little more creative now to structure various trials in the world we are in today.”

Many believe there will be a spike in the diagnosis of more advanced cancers as people finally get screened post pandemic but, according to Kyei, there is another post-pandemic concern: treating patients for cancer years after they have had COVID-19. Although the exact numbers are unknown, many people develop post-infection complications, which could become a pre-existing condition that affects cancer treatment down the road.

“Some people will develop permanent lung damage and cardiac injuries, and neurologic symptoms,” Kyei said. These are issues related to some cancer treatments, although usually among older patients. But with younger patients recovering from COVID-19, the issues could affect treatment options in the future.


1. World Health Organization. Applications and services for diverse context. In: 

Telemedicine: Opportunities and Developments in Member States: Report on the Second Global Survey on eHealth 2009

. WHO; 2010:10. Accessed March 4, 2021. https://bit.ly/3rtd6q9

2. Coronavirus Preparedness and Response Supplemental Appropriations Act, 2020. Department of Health and Human Services. March 6, 2020. Accessed March 4, 2021. https://bit.ly/3m2wIQP

3. ASCO Special Report: A Guide to Cancer Care Delivery During the COVID-19 Pandemic. ASCO. Updated December 15, 2020. Accessed March 4, 2021. https://bit.ly/3rGr2NX

4. Broom A, Kenny K, Page A, et al. The paradoxical effects of COVID-19 on cancer care: current context and otential lasting impacts. 

. 2020;26(22):5809-5813. doi:10.1158/1078-0432.CCR-20-2989

5. Non-emergent, elective medical services, and treatment recommendations. CMS. April 7, 2020. Accessed March 4, 2021. https://go.cms.gov/39mXbn2

6. Stone W. As coronavirus strains hospitals, cancer patients face treatment delays, uncertainty. NPR. April 2, 2020. Accessed March 4, 2021. https://n. pr/3ryUs04

7. Jazieh AR, Akbulut H, Curigliano G, et al; International Research Network on COVID-19 Impact on Cancer Care. Impact of the COVID-19 pandemic on cancer care: a global collaborative study. 

. 2020;6:1428-1438. doi:10.1200/GO.20.00351

8. COVID-19 and acute myeloid leukemia: frequently asked questions. American Society of Hematology. Updated January 22, 2021. Accessed March 4, 2021. https://bit.ly/3u7BEXp

The pandemic brought about by severe acute respiratory syndrome coronavirus 2 has put some aspects of life on hold for over a year now. However, for people living with serious and potentially fatal illnesses, putting life on hold is not an option.

Lessons Learned From COVID-19— 1 Year Later

A tumor-agnostic approach in which treatment is developed based on a tumor’s genetic and molecular features without regard to the cancer type or primary tumor location in the body, is the focus of the National Cancer Institute (NCI)-MATCH trial (NCT02465060). Investigators from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group and NCI

 sought to determine whether therapy could be better targeted if oncologists could identify molecular alterations using next-generation sequencing (NGS) and administer currently available approved or experimental drugs—either singly or in combination—tailored to those targets. Results of this umbrella/basket trial were published in the November 2020 issue of the Journal of Clinical Oncology.

“The objective of this study was to determine whether matching drugs targeted against a specific gene abnormality would be effective in treating patients [with cancer] with that mutation, regardless of their tumor type,” said Lyndsay Harris, MD, in an email interview with Targeted Therapies in Oncology. Harris is the associate director of the Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis at NCI in Bethesda, Maryland, and one of the study report’s coauthors.

The MATCH trial comprised 30 parallel, single-arm, phase 2 subprotocols. Each subprotocol, or arm, featured a different molecular marker-treatment pair. Patients with tumor alterations that could be addressed by a targeted treatment were assigned to the corresponding arm, irrespective of tumor histology. For example, subprotocol H (EAY131-H) investigated the selective BRAF inhibitor dabrafenib (Taflinar) and the MEK1/2 inhibitor trametinib (Mekinist) in patients with BRAF V600–mutant cancers.

A database that catalogs mutations associated with different tumor types already exists. However, this database, The Cancer Genome Atlas, concentrates on primary tumors that could potentially respond to surgery, either alone or as part of a broader treatment regimen. MATCH, on the other hand, enrolls patients who have relapsed/refractory advanced or metastatic disease.

Nearly 6000 adults have enrolled in the multiarm trial. Eligible patients could have any solid tumor, lymphoma, or myeloma that either had progressed despite standard therapy or for which no curative treatment was available. Other inclusion criteria were an ECOG performance status of 1 or better and adequate hematopoietic, kidney, and liver function.

Patients were required to submit a tumor biopsy specimen obtained within 6 months of study registration. A total of 5540 biopsy samples were sequenced.

Of the 5540 patients screened, 38% had tumors that harbored actionable mutations and 18% were assigned to treatment arms. Of the assigned patients, 70% (n = 686) were ultimately enrolled in a subprotocol arm and received treatment. The accrual goal for each subprotocol was at least 31 eligible patients; as of November 2020, 11 subprotocols had reached this goal.

 Currently, 11 trial arms are open and recruiting patients (TABLE).

There were 4 major findings from the study:

The proportion of patients who had gene abnormalities that matched targeted drugs was 37.6%.

Uncommon cancers had some of the highest match rates.

Many patients’ tumors had more than 1 genetic driver of cancer growth.

Genetic defects exhibited surprisingly little change between primary and metastatic tumors.

It's noteworthy that the trial established the feasibility of sequencing large numbers of tumors in a short time frame. The speedy return of results will enable targets to be identified in time for therapy decisions, according to Harris.

Most Frequent Mutations Not Necessarily Actionable

The most frequently found mutations were in 

 (47.4%), KRAS (21.2%), and APC (12.4%). Among co-occurring mutations, the pair with the highest incidence was 

 Despite their frequency, some of the most commonly observed mutations were not actionable; when MATCH was initiated, there were few drugs targeting cancers with 

 mutations, for example. As a result, there was no subprotocol for this patient segment.

For many common molecular subsets, though much is known, there remains the need to develop actionable therapies.

 (6.3%) were the most common. All other actionable mutations occurred in 3% or fewer of patients.

Although targeted therapies were not currently available for many of the patients’ tumors, this study does have important implications for targeted therapy approaches. MATCH demonstrated that genomic sequencing will reveal targets of interest in a substantial proportion of patients, Harris pointed out, adding, “As we move into an era of more extensive sequencing, it is certain that additional targets will be discovered.” Additionally, Harris noted that a large number of mutations that could lead to treatment resistance was identified in many tumor types, which may explain why some of the study arms had lower response rates.

“We know that melanoma has a high percentage of patients with 

 mutations,” said April K.S. Salama, MD, a medical oncologist at Duke Cancer Center in Durham, North Carolina, and an investigator on subprotocol H, during an interview with Targeted Therapies in Oncology.

Targeted therapies have led to significant improvements in patient survival and outcomes, and they have been shown to be effective therapies for melanoma.

“While we’ve seen these great response rates in melanoma and some other cancers, like thyroid cancer, we’ve seen relative resistance in cancers like colorectal cancer that, despite having 

 mutations and despite getting these highly selective BRAF and MEK inhibitors, showed relatively little benefit and pretty low response rates. And [the inhibitors were] felt not to be all that effective,” Salama said. “And that’s where a trial like MATCH and others like it come in.”

According to Salama, these types of studies can flip the traditional cancer trial, for which a patient must have a certain cancer type to enroll. Instead, MATCH enrolled patients based on certain molecular features. Although there was uncertainty about whether this one-size-fits-all approach would be feasible with 

 mutations and whether the same drugs would be efficacious in different cancers, her subprotocol study produced positive findings. “It provided further data to suggest that inhibiting BRAF may be an effective strategy against the majority of 

-mutated cancers.” Salama acknowledged that her study included only approximately 30 patients, and pointed to interest in expanding the research.

As noted above, one important finding from MATCH was an average match rate of nearly 38% between genetic alterations and targeted therapies. Rather moderate match rates were found in the most common cancers: non–small cell lung cancer (NSCLC; 17.4%), colorectal cancer (13.7%), breast cancer (17.8%), and prostate cancer (23.0%). Cancers with assignment rates more than 25% included central nervous system cancer (37.2%), urothelial cancer (36.0%), cholangiocarcinoma pancreaticobiliary cancer (25.9%), cervical cancer (28.4), gastroesophageal cancer (27.8%), melanoma (26.3%), uterine cancer (26.2%), and anal cancer (25.5%). The lowest actionability rates were found in pancreatic cancer (5.8%), small cell lung cancer (5.1%), and lymphoma (5.0%).

The second important finding was that some uncommon cancers, such as cholangiocarcinoma, pancreaticobiliary, gastroesophageal, and cervical, had some of the highest match rates. The most common cancers (breast, colorectal, NSCLC, and prostate) had rates that hovered around 17%. “Although the match rate varied widely across the board, some of the less common/rare tumors had the highest match rates, reflecting the larger number of actionable mutations in those types,” Harris said.

Another important point made by the investigators regarded the study’s utility. Using NGS, they wrote, patients could be triaged to investigational therapies, “provided that a sufficiently large pool of agents is made available.”

Although much research still needs to be done, Harris explained that these findings should encourage community oncologists to direct patients to further trials. “Oncologists should understand that tumor sequencing in metastatic populations is likely to lead to discovery of a potentially actionable mutation that could provide further opportunities for treatment for their patients,” she said. “Furthermore, in advanced, often heavily pretreated cancer populations, single-agent targeted therapies may not be adequate and combinations of agents may be necessary.” Patients enrolling in clinical trials of such combinations would help the oncology community further develop optimal therapies, which would potentially provide greater benefit to patients.

Another benefit of MATCH was the accessibility of the trial. Support from the NCI's National Clinical Trials Network and Community Oncology Research Program made the study broadly accessible to local communities. “In fact, the majority of the patients came from community sites,” Harris said. “This demonstrates that clinical trials such as these can allow physicians to treat their patients where they live, rather than needing to travel to an academic site, and should be encouraged. The MATCH trial is ongoing and enrolling patients at more than 1100 cancer centers and community hospitals in every state, the District of Columbia, and Puerto Rico.”

The MATCH trial is just the beginning. “Although we did see a number of study arms that met their primary end point[s] for the study, the majority had lower response rates,” Harris said. “We discovered a large number of resistance mutations in these tumors, suggesting that a single target may not be sufficient for efficacy in a patient with an advanced tumor.” A new study, ComboMATCH, has been launched and will look at combinations of targeted agents. Like the original trial, ComboMATCH will be a signal-seeking study. Although MATCH treatments mostly consist of single drugs, ComboMATCH will test combinations of targeted drugs sup-ported by preclinical in vivo evidence. The principal is to overcome drug resistance to single-agent therapy by developing genomically-directed targeted agent combinations.

 Harris encouraged oncologists to direct patients to clinical trials such as MATCH.

Salama agreed. “We know that many adult patients in oncology are not treated in clinical trials,” she said. “I think continued interest and participation in clinical trials ... is what we really need to advance the field.”

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Flaherty KT, Gray RJ, Chen AP, et al; NCI-MATCH Team. Molecular landscape and actionable alterations in a genomically guided cancer clinical trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH). 

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A tumor-agnostic approach in which treatment is developed based on a tumor’s genetic and molecular features without regard to the cancer type or primary tumor location in the body, is the focus of the National Cancer Institute -MATCH trial. 

NCI-MATCH Trial Explores Tumor-Agnostic Approach

Chimeric antigen receptor (CAR) T-cell therapies quickly burst into the spotlight of hematology-oncology disease management because of their potential to illicit deep and durable responses from patients whose disease is relapsed or refractory to multiple previous lines of therapy. Relevant professional meetings and oncology publications exploded with research and news about CAR T cells, and this cellular therapy strategy is now being explored across hematologic and solid malignancies.

“CAR T cells are a scientific revolution,” Tania Jain, MBBS, assistant professor of oncology at Johns Hopkins University in Baltimore, Maryland, said in an interview with 

 (TTO). “They have brought about a paradigm shift in terms of how we’re treating patients.”

The 2 currently FDA-approved CAR T-cell therapies, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah), are both indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma; additionally, tisagenlecleucel is approved for patients up to 25 years with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

With a second wave of approvals likely on the horizon for therapies such as lisocabtagene maraleucel (liso-cel) and idecabtagene vicleucel (bb2121), CAR T is gaining traction and will likely play an increasingly prominent role in the future treatment paradigm in oncology.

CAR T-cell therapy administration is largely limited to the inpatient setting at both academic institutions and large accredited cancer centers, making such treatments unavailable to most patients. Other challenges with this type of therapy include its potential to cause serious toxicities resulting in organ damage and death.

Due to the promising efficacy of these agents, investigators have been working toward viable solutions to bring CAR T-cell therapies to more patients by alleviating difficulties associated with therapy delivery and patient care.

Barriers to Manufacturing CAR T Cells Are Addressed

CAR T-cell therapies, both those currently approved and the many being explored in late-phase clinical trials, are produced from autologous T cells obtained from the patient receiving therapy. This personalization has led to tremendous success, yet it is a large part of why CAR T-cell therapy use remains limited to a select group of patients.

Time is an important consideration for patients who have experienced multiple relapses and may be too weakened by numerous lines of prior therapy to wait several weeks for the CAR T-cell manufacturing process. The effects of previous treatments or the disease itself can also present challenges, as manypatients are rendered lymphopenic and may be unable to produce enough T cells for harvesting. Roadblocks may remain for patients who are not limited by these factors; manufacturing success and effectiveness of the CAR T-cell product can be negatively influenced by disease-related dysfunctions of patients’ T cells.

A new option, off-the-shelf CAR T-cell products, may help solve these problems. These premade products are manufactured using allogeneic donor cells (instead of autologous cells from the patient), and they present immediate advantages to clinicians, such as immediate availability, opportunity for product standardization, and decreased cost.

“The advantages [include] being able to access the cellular therapy in real time, as opposed to autologous products that havetobe manufactured,”Craig S. Sauter, MD, clinical director of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center in New York, New York, explained in an interview withTTO. This is particularly important for patients who are not responding to therapy, which is a current requirement for treatment with CAR T cells, he added.

Findings from a phase I trial (NCT01430390) in patients with relapsed or refractory B-cell malignancies showed that patients with non-Hodgkin lymphoma (NHL) experienced durable responses with an Epstein-Barr virus–specific cytotoxic lymphocyte CAR product derived from cells harvested from third-party donors (rather than from their more precisely matched stem cell donors). All 4 patients with NHL and a single patient with chronic lymphocytic leukemia, who were treated with third-party cells, remained disease free and alive at the time of analysis, with a median follow-up of over 2 years.

“The advantages [of this type of therapy are] that it eliminates the need for apheresis [and] shipping cellular products back and forth. [Instead, clinicians] have a pharmaceutical product on the shelf for access,” Sauter, who was an author on the trial, said. Another notable product being investigated in clinical trials is UCART19, an allogeneic engineered anti CD19CAR T-cell product, which is being evaluated in the phase I CALM trial in adult patients with relapsed or refractory B-cell ALL (NCT02746952) and in the phase I PALL trial of pediatric patients with relapsed or refractory CD19-positive B-cell ALL (NCT02808442). Other off-the-shelf agents are described in theTABLE.

Optimizing Adverse Event Management for the Outpatient Setting

Issues with inpatient CAR T-cell therapy administrationinclude high demands on health care resources and strain on patients and their families. Moving treatment to the outpatient setting has the potential to reduce this strain; however,clinicians taking over care of patients receiving CAR T-cell therapy must be prepared with the proper resources to identify and manage adverse events associated with therapy.

One of the most notable risks to patients receiving CAR T-cell therapy is cytokine release syndrome (CRS), a systemic inflammatory response that is characterized by increased serum levels of inflammatory cytokines, fever, hypotension, hypoxia, and organ dysfunction.

 “[CAR T] can also lead to neurological events and can cause confusion and, in some patients, seizures,”Carlos R. Bachier, MD, Director of Cellular Research at Sarah Cannon Cancer Center in Nashville, Tennessee, explained in an interview with TTO.

Regardless of the infusion setting, patients require close monitoring in the hours and days following therapy administration. A review byLucrecia Yáñez, PhD, MS, and colleagues stated that key criteria for treating patients in the outpatient setting include an educated caregiver and necessary infrastructure allowing for outpatient visits plus adequate emergency and intensive care unit (ICU) access. Patients followed as outpatients must be given twice-daily temperature checks for a minimum of 14 days following treatment and preferably extending up to 3 to 4 weeks following infusion. Anysigns of back pain, skin rash, dizziness, chills, shortness of breath, chest pain, tachycardia, or neurological events that may indicate neurotoxicity or signs of CRS must be reported immediately so treatment can begin as quickly as possible.

Because of the risk of CRS and neurotoxicity, both FDA-approved agents are restricted under the Risk Evaluation and Mitigation Strategy, an FDA-mandated program that builds in caution for use of agents with serious safety concerns.

 Therefore, 2 doses of tocilizumab (Actemra), an interleukin (IL)-6 receptor antagonistthat was approved in 2017 for management of CRS associated with CAR T-cell therapy,

should be on hand for each patient before the infusion of CAR T cells. Steroids have also demonstrated efficacy against CRS, but concernssurrounding CAR T-cell suppression with these agents have established them as a second-line choice after tociluzumab.

Immune effector cell–associated neurotoxicity syndrome (ICANS) is a group of neurologic symptoms associated with treatments such as CAR T-cell therapy. Predisposing factors include younger age, higher tumor burden, high levels of pretreatment inflammation, and history of early or high-grade CRS. Treatments for complications of ICANS vary. Some centers may prescribe prophylactic antiepileptic medications, such as levetiracetam, to prevent seizures in patients with grade 2 or higher neurologic events. Anti–IL-6 therapy can be considered in patients with concurrent CRS, but corticosteroids are the preferred regimen in those with neurotoxicity alone.

Moving Liso-Cel to the Outpatient Setting

In February of this year, the investigational CAR T-cell product liso-cel was granted priority review by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma who had undergone at least 2 prior therapies.

Investigators believe that liso-cel therapy may have a place in a broad range of patients and in the outpatient setting.

“It turns out liso-cel has a low incidence of [CRS and ICANS], and they occurred relatively late compared with other products,” said Bachier. “Because of this low incidence, the strategy was to deliver liso-cel in an outpatient setting.”

The feasibility of liso-cel administration on an outpatient basiswas evaluatedby Bachier and colleagues, and the results were presented at the 2020 Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy and the Center for International Blood & Marrow Transplant Research, held February 19 to 23, 2020, in Orlando, Florida.

The authors analyzed data from 3 clinical trials of liso-cel, with a focus on the subset of participants who were treated as outpatients. The included trials were the phase I TRANSCEND-NHL-001 (NCT02631044) and phase II OUTREACH (NCT03744676) trials in patientswhohadundergone at least 2 lines of prior treatment, as well as the PILOT study (NCT03483103), which examined liso-cel as second-line therapy in patients who were ineligible for autologous hematopoietic stem cell transplant because of age, organ function, or ECOG performance score. All 3 studies allowed outpatienttreatment, with some patients receiving their therapy in the nonuniversity setting.

Relevant professional meetings and oncology publications exploded with research and news about chimeric antigen receptor T cells, and this cellular therapy strategy is now being explored across hematologic and solid malignancies.

Marijke Vroomen Durning, RN | Authors

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