The journal ONCOLOGY® provides oncology professionals with practical and timely clinical information necessary to deliver the highest level of patient care. Expert authors and peer review ensure the quality of the journal’s articles and features. Focused discussions capture key clinical take-aways for application in today’s time-constrained practice environment.

Remarkable advances in precision oncology over the last 2 decades have highlighted the necessity for genotyping in patients with advanced cancers to ensure appropriate therapy selection. Practice guidelines outlined by the National Comprehensive Cancer Network, the European Society for Medical Oncology, and the Japanese Society of Medical Oncology now include recommendations for genotyping to guide therapy selection in different cancer types.

Although impressive progress has been achieved through the development of biomarker-targeted clinical trials, the pace of precision oncology innovations remains limited due to the daunting logistical realities of patient identification. Furthermore, because many actionable targets are present in only a small fraction of patients, hundreds or even thousands of patients need to be screened for enrollment in a single study. Compounding this patient identification
barrier are the additional substantial challenges associated with traditional trial designs—such as the high cost of genotyping, lengthy screening periods, and limited access to screening populations—which collectively lead to increasingly low enrollment rates of otherwise eligible patients.

Patients with metastatic colorectal cancer (mCRC) are no exception. To date, several established and actionable genomic alterations have been identified in mCRC, including 

 amplification, microsatellite instability–high or mismatch repair–deficient tumors, and 

 Additional targetable genomic alterations are emerging in mCRC, such as 

mutations, homologous recombination deficiency, 

The COlorectal Cancer and Liquid BiOpsy Screening Protocol for Molecularly Assigned ThErapy (COLOMATE; NCT03765736) trial discussed by Kristen K. Ciombor, MD, MSCI, and colleagues herein is a screening platform for mCRC developed by the Academic and Community Cancer Research United consortium. COLOMATE utilizes Guardant360 (Guardant Health) molecular profiling, a comprehensive 74-gene circulating tumor DNA (ctDNA) sequencing assay, to identify potential patients for COLOMATE-associated studies.

 Complementary to this trial is the SCRUM-Japan screening project that was launched in January 2018; it initiated the GOZILA platform, a nationwide plasma genomic profiling platform study involving 31 core institutions using the same Guardant360 assay. The clinical utility of such rapid screening methods based on ctDNA genotyping has been leveraged in umbrella- and basket-type clinical trials
utilizing the GOZILA platform.

The GOZILA investigators compared data derived from the ctDNA of 1687 patients with advanced gastrointestinal cancers in GOZILA with data derived from tumor samples of 5621 patients in SCRUM-Japan GI-SCREEN to assess the clinical utility of ctDNA genotyping vs tissue analysis for the identification of patients as candidates for targeted clinical trials.6 Although the composition of the screening populations was similar, the tumor testing characteristics were significantly better in GOZILA compared with those in GI-SCREEN. Specifically, for GOZILA vs GI-SCREEN, the sample unavailability rate was 0.3% vs 1.5%, respectively; the failure rate was 0.1% vs 10.6%; the median sample acquisition duration was 4 vs 14 days; and the median turnaround time (TAT) was 7 vs 19 days. Furthermore, the median time from testing to trial enrollment was only 1.0 months for cell-free DNA testing vs 5.9 months for tumor testing, representing an 83% decrease. Overall, ctDNA genotyping led to a statistically significant increase in enrollment in genotype-matched clinical trials relative to enrollment conducted via tumor-based screening
(9.5% vs 4.1%, respectively; 

 < .0001) without compromising treatment efficacy (response rate, 20.0% vs 16.7%; median progression-free survival, 2.4 months vs 2.8 months). Given our GOZILA experience, we believe that the COLOMATE approach will maximize both efficient trial enrollment and opportunities for patients while accounting for a dynamic tumor environment, thus serving as a model for clinical cancer research in the years ahead.

Notably, key elements necessary to maintain such a genomic screening platform include (1) an overall high “hit rate,” (2) a quick TAT between informed consent and enrollment in a molecularly matched trial, (3) actionable targets treated with best-in-class therapies, (4) a dynamic trial structure allowing the opening and closing of treatment cohorts based on the best available science, (5) flexibility to maximize academia and biopharma partnerships (investigator-initiated vs biopharma-sponsored trials) depending on the target, and (6) financial sustainability.
Although some investigators and pharmaceutical companies remain skeptical of this platform, we anticipate that in the near future, most will accept this without any reservation; their attitude will shift from “maybe” to “must be” regarding an indispensable genomic screening 

platform. The GOZILA group advocates that the COLOMATE platform receive more support from related pharmaceutical companies and public funds. Such support is also crucial to perform attractive translational studies and longitudinal liquid biopsy tests; these have the advantage in potentially evaluating early therapeutic effects as well as elucidating mechanisms of resistance.

Both the COLOMATE and GOZILA platforms have identified patients with mCRC for studies examining 

 alterations, and anti-EGFR antibody rechallenge. Both are well-qualified ctDNA-based screening platforms for matched target therapies, particularly in patients with mCRC. The existence of various associated trials for common target alterations using these platforms can lead to future international collaboration.

 TY reports research grants from Amgen Inc; Chugai Pharmaceutical Co, Ltd; Daiichi Sankyo Co, Ltd; Ono Pharmaceutical Co, Ltd; Parexel International; MSD; Sanofi; Sumitomo Dainippon Pharma; and Taiho Pharmaceutical Co, Ltd.

NCCN Guidelines: colon cancer. National Comprehensive Cancer Network. Accessed August 11, 2021. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428

El-Deiry WS, Goldberg RM, Lenz H-J, et al. The current state of molecular testing in the treatment of patients with solid tumors, 2019.

 2019;69(4):305-343. doi:10.3322/caac.21560

Yoshino T, Arnold D, Taniguchi H, et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. 

 2018;29(1):44-70. doi: 10.1093/annonc/mdx738

Benson AB, Venook AP, Al-Hawary MM, et al. Colon Cancer, version 2.2021, NCCN Clinical Practice Guidelines in Oncology. 

 2021;19(3):329-359. doi:10.6004/jnccn.2021.0012

Odegaard JI, Vincent JJ, Mortimer S, et al. Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies. 

. 2018;24(15):3539-3549. doi:10.1158/1078-0432.CCR-17-3831

Nakamura Y, Taniguchi H, Ikeda M, et al. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. 

 2020;26(12):1859-1864. doi: 10.1038/s41591-020-1063-5

Articles

Perspective

Takayuki Yoshino, MD, PhD provides perspective on key issues surrounding therapy selection in gastrointestinal cancers.

The COLOMATE Platform: An Indispensable Initiative Promoting True Precision Oncology Prioritized for Patients With Cancer—From “MAYBE” to “MUST BE”

Can you briefly describe margetuximab’s mechanism of action?

A: The mechanism of action of margetuximab [Margenza] is exciting; we’re now moving into this new era of monoclonal antibody technology. We’ve been using monoclonal antibodies since the 1990s, and the way I teach [about] them in school is [that there are] naked monoclonal antibodies, the first ones at least; now, we’ve advanced to antibody-drug conjugates, where we’re tacking on a cytotoxic component, and bispecific monoclonal antibodies [that] have dual binding. When we talk about the mechanism of action of margetuximab, it’s a bispecific monoclonal antibody, and it has 2 binding sites. It has one binding that targets the HER2 receptor. It’s been genetically modified and engineered to bind to the natural killer [NK] cell. What’s exciting about this mechanism of action is that we’re building on this technology with this dual binding, so we’re enhancing this basic monoclonal antibody that we’ve been using, at least with trastuzumab [Herceptin], since the 1990s.

More specifically, the mechanism of action of margetuximab is that it targets the HER2 receptor, the extracellular domain, and the FC [fragment crystallizable] component of that monoclonal antibody has been genetically engineered to target and bind to the NK cell. When it binds to the NK cell, the idea is that you’re enhancing the antibody-dependent cellular cytotoxicity. Margetuximab has the same binding, as well as binding affinity, to the HER2 receptor as trastuzumab. We have 2 monoclonal antibodies, trastuzumab and margetuximab, binding to the same site with a similar binding affinity to that receptor, which is different from pertuzumab [Perjeta].

What are some of the concerns with margetuximab’s toxicity profile? Have any new safety concerns become more apparent with its use in the real-world treatment setting?

A: Margetuximab is an antibody that targets HER2. Two things are really important to highlight about the safety profile of margetuximab that were observed in the SOPHIA trial [NCT02492711]. First, the infusion-related reactions: About 13% of patients in SOPHIA experienced infusion-related reactions, primarily grade 1 and grade 2 [in severity]. When compared with trastuzumab in that study, only about 3% experienced infusion-related reaction.

In the real world, we really don’t see infusion-related reactions with trastuzumab. It’s not very common with trastuzumab, and we don’t premedicate [for it] with trastuzumab. However, I’m not really surprised by that in the sense that in the nomenclature of these drugs, we know that there is a difference. Trastuzumab is a humanized monoclonal antibody, as indicated by the “

” in the nomenclature. Margetuximab is a chimeric monoclonal antibody, as indicated by “

” in the nomenclature. Infusion-related reactions are more commonly seen with chimeric monoclonal antibodies because of that murine base compared with humanized monoclonal antibodies. This can partially explain the difference in higher incidence of infusion-related reactions with margetuximab compared with trastuzumab. Another possible reason for increased infusion-related reactions may be related to its mechanism of action with an enhanced immune response.

Infusion-related reactions in the SOPHIA trial primarily happened in cycle 1 and with subsequent cycles if [disease was] low grade 1 or grade 2. To manage those, we were able to add premedications [such as] antihistamines, antipyretics, and corticosteroids. Another recommendation is slowing the infusion.

It’s important that we all think about cardiotoxicity with any HER2-directed monoclonal antibody. We associate cardiotoxicity with any monoclonal antibody that targets HER2; we see that with trastuzumab or pertuzumab. What does that cardiotoxicity look like with margetuximab? Does this FC-engineered component add or worsen cardiotoxicity? What we’ve seen and what’s been published [show that] it does not appear that it has any more cardiotoxicity than trastuzumab. In the clinical trials, about 3% of patients experience a decline in the ejection fraction, which was similar to trastuzumab.

This agent was approved in December 2020, and no additional safety pharmacovigilance reports that I’m aware of say that there’s more cardiotoxicity than what was observed in the clinical trial. Also, it had similar cardiotoxicity in terms of lower ejection fraction [and] it was reversible, like what we see with trastuzumab and other HER2[-targeted] monoclonal antibodies. In the clinical trials, it is primarily asymptomatic. These declines in ejection fraction were observed via monitoring, not because the patient was symptomatic.

Q: What are some of the risks of left ventricular dysfunction associated with this agent?

A: [Speaking specifically about] left ventricular dysfunction, just knowing the mechanism of action [of this agent and] that it targets the HER2 receptor, we know that there will be, just from the mechanistic perspective, some level of cardiotoxicity, given our [experience with] previous agents. Again, margetuximab had about 3% of cardiotoxicity, primarily manifesting as decrease in ejection fraction, [which was] asymptomatic and reversible. The management is [similar to what] we do with trastuzumab. If it’s greater than or equal to a 16% drop from pretreatment ejection fractions, you’re going to hold [the drug] and at that point, you should consult a cardio-oncologist. Once it recovers, you can restart.

Q: Are dosing modifications common with the use

A: Because margetuximab is a monoclonal antibody, the dosing adjustments are primarily centered around [ejection fraction]. The recommendation is to get a baseline [echocardiogram] or ejection fraction and to continue monitoring that every 3 months. If you do see a decline in the ejection fraction greater than or equal to 16%, you’re going to hold and wait for it to recover. In terms of dosing adjustments, it’s pretty much like all monoclonal antibodies: Either give or you don’t give. When you hold, it’s because of a decrease or a significant increase in ejection fraction or for more severe infusion-related reactions. There are no hepatic or renal adjustments. This was given in combination with chemotherapy. If a patient experiences neutropenia or diarrhea, it’s likely because of the chemotherapy component vs margetuximab. This agent has a very similar [adverse] effect profile to trastuzumab, with the exception of the infusion-related reactions; we’re seeing those be a little bit more enhanced with margetuximab.

Q: Are there any major drug interactions with margetuximab that clinicians should

A: Margetuximab skips the cytochrome P450 pathway. The important drug interactions are with other cardiotoxic drugs. In the breast cancer world, the primary drug interaction here would be doxorubicin. You would not want to give this drug concomitantly with doxorubicin. I would say it’s contraindicated, similar [to] trastuzumab. No anthracycline would be recommended concomitantly with margetuximab because of the additional additive cardiotoxic toxicity.

Q: Have any barriers to administration or receipt by the patient emerged since this agent’s approval, such as common reimbursement issues or logistical challenges to obtaining the medication?

A: Margetuximab was approved in December 2020, and [so far], in terms of access or administration, we have observed no real challenges or barriers with access or administration. We are just on the lookout for those infusion-related reactions in the 13% of patients who get them. When we were building our EPIC protocol, that was a question: “Do we automatically just give some premedications? Or do we watch and wait?” But no, there are no major barriers or access issues with this agent. It’s a welcome addition to patients in the third-line and beyond setting [with] metastatic HER2-positive breast cancer.n

 The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Rugo HS, Im SA, Cardoso F, et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. 

 2021;7(4):573-584. doi:10.1001/jamaoncol.2020.7932

Margetuximab. Prescribing information. Macrogenics; 2020. Accessed August 23, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761150s000lbl.pdf

Product Profile

In an interview with ONCOLOGY®, Sandra Cuellar, PharmD, BCOP, FASHP, offers a comprehensive review of real-world treatment considerations of margetuximab as therapy for adult patients with metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2 regimens with at least 1 being for metastatic disease. 

Expert Commentary on the Product Profile of Margetuximab for HER2-Positive Breast Cancer

Immunotherapy has cemented itself as a standard of care across multiple lung cancer indications, but investigators continue to seek solutions that may help broader patient populations in the future.

Roman Perez-Soler, MD, who is chief of the Division of Oncology in the Department of Medicine at Albert Einstein College of Medicine as well as a professor in the Department of Medicine and Department of Molecular Pharmacology, discusses the modern history of systemic treatments for lung cancer, current research surrounding prevention, and what he would do if he were an early-
career oncologist.

Perez-Soler has been a part of many innovative trials, and one recent study in particular explored the use of inhaled azacitidine to treat patients with stage IV or recurrent non–small cell lung cancer (NCT02009436), which he details in his interview with 

How far has immunotherapy come in the lung cancer space?

A: I’m not involved personally in the newest trials, which is an advantage and a disadvantage. The advantage is that you can look at things from a distance. We really started extremely well by showing that pembrolizumab [Keytruda] alone [works] in patients who have more than 50% PD-L1 [expression]. That’s a great response, and the long-term survival is significant. Then, [in patients with lower than 50% PD-L1 expression], we also partner it with chemotherapy, and we get very good results.

[We’ve seen] the development of the immunotherapy combination ipilimumab [Yervoy] and nivolumab [Opdivo],

 which is still trying to find a home in a way. This is probably a good option for some patients, particularly those who are PD-L1 negative. The main problem is the added toxicity; that’s what people claim to be the disadvantage. The combination is looking for a home, but the addition of ipilimumab is doing something.

The other [challenge] is trying to find better biomarkers to predict who is going to respond best to these [agents]. PD-L1 has been useful, but it’s not perfect. Other elements determine whether you’re going to respond, and in all investigations, we try to answer that question. There’s a real need to better understand which patients will benefit the most from this approach.

There’s no question that immunotherapy has represented the major events in lung cancer treatment in the last decade. In the prior decade, [we saw] EGFR inhibitors, ALK inhibitors, and other inhibitors of the different pathways…. It is good to see that the RAS target eventually has resulted in a drug that is active there; that’s a success, especially in [the context of] precision medicine. The interesting question here is that those patients who have actionable mutations tend to be the ones who respond least to immunotherapy.

Among patients with lung cancer, those in the nonsmoking population tend to have targets that we effectively treat. Then, the smokers have tumors that are highly immunogenic with a lot of new antigens. Immunotherapy seems to be the way to go. We don’t know how to administer therapy for the others. For patients who can’t use targeted therapies, we always hoped we could use immunotherapy when those compounds fail. However, we found out that immunotherapy doesn’t work as well, which in turn shows us that those tumors are not immunogenic.

Are there any studies exploring biomarkers other than PD-L1 for immunotherapy response?

A: I’m not aware of any definitive ongoing study, but I know exploratory studies are [continuing]. The problem is that once we have drugs approved for patients, it is very difficult to do definitive studies. This happens because [once] the drug is approved [and] you want to study whether a certain biomarker predicts response or lack of response in some patients, then you must randomize patients based on your biomarkers. This means that some patients will be treated with immunotherapy [and some will not]. It is difficult to recommend that patients [not receive] immunotherapy because of the [known] response.

It’s typical to continue investigating the drug after the drug is available. This leaves us with retroactive analyses that are more exploratory, but they are never definitive.

It’s very hard to change the package insert and the indication based on a retrospective study. [For example], it was found that patients with colorectal cancer and 

 mutation will not respond to cetuximab [Erbitux].

 It’s very hard in studies like this to find volunteers, because you must do a study for those in whom the drug won’t work.

What unanswered questions about lung cancer would you like to see answered by research?

A: Every doctor has things that we believe should be studied; that’s the beauty of science. Anything can be intellectual, where 1 person may think something is going to work out [but] a million more people say, “that will never work.” At the end of the day, we don’t know which idea will lead to the next breakthrough. We must choose which studies we believe are important based on educated guesses, intuition, and assessing the situation.

I’ve always been interested in investigating diseases in their early stages. For example, why does it take tobacco about 30 years to produce lung cancer? Some of the questions I ask when investigating are: What are the changes that happened as these people continued to smoke for years and years? Will there ever be any possibility of discovering a target that we could intervene on early? Will there ever be a treatment that could reverse this damage when it is not lung cancer yet, but premalignant damage? I’ve always been interested in that area because I really believe that prevention is better than treatment.

What can we do for those who are going to smoke no matter what? How can we reverse the damage? It’s a very controversial approach because if you tell smokers that you now have an antidote, they will smoke as much as they want and still take the treatment. A way to make tobacco safe rather than unsafe—that would represent progress, but it’s very controversial. Over the last few years, this has become [the research I’m interested in].

A: In the [inhaled] azacitidine trial we conducted with Haiying Cheng, MD, PhD, and Yiyu Zou, PhD, we understood that the poison came from the inhalation of smoke, so we thought maybe the solution could come through inhalation as well. It would mimic the treatment of asthma [wherein patients would] utilize bronchodilators and reduce the obstruction of the airways. It was really a very early experiment, and we were able to get it to patients and show that it’s not toxic. I hope somebody else will lead this study and continue it.

These are long-term projects, so it’s all about how you continue once you start. I would love to see someone continue. We’re the only ones doing this. I started in 1991 with the first clinical study that included an antibody against EGFR, and people were telling me this will never work.

 However, that became the first study with an anti-EGFR compound. This was the first completed phase 1 dose-escalation study, but many people didn’t believe in it.

Can you discuss some newer research in lung cancer with regard to the latest targets, new immunotherapies, or new combinations?

A: Right now, I am very impressed by the results, understanding, and mechanism of resistance of immunotherapy. Immunotherapy works in some patients but doesn’t work in others. I think that’s a very intriguing question, and a lot of smart people want to contribute. Everybody’s jumping on it. Young investigators have that scientific curiosity, and they are convinced that something could result in improving therapy.

One thing I find fascinating is that the immune system can attack these tumors if we can neutralize the mechanism that the tumors developed to prevent that attack. There must be ways by which certain patients do not respond to these mechanisms, and they are able to neutralize the defense. I’m pretty sure that’s going to be less complicated in deed than in words when we find it. 

Paz-Ares L, Ciuleanu T-E, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. 

. 2021;22(2):198-211. doi:10.1016/S1470-2045(20)30641-0

Lièvre A, Bachet J-B, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer

 2006;66(8):3992-3995. doi:10.1158/0008-5472.CAN-06-0191

Perez-Soler R, Donato NJ, Shin DM, et al. Tumor epidermal growth factor receptor studies in patients with non-small-cell lung cancer or head and neck cancer with monoclonal antibody RG 83852.

. 1994;12(4):730-739. doi:10.1200/JCO.1994.12.4.730

Interview

“That’s the beauty of science. Anything can be intellectual.”

Investigators Look Past Standard Immunotherapy for Additional Lung Cancer Solutions

Even prior to the COVID-19 pandemic, hematology/oncology physicians who specialize in the care of patients with cancer reported high levels of symptoms consistent with burnout, including frustration (78%), emotional exhaustion (69%), and work dissatisfaction (50%).

 The difficulties associated with COVID-19 in oncology are significant as patients are often older, immunocompromised, and have other co-morbidities that put them at increased risk for infection and death. Practice changes during the pandemic have included treatment delays and modifications, clinical trial suspensions or delays, isolation of patients without family support, and increased use of telehealth care. Unfortunately, all of these issues have led to an increase in pandemic-related stress, which may compromise clinician wellness.

In addition to patient-related issues, personal issues such as financial concerns about compensation, personal concerns about COVID-19 infection in the physician or family, and impact on professional life are present. As hematologists/oncologists, we need to be aware of the effect of these issues on not only our professional, but also our personal lives. What can institutions, professional societies, or individual physicians do to help mitigate these difficulties? Studies have demonstrated that specific institutional interventions were associated with a reduction in physician burnout, such as providing time and/or a meal so that physicians can interact with colleagues in a structured format to explore challenges and discuss improvements.

 Optimization of organizational resiliency programs to share common elements and strategies, including a shared mission, can be helpful. A mutual collaboration between leadership and physicians designed to improve well-being through education, training, research, and peer support forms a good foundation. In addition, promoting flexibility, fostering resiliency, and encouraging good work/life balance are other key components of successful intervention.

Physicians often work extended hours adding up to 60 or more hours of work per week. However, physicians also need to take control by facing burnout and promoting wellness as a personal and shared responsibility. On a personal level, taking a few lessons from what we tell our patients—including eating a healthy diet, getting adequate sleep, exercising regularly, and practicing mindfulness—remain important. The pandemic has been very isolating for many groups, including physicians who have fewer in-person meetings, no in-person professional educational meetings, and decreased social interactions with colleagues. Teamwork and helping our colleagues when illness or personal issues occur can improve the “work family” concept of support. As oncologists, we must be receptive to burnout interventions and adapt to new situations at a moment’s notice while still delivering optimal cancer care.

Allegra CJ, Hall R, Yothers G. Prevalence of burnout in the US oncology community: results of a 2003 survey. 

 2005;1(4):140-147. doi:10.1200/JOP.2005.1.4.140

West CP, Dyrbye LN, Satele D, et al. A randomized controlled trial evaluating the effect of COMPASS (COlleagues Meeting to Promote and Sustain Satisfaction) small group sessions on physician well-being, meaning, and job satisfaction. 

Editorial

ONCOLOGY® co–editor-in-chief, Julie Vose, discusses how the COVID-19 pandemic has caused physician burnout and what may be done to prevent it. 

Addressing Stress and Burnout in Hematology/Oncology Physicians

A White female patient, aged 50 years, was diagnosed with a nodular melanoma of the back in 2008 and treated with a wide excision and an axillary lymphadenectomy. On follow-up, the patient was diagnosed with multiple locoregional recurrences, all surgically treated. In 2013, a metastasectomy of a single lung lesion was performed. No further treatment was given.

In 2017, multiple lung and pancreatic metastases were detected in a follow-up PET scan. A brain MRI was performed; no evidence of disease was found. A 

 V600E mutation was documented. Treatment with nivolumab (Opdivo) was started. After 9 months of treatment, progression of disease to soft tissue, myocardium, pericardium, lung, pancreas, left adrenal gland, and bone was documented (

). Treatment with dabrafenib (Tafinlar) plus trametinib (Mekinist; D+T) was started. A reduction of the tumor burden was achieved after 2 months of treatment, and after 6 months, the patient had a deep partial response of more than 80% reduction of the tumor load. After 1 year of treatment, the patient came to the clinic with neurological symptoms. A brain CT scan revealed multiple supratentorial lesions, with the largest, measuring 23 mm, localized in the parietooccipital region. Other lesions, each measuring less than 1 cm, were localized in the right parietal region, frontal region, and left parietal lobe (

). A CT scan ruled out progressive disease in other sites (

A. Time from surgery to recurrence does not affect the benefit of a surgical approach.

B. Whole-brain radiotherapy (WBRT) is the standard of care over other radiotherapy techniques for central nervous system (CNS) disease control.

C. Both surgery and radiotherapy may extend the time of treatment with immunotherapy or targeted therapies beyond progression in selected patients.

D. All patients with progressive disease after a systemic therapy should switch to a different systemic therapy regardless of the type of progression.

Cutaneous melanoma is the third leading cause of skin cancer worldwide and is among the most aggressive types of cancer. In 2020, approximately 324,635 new cases of melanoma were reported worldwide.

 Melanoma rates have increased in recent decades; an estimated 5.8% more new melanoma cases were diagnosed in 2021 than in 2020.

 In the United States, where more than 80% of patients are diagnosed with localized disease, the 5-year relative survival for melanoma patients is 93.3%.

 This may not be the case for patients in middle- and low-income countries, where disease may be more likely to be diagnosed when it is regional or metastatic. Although the 5-year survival rate for localized melanoma is as high as 99.4%, 5-year survival for patients with distant disease decreases to 29.8%.

Molecular evaluation has identified 4 main genomic subtypes of melanoma: 

 mutated (14%), and triple wild-type (8%).

Although surgical treatment remains the mainstay of treatment for local and regional disease, the cornerstones of treatment for patients with 

-mutated metastatic melanoma have become immunotherapy (IO) and targeted therapy (TT), as they demonstrate durable responses and significant improvement in survival.

 Nevertheless, several clinical questions regarding treatment optimization remain unanswered.

Although these newer treatments have great benefit, about 40% to 65% of patients treated with TT and 20% to 30% of those treated with IO will eventually develop resistance and will progress.

 Most patients will present with multiple site progression.

Oligoprogressive disease has been described for multiple neoplasms. The concept of oligoprogression varies across tumors, but it is generally defined as a clinical situation in which a limited number of metastatic tumor sites have progressed, whereas all other metastases remain controlled by systemic therapy.

 About 4.1% to 10% of patients with melanoma treated with IO or TT will develop oligoprogressive disease.

 This pattern of progression reflects acquired focal resistance, which is biologically different from generalized progression caused by innate or secondary resistance of the disease.

 Due to this characteristic, oligoprogression may be managed with local therapy; this limits the focal progression and allows continued systemic treatment, which maintains the benefit on the sites of disease that are already controlled.

In contrast to IO, in which continuing treatment beyond progression without other local therapy has been associated with benefit in overall survival (OS) for certain populations,

 TT is rarely continued beyond progression without adding another local treatment strategy.

Multiple combinations of BRAF and MEK inhibitors (BRAF-MEKi) have demonstrated benefit in patients with 

-mutated metastatic melanoma by increasing objective response rates, progression-free survival (PFS), and OS compared with a BRAF inhibitor alone. Nevertheless, about 30% of patients will progress,

 and between 50% and 60% of patients treated with a BRAF-MEKi will receive a subsequent therapy.

 In general, but not always, the most frequent treatment is systemic therapy. For instance, in the COMBI-d (NCT01584648) and COMBI-v (NCT01597908) trials, although most patients received immunotherapy (66%), local therapies such as surgery (18% in the COMBI-V trial) and radiotherapy (about 50% in both trials) were also used.

Patterns of oligoprogression after IO or TT for metastatic melanoma have been addressed by several retrospective studies.

 In most series, oligoprogressive disease is defined as progression in fewer than 3 metastatic sites after achieving a complete or partial response or stable disease with a specific agent. The CNS seems to be the most frequent site of oligoprogression (10%-23%), followed by lymph nodes (8%-18%), subcutaneous tissue (5%-16%), and lung (11%-12%), among others.

 There is some evidence that adding a local therapy and continuing IO beyond progression can extend OS,

 but evidence for this strategy’s efficacy in patients treated with TT is scarce.

Local therapies commonly used in this context include surgery, radiotherapy, and ablative techniques.

The role of surgery in oligometastatic and oligoprogressive melanoma

The main objectives of surgery in the management of recurrent/oligometastatic disease in melanoma are to increase PFS and OS and to control symptoms (eg, bleeding, infection, refractory pain).

Evidence of the benefit of surgical treatment in these settings comes from several studies. The results of the SWOG 9430 trial (NCT00002860) showed that 89% of eligible patients with metastatic disease were able to undergo complete resection.

 The MSLT-I trial (NCT00275496) reported that patients who underwent metastasectomy had an increase in OS compared with those who did not. Patients who underwent both systemic treatment and surgery showed a median OS of 15.8 months vs 6.9 months for those receiving systemic treatment alone. This benefit is even higher when the disease-free period is longer than 12 months (HR, 0.41; 

 <.001), and this is independent of the type of metastatic disease: 4-year OS for M1a disease treated with systemic treatment and surgery vs systemic treatment only: 69.3% vs 0%, respectively (

 = .0001). The number of metastatic lesions is also important; cases with fewer than 2 lesions had more favorable outcomes.

A significant improvement in OS has been reported independent of the anatomical site of metastases. After complete lung metastasectomy, OS has been reported to improve by 25%, with a median survival of 20.5 months vs 13 months for the no surgery group.

 However, the presence of more than 2 lesions and the diameter of any that are larger than 2 cm are adverse prognostic factors.

 Resection of abdominal metastases may also improve survival (median OS, 18 months vs 7 months).

 Metastasectomy at other sites, such as gastrointestinal (median OS, up to 64 months27), adrenal gland (median OS, 29.2 months

), seems to improve outcomes as well. Bone metastasectomy also provides significant benefit, as median OS improves from 4.8 months to 11.8 months; however, the number of metastases is an adverse prognostic factor.

 Finally, the prognosis for patients with metastatic lesions in the CNS is poor, with OS of 4 to 6 months; surgery is indicated only for single lesions or as palliative treatment.

In the era of IO and TT, there is evidence that systemic treatment increases the potential of surgery to be curative for residual oligometastatic disease (15.9% vs 4.3% with no systemic treatment; 

 = .045). For patients who underwent metastasectomy of residual disease, an OS benefit has also been reported: median OS, 16 months vs 6 months for those who did not.

In conclusion, surgery is likely to increase OS in patients with recurrent/metastatic melanoma, and the decisions about who are the best surgical candidates should be discussed in multidisciplinary teams. The best candidates are patients who have a disease-free period of 12 months or more, fewer than 2 metastatic lesions, and a tumor burden less than 2 cm. In all cases, assessing potential resectability should be done with surgical consultation. Access to TT or IO is not universal, so surgery might be the only option in some cases.

The role of radiotherapy in oligometastatic and oligoprogressive melanoma

Melanoma is considered a relative radioresistant tumor; until recently, radiotherapy was mainly reserved for palliative treatment or for adjuvant treatment in a specific subset of patients. With the introduction of stereotactic radiosurgery (SRS), radiotherapy has become an option for local control with minimal toxicity. Although some evidence of benefit has been reported in patients with extracranial metastases,

 the main role of SRS has been in treating melanoma that has metastasized to the brain.

Local treatments of brain metastases from melanoma include surgical resection, SRS, and WBRT.

 While for many years WBRT has been considered among the main treatment options,

 outcomes are notably inferior compared with those of newer systemic treatments and radiation techniques (median OS, WBRT alone vs WBRT alone vs IO alone vs SRS alone: 4.2 vs 11.5 months vs 10.9 months), and its use alone should be avoided whenever possible to help avoid further cognitive decline.

 When WBRT with conventional dose fractionation is planned as a reasonable treatment option in the setting of multiple brain metastases, a hippocampus-sparing technique is strongly encouraged because it is associated with significant memory and
quality-of-life preservation.

SRS could be considered the preferred treatment option for brain metastases of melanoma due to better preservation of neurocognition. The results of 2 randomized controlled trials (RCTs) support SRS for patients with 1 to 3 brain metastases. The results of one trial (NCT00548756) indicated that learning and memory functions were less likely to decline with SRS alone than with SRS plus WBRT (24% vs 52% decline).38 The other trial (NCT00377156) found less cognitive deterioration after SRS than after SRS plus WBRT (64% vs 92% decline) without compromising median OS (10.4 vs 7.4 months).

 More recently, another RCT (NCT01592968) provided level 1 evidence to support SRS as a viable treatment option for patients with 4 to 15 brain metastases. The SRS arm experienced lower decline in cognitive function than the WBRT group (6% vs 50%); OS did not differ (7.8 vs 8.9 months).

Despite the better neurocognitive outcomes associated with SRS, higher intracranial tumor control was observed in patients who received WBRT (93.7% vs75.3%).

 The latter could be explained theoretically by the higher number of brain metastases in the population treated with WBRT compared with those treated with SRS alone and the higher risk of having microscopic dissemination of tumor in the brain, not identifiable by current imaging techniques, at the time of treatment with SRS.

The combination of SRS plus targeted agents and/or IO appears to be safe, and its effectiveness may be due to the potential synergistic boost this combination might provide to tumor response.

 A retrospective analysis of data from a national cancer database of melanoma brain metastases observed that SRS combined with IO provided the higher median OS compared with IO alone or SRS alone (19.9 months vs 11.5 months vs 10.9 months, respectively).

 A high dose of localized radiation therapy with SRS or stereotactic body radiation therapy, particularly combined with IO or targeted therapy, can induce a tumor response in nonirradiated metastases, known as the abscopal effect.

In summary, radiation therapy is a useful tool for local control of melanoma metastatic disease, especially of brain disease. Currently, in patients with fewer than 5 lesions, none larger than 3 cm, SRS is the preferred option since it is noninferior to WBRT in terms of OS and has fewer neurocognitive adverse effects. Combinations of SRS with other systemic therapies seem promising, warranting further evaluation.

The patient had only 1 metastatic site of progression. WBRT was started because she had multiple brain lesions. After treatment, the patient recovered an ECOG 1 functional status. The case was discussed by a multidisciplinary team. Since access to a clinical trial or an IO combination was not available, treatment with D+T was continued. The patient persisted with clinical benefit for 11 months until she developed symptomatic brain progression. D+T was stopped, and best supportive care was started. 

 is a speaker for MSD, Bristol Myers Squibb, Novartis, and serves as an advisor for and receives research funding from MSD, Bristol Myers Squibb. 

 is a speaker for MSD, Bristol Myers Squibb, Novartis; 

is a speaker for MSD, Bristol Myers Squibb, Novartis, and serves as an advisor for and receives research funding from MSD, Bristol Myers Squibb.

Maria T. Bourlon, MD, is associate professor, Head Urologic Oncology Clinic; national researcher, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. She is also a member of ASCO’s IDEA Working Group.

E. David Crawford, MD, is chairman, Prostate Conditions Education Council; editor in chief, 

; and professor of urology, University of California San Diego, La Jolla, CA.

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This clinical quandary discusses oligoprogressive disease in metastatic melanoma and how treatment with immunotherapy and targeted therapy affect the disease. 

ONCOLOGY Vol 35, Issue 9 | Oncology

The COLOMATE Platform: An Indispensable Initiative Promoting True Precision Oncology Prioritized for Patients With Cancer—From “MAYBE” to “MUST BE”

Expert Commentary on the Product Profile of Margetuximab for HER2-Positive Breast Cancer

Investigators Look Past Standard Immunotherapy for Additional Lung Cancer Solutions

Addressing Stress and Burnout in Hematology/Oncology Physicians

Oligoprogression After Immunotherapy and Targeted Therapy in Metastatic Melanoma

The Current Molecular Treatment Landscape of Advanced Colorectal Cancer and Need for the COLOMATE Platform

Plasma Glutamine as a Prognostic Biomarker in Localized Prostate Cancer: Comparison of Conventional Variables in Risk Stratification