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.

Melanoma of skin. International Agency for Research on Cancer / World Health Organization. December 2020. Accessed June 20, 2021. https://gco.iarc.fr/today/data/factsheets/cancers/16-Melanoma-of-skin-fact-sheet.pdf

Cancer facts and figures 2021. American Cancer Society. 2021. Accessed January 13, 2021. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf

Cancer stat facts: melanoma of the skin. National Cancer Institute / Surveillance, Epidemiology, and End Results Program. Accessed June 25, 2021. https://seer.cancer.gov/statfacts/html/melan.html

Curti BD, Faries MB. Recent advances in the treatment of melanoma. 

. 2021;384(23):2229-2240. doi:10.1056/NEJMra2034861

Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. 

. 2019;381(7):626-636. doi:10.1056/NEJMoa1904059

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. 

. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836

Gide TN, Wilmott JS, Scolyer RA, Long GV. Primary and acquired resistance to immune checkpoint inhibitors in metastatic melanoma. 

. 2018;24(6):1260-1270. doi:10.1158/1078-0432.CCR-17-2267

Schadendorf D, van Akkooi ACJ, Berking C, et al. Melanoma. 

. 2018;392(10151):971-984. doi:10.1016/S0140-6736(18)31559-9. Published correction appears in 

Comito F, Leslie I, Boos L, et al. Oligoprogression after checkpoint inhibition in metastatic melanoma treated with locoregional therapy: a single-center retrospective analysis. 

. 2020;43(8):250-255. doi:10.1097/CJI.0000000000000333

Sindhu KK, Leiter A, Moshier E, et al. Durable disease control with local treatment for oligoprogression of metastatic solid tumors treated with immune checkpoint blockade. 

. 2020;25:100216. doi:10.1016/j.ctarc.2020.100216

Guida M, Bartolomeo N, De Risi I, et al. The management of oligoprogression in the landscape of new therapies for metastatic melanoma. 

. 2019;11(10):1559. doi:10.3390/cancers11101559

Arozarena I, Wellbrock C. Phenotype plasticity as enabler of melanoma progression and therapy resistance. 

. 2019;19(7):377-391. doi:10.1038/s41568-019-0154-4

Palma DA, Salama JK, Lo SS, et al. The oligometastatic state – separating truth from wishful thinking. 

. 2014;11(9):549-557. doi:10.1038/nrclinonc.2014.96

Beaver JA, Hazarika M, Mulkey F, et al. Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis. 

. 2018;19(2):229-239. doi:10.1016/S1470-2045(17)30846-X

Borcoman E, Nandikolla A, Long G, Goel S, Le Tourneau C. Patterns of response and progression to immunotherapy. 

. 2018;38:169-178. doi:10.1200/EDBK_200643

Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. 

. 2016;17(9):1248-1260. doi:10.1016/S1470-2045(16)30122-X

Ascierto PA, Dummer R, Gogas HJ, et al. Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. 

. 2020;126:33-44. doi:10.1016/j.ejca.2019.11.016

Versluis JM, Hendriks AM, Weppler AM, et al. The role of local therapy in the treatment of solitary melanoma progression on immune checkpoint inhibition: a multicentre retrospective analysis. 

. 2021;151:72-83. doi:10.1016/j.ejca.2021.04.003

Klemen ND, Wang M, Feingold PL, et al. Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma. 

. 2019;7(1):196. doi:10.1186/s40425-019-0672-3

Sondak VK, Liu PY, Warneke J, et al. Surgical resection for stage IV melanoma: a Southwest Oncology Group trial (S9430). 

. 2006;24(18_suppl):abstr 8019. doi:10.1200/jco.2006.24.18_suppl.8019

Howard JH, Thompson JF, Mozzillo N, et al. Metastasectomy for distant metastatic melanoma: analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I). 

. 2012;19(8):2547-2555. doi:10.1245/s10434-012-2398-z

Treasure T, Milošević M, Fiorentino F, Macbeth F. Pulmonary metastasectomy: what is the practice and where is the evidence for effectiveness? 

. 2014;69(10):946-949. doi:10.1136/thoraxjnl-2013-204528

Schuhan C, Muley T, Dienemann H, Pfannschmidt J. Survival after pulmonary metastasectomy in patients with malignant melanoma. 

. 2011;59(3):158-162. doi:10.1055/s-0030-1250669

Chua TC, Scolyer RA, Kennedy CW, Yan TD, McCaughan BC, Thompson JF. Surgical management of melanoma lung metastasis: an analysis of survival outcomes in 292 consecutive patients. 

. 2012;19(6):1774-1781. doi:10.1245/s10434-011-2197-y

Younes R, Abrao FC, Gross J. Pulmonary metastasectomy for malignant melanoma: prognostic factors for long-term survival. 

. 2013;23(4):307-311. doi:10.1097/CMR.0b013e3283632cbe

Wollina U, Brzezinski P. The value of metastasectomy in stage IV cutaneous melanoma. 

. 2019;169(13-14):331-338. doi:10.1007/s10354-018-0630-6

Deutsch GB, Flaherty DC, Kirchoff DD, et al. Association of surgical treatment, systemic therapy, and survival in patients with abdominal visceral melanoma metastases, 1965-2014: relevance of surgical cure in the era of modern systemic therapy. 

. 2017;152(7):672-678. doi:10.1001/jamasurg.2017.0459. Published correction appears in 

Flaherty DC, Deutsch GB, Kirchoff DD, et al. Adrenalectomy for metastatic melanoma: current role in the age of nonsurgical treatments. 

. 2015;81(10):1005-1009. doi:10.1177/000313481508101019

Ryu SW, Saw R, Scolyer RA, Crawford M, Thompson JF, Sandroussi C. Liver resection for metastatic melanoma: equivalent survival for cutaneous and ocular primaries. 

. 2013;108(2):129-135. doi:10.1002/jso.23361

Colman MW, Kirkwood JM, Schott T, Goodman MA, McGough RL III. Does metastasectomy improve survival in skeletal melanoma? 

. 2014;24(4):354-359. doi:10.1097/CMR.0000000000000076

Eigentler TK, Figl A, Krex D, et al; Dermatologic Cooperative Oncology Group and the National Interdisciplinary Working Group on Melanoma. Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma. 

. 2011;117(8):1697-1703. doi:10.1002/cncr.25631

Smith MJF, Smith HG, Joshi K, et al. The impact of effective systemic therapies on surgery for stage IV melanoma. 

. 2018;103:24-31. doi:10.1016/j.ejca.2018.08.008

Youland RS, Blanchard ML, Dronca R, et al. Role of radiotherapy in extracranial metastatic malignant melanoma in the modern era. 

. 2017;6:25-30. doi:10.1016/j.ctro.2017.09.002

Goyal S, Silk AW, Tian S, et al. Clinical management of multiple melanoma brain metastases: a systematic review. 

. 2015;1(5):668-676. doi:10.1001/jamaoncol.2015.1206

Tsao MN, Rades D, Wirth A, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. 

. 2012;2(3):210-225. doi:10.1016/j.prro.2011.12.004

Moyers J, Chong EG, Sufficool D, et al. Treatment outcomes in melanoma with brain metastases in the era of immunotherapy: an analysis of the National Cancer Database. 

. 2020;38(15_suppl):abstr e14513. doi:10.1200/JCO.2020.38.15_suppl.e14513

Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. 

. 2014;32(34):3810-3816. doi:10.1200/JCO.2014.57.2909

Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. 

. 2009;10(11):1037-1044. doi:10.1016/S1470-2045(09)70263-3

Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. 

. 2016;316(4):401-409. doi:10.1001/jama.2016.9839. Published correction appears in 

Li J, Ludmir EB, Wang Y, et al. Stereotactic radiosurgery versus whole-brain radiation therapy for patients with 4-15 brain metastases: a phase III randomized controlled trial. 

. 2020;108(3):S21-S22. doi:10.1016/j.ijrobp.2020.07.2108

Arina A, Gutiontov SI, Weichselbaum RR. Radiotherapy and immunotherapy for cancer: from “systemic” to “multisite.” 

. 2020;26(12):2777-2782. doi:10.1158/1078-0432.CCR-19-2034

Mazzola R, Jereczek-Fossa BA, Franceschini D, et al. Oligometastasis and local ablation in the era of systemic targeted and immunotherapy. 

. 2020;15(1):92. doi:10.1186/s13014-020-01544-0

Sha CM, Lehrer EJ, Hwang C, et al. Toxicity in combination immune checkpoint inhibitor and radiation therapy: a systematic review and meta-analysis. 

. 2020;151:141-148. doi:10.1016/j.radonc.2020.07.035

Ratnayake G, Reinwald S, Shackleton M, et al. Stereotactic radiation therapy combined with immunotherapy against metastatic melanoma: long-term results of a phase 1 clinical trial. 

. 2020;108(1):150-156. doi:10.1016/j.ijrobp.2020.05.022

Watanabe T, Firat E, Scholber J, et al. Deep abscopal response to radiotherapy and anti-PD-1 in an oligometastatic melanoma patient with unfavorable pretreatment immune signature. 

. 2020;69(9):1823-1832. doi:10.1007/s00262-020-02587-8

Articles

Clinical Quandaries

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

Oligoprogression After Immunotherapy and Targeted Therapy in Metastatic Melanoma

Metastatic Colorectal Cancer and Treatment Challenges

Colorectal cancer (CRC) is estimated to be the third most prevalent cause of cancer death in both men and women in the United States in 2021.

 While some patients are diagnosed with localized disease and cured with appropriate treatments, most patients who are diagnosed with de novo or recurrent advanced disease face a life-limiting illness. Median overall survival (OS) in metastatic CRC (mCRC) continues to increase over time, largely due to improving systemic therapies, but more therapies are still needed. For the majority of patients with mCRC, even initially effective systemic therapies become intolerable or cancer resistance to chemotherapy develops.

In the last decade, the identification of actionable genomic alterations in mCRC has led to the FDA approval of several effective therapeutic regimens targeting these alterations (see below). Still, even guideline-aligned biomarker testing for alterations such as 

, and microsatellite instability high (MSI-H)/mismatch repair deficiency (dMMR) in mCRC remains suboptimal,

 highlighting the need for more streamlined testing. Once therapeutic resistance develops, recognition of this is necessary and new therapeutic options are needed. This article will describe currently established and actionable genomic alterations in mCRC, emerging targets, and a novel clinical trial platform designed to optimize therapeutic selection for patients with mCRC.


Next-Generation Sequencing Utilizing Tumor Tissue and/or Blood

The identification of actionable genomic alterations in tumors such as mCRC was once performed by Sanger DNA sequencing of tumor DNA that was extracted from fixed paraffin-embedded tumor tissue, but this has now been replaced by next-generation sequencing (NGS), which allows for larger-scale and automated genome sequencing. Multiple commercial vendors, such as Foundation One, Caris, and Tempus, among others, provide comprehensive tumor molecular profiling. However, utilizing NGS data from a tumor biopsy of 1 anatomic location at 1 time point may be insufficient to treat patients with mCRC, as we recognize that there can be spatial tumor heterogeneity (between the primary tumor and metastatic lesions) and temporal tumor heterogeneity (when targeted therapies exert pressure for certain mutations to disappear and new mutations to evolve).

 The invasiveness of serial tissue biopsies and the turnaround time of 2 to 4 weeks for NGS analysis can both be limitations for clinical use. Thus, the development of blood-based NGS testing as a method to analyze circulating tumor DNA (ctDNA) has been a welcome one. This allows clinicians to identify the prominent actionable genomic alterations from the patient’s cancer as a whole, and to monitor the dynamic changes in the molecular profile serially as the patient progresses from one treatment to another.

The FoundationOne Liquid CDX test (Foundation Medicine, Inc, Cambridge, MA) is now FDA approved as a companion test for multiple biomarkers, including 

2 genes in ovarian cancer for rucaparib (Rubraca) treatment, 

 rearrangements in non–small cell lung cancer (NSCLC) for alectinib (Alecensa) treatment, 

 mutations in breast cancer for alpelisib (Piqray) treatment, and 

 mutations in prostate cancer for olaparib (Lynparza) treatment. The Guardant360 CDX (Guardant Health, Redwood City, CA) assay has been FDA approved as a companion test for 

 mutation for the use of osimertinib (Tagrisso) for patients with NSCLC. Thus, blood-based NGS should be considered an additional test that clinicians can utilize in the care of patients with mCRC.

Established Actionable Genomic Targets in Metastatic Colorectal Cancer

Several genomic alterations are now established and actionable in mCRC, including 

 We will briefly review the current clinical trial data behind these actionable alterations.

 mutations in mCRC have long been recognized as a negative predictive biomarker, identifying patients who would not benefit from anti-EGFR antibody treatments such as cetuximab (Erbitux) or panitumumab (Vectibix).

 exon 2 mutations were initially thought to be the sole predictive biomarkers in mCRC, subsequent data have shown that 

 exon 2, 3, and 4 mutations are all predictive. As such, guideline-aligned biomarker testing now includes extended RAS testing for completeness. For patients with 

 wild-type mCRC, treatment with cetuximab or panitumumab, either in combination with other cytotoxic chemotherapies or as monotherapy, can be an effective treatment strategy. For these patients, primary tumor sidedness is also prognostic, with left-sided primary tumors being associated with better overall prognosis independent of therapy

; left-sidedness is predictive of response to anti-EGFR therapy as well.

In addition to its known role as a negative predictive marker, 

 is now also a positive predictive biomarker. Long thought to be the “undruggable” target due to its high affinity for GTP and its lack of large binding pocket for allosteric inhibitors,

 the discovery of small molecules that can bind to KRAS G12C led to rapid drug development.

 A phase 1 trial (NCT03600883) investigated sotorasib (Lumakras), an irreversible KRAS G12C inhibitor, in patients with advanced solid tumors harboring the 

 Overall, 7.1% of the 42 mCRC patients treated on study had a confirmed objective response, and 73.8% had disease control. However, median progression-free survival was only 4 months. Other KRASG12C inhibitors in development such as MRTX849 have also shown encouraging preclinical and early clinical data,

 although mechanisms of resistance—such as MAPK reactivation, stimulation of CDK4/6-dependent cell-cycle transition, and immune defects to KRAS G12C inhibition—are now being identified.

 G12C mutations are present in only approximately 3% of CRC cases, just a small minority of patients are eligible for this targeted approach. However, the fact that a previously undruggable target may now be druggable in mCRC has been an exciting development and holds promise for future drug development and discovery.

 V600E mutations are both prognostic and predictive biomarkers in mCRC and are present in approximately 8% to 10% of mCRC cases.

 Interestingly, non-V600E mutations do not confer a prognosis that is as poor,

 but they are also targets of interest in drug discovery. For patients with previously treated 

 V600E–mutant mCRC, the phase 3 BEACON CRC study (NCT02928224) found that combined inhibition of 

 with encorafenib (Braftovi) and cetuximab, respectively, led to improvements in OS, objective response rate (ORR), and progression-free survival (PFS) when compared with treatment with standard chemotherapy.

 Median OS, ORR, and PFS for the doublet arm were 9.3 months, 19.5%, and 4.3 months, compared with 5.9 months, 1.8%, and 1.5 months, respectively, for the control arm. These results led to combined 

 inhibition in previously treated patients with

 V600E mutant mCRC becoming a new standard of care.

Patients with colorectal cancer could benefit from the COLMATE platform as it allows for opportunities in clinical trial enrollment. 

ONCOLOGY Vol 35, Issue 9 | Oncology

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