Deborah Abrams Kaplan

What if there were a test that involved just a blood draw or saliva to determine whether a patient with cancer would likely respond to and benefit from immunotherapy or adjuvant therapy? What about a blood test any oncologist could order that would identify lingering cancer cells months before they might show on imaging? That future is rapidly approaching; several hundred trials are using circulating tumor DNA (ctDNA) detection and quantification for either intervention or observation.

One advantage ctDNA has over traditional scanning methods is that even if all the disease appears to be eliminated with treatment, ctDNA can show minimal residual disease (MRD). MRD is a biomarker that facilitates prognosis, treatment stratification, and personalization based on tumor profile.

 It also helps identify potential for recurrence of disease.

As a component of cell-free DNA, ctDNA is shed by malignant tumors into bodily fluids such as blood, urine, and saliva. Using MRD for diagnosis and monitoring requires detecting tiny bits of tumor remaining after curative intent treatment. Given that ctDNA levels are usually low, especially for localized disease, highly sensitive assays and detection methods are needed. Investigators have shown that “when a patient has MRD detected after treatment, they have a high chance of relapse that can be mitigated with treatment,” Aadel Chaudhuri, MD, PhD, assistant professor of radiation oncology at Washington University School of Medicine in St Louis, Missouri said in an interview with Targeted Therapies in Oncology. By identifying high-risk patients through MRD detection and then treating them, outcomes can improve, he said.

Although MRD is commonly associated with hematological malignancies, investigators are also exploring the use of liquid biopsies to quantify and analyze MRD in solid tumors through ctDNA analysis. “We haven’t really had good MRD biomarkers for solid tumor malignancies, with the exception of ultrasensitive PSA [prostate-specific antigen] for prostate cancer,” Chaudhuri said.

ctDNA MRD can show residual disease in solid tumors like lung cancer earlier than use of imaging techniques during routine clinical surveillance.1 Although standard imaging can detect macroscopic disease recurrence, it can be difficult to assess disease presence caused by inflammation or fibrosis, which can appear similar to tumor tissue, particularly after radiation therapy. With disease progression, outcomes can be poor in patients with lung cancer. Detecting MRD through ctDNA could make disease recurrence easier to detect and allow for earlier treatment and potentially better clinical results.

MRD Testing in Hematologic Malignancies and in Clinical Practice 

Tumor-specific mutations were first found in patients with hematologic malignancies in 1994.

 The potential use of ctDNA involves the detection of specific mutations in plasma or serum of cancer patients, suggesting that it could serve as a real-time marker of disease burden. A recent meta-analysis showed ctDNA’s advantages for specificity in diagnosing hematological malignancies and as a good alternative to biopsy because of noninvasive collection methods. For sensitivity, however, ctDNA did not prove superior to biopsy. Investigators note that the lack of sensitivity could be due to the highly heterogeneous nature of hematologic tumors.

 They recommend a panel-based next-generation sequencing (NGS) approach.

MRD is not widely used outside research as a biomarker for treatment in hematology and solid tumors. “These studies are really opening the door toward new standards of care,” said Chaudhuri. Several commercially available assays are quite sensitive, he said, and are available for clinicians to order and use with patients for testing. “[Some] clinicians are using these to inform treatment decisions and to identify resistance mutations.” However, no MRD guidelines are available for clinical decision-making. “As some of these trials get reported, that will change.”

Some clinicians are relying on trials such as the IMvigor010 trial (NCT02450331) for bladder cancer and other major studies with results reported over the past year, for patients with challenging cases. When unsure whether the patient has residual disease, these investigators are ordering assays and bringing the results to a molecular tumor board to determine whether they can make an informed treatment decision, Chaudhuri said. None of the assays have FDA approval but some have been fast-tracked, he said. “And those are the ones that clinicians have the option to order. Those companies are reaching out to clinicians and trying to make a case that, for challenging cases, ctDNA MRD can help add data.”

Current assays can detect ctDNA levels as low as around 10 or 20 parts per million (ppm), Chaudhuri said. “That’s a level so low it’s almost like finding a needle within a city of haystacks.” Different assay types utilize different methods. Some assays focus exclusively on genomic alterations; others look at methylation signatures, which have been shown to exhibit sensitivity and specificity for cancer, he said. There are also assays with a genome-wide approach to assessing ctDNA MRD, rather than a more targeted approach. Some require a patient tumor sample to generate a personalized assay, whereas others are off-the-shelf and can be applied in a tumor-naive fashion.

Research, including some by Chaudhuri, is also detecting ctDNA with other bodily fluids, albeit at lower levels. When using urine, the assays seem to be more sensitive in malignancies like bladder cancer.

 “The biofluid that is most proximal to the tumor tends to be enriched for the malignancy,” he said. “We were surprised that we were able to detect any ctDNA in urine, following neoadjuvant chemotherapy for oligometastatic colorectal cancer. Levels were extremely low, about 10-fold lower than what they were in plasma.” But as this noninvasive approach using urine is promising, he said, he is also collaborating on research for head and neck cancer using saliva.

Research on several solid tumor malignancies is focusing on ctDNA for MRD assessment, including cancers such as lung, colon, breast, bladder, esophageal, gastric, and melanoma.

Lung Cancer In a landmark 2017 lung cancer study, Chaudhuri said, investigators detected ultralow levels of ctDNA shortly after intense treatment in patients with local disease and poor outcomes.

 The patients whose disease progressed rapidly and who subsequently died had detectable MRD, whereas those without detectable MRD did well after treatment, he said. The study found that ctDNA identified disease earlier than CT imaging in 72% of patients, a median of 5.2 months earlier than with imaging. This gap presents an opportunity to offer earlier treatment when the patient has a lower disease burden, or to give adjuvant treatment. This research “has informed an entire field, where we now aim to detect ctDNA MRD shortly after treatment, with the goal of intensifying treatment for highrisk patients,” he said.

A 2020 study in locally advanced nonsmall cell lung cancer showed that ctDNA predicted benefits from consolidation immunotherapy.

 The study also showed that patients with detectable MRD after chemoradiation who subsequently underwent consolidation immunotherapy had significantly better outcomes compared with those who did not undergo the consolidation therapy.

After chemoradiation therapy, patients with undetectable ctDNA MRD showed excellent outcomes with or without receiving consolidation immune checkpoint inhibition therapy. The authors concluded that ctDNA analysis can enrich personalized therapy decisions.

Colon cancer is another area with ctDNA MRD trials. An oral abstract from the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting shared results from a multicenter study of 265 patients with stage I to III colorectal cancer, noted to be the largest ctDNA cohort assessed to date.

 Researchers collected plasma samples at different times, with a median follow-up of 28.4 months. In the 9.1% of patients who were MRD-positive postoperatively, 75% relapsed eventually. In the MRD-negative cases, just 13.6% relapsed. Investigators concluded that ctDNA analysis predicted recurrence risk and was a more reliable biomarker to monitor treatment response.

A poster presented at the 2021 ASCO Annual Meeting focused on detecting MRD using personalized assays for stage II to III colorectal cancer (FIGURE).

 Investigators monitored MRD before and after surgery before giving adjuvant chemotherapy. MRD was detected in 13% of patients postoperatively; of these patients, 42.9% relapsed. Of the MRD-negative patients, 8.6% relapsed.

The investigators noted that ctDNA status was the most significant factor associated with recurrence-free survival. 

Data presented at the European Society for Medical Oncology Immuno-Oncology Virtual Congress 2020 included a ctDNA exploratory analysis to evaluate clinical benefits of atezolizumab (Tecentriq) versus observation in patients with detectable ctDNA

 Investigators found positive ctDNA MRD in 37% of patients, associated with nodal status and tumor stage, to a lesser extent. Those with detectable ctDNA MRD showed a substantial disease-free survival benefit with atezolizumab compared with observation, and authors concluded that detecting MRD in an adjuvant setting allowed clinicians to offer personalized treatments. Lead author Thomas Powles, MD, MBBS, MRCP, professor of genitourinary oncology and lead for Solid Tumour Research, Barts Cancer Institute, and director, Barts Cancer Centre, United Kingdom, said during a presentation of the data that these findings could have practice-changing implications for treatment of bladder cancer as well as other malignancies, in that patients can be selected for adjuvant therapy based on a ctDNA MRD biomarker, which could not previously have been done. Patients with detectable ctDNA MRD had an 80% chance of recurrence.

Chaudhuri said similar studies are being performed in other cancer types, too, which will be important in proving the value of ctDNA MRD as an across-the-board predictive biomarker. 

Using ctDNA for MRD still has challenges. In small tumors with a curative resection, detecting ctDNA at low levels is difficult. Low assay sensitivity and false negatives are a challenge, Chaudhuri said. The other issue is noise. “As we get older, we generate mutations in our blood through a process called clonal hematopoiesis that can make it difficult to discriminate solid tumor-derived ctDNA mutations from these similar-looking mutations in blood cells,” Chaudhuri explained.

There is a lot of interest in ctDNA, with its promise for early cancer detection and screening, response monitoring for tumor burden, and potential to identify resistance mutations, Chaudhuri said. “Everyone along that spectrum is excited about ctDNA,” he said. “I think it will be actionable along this entire spectrum. We’re already using it clinically for resistance mutation detection, and we’re going to use it for MRD detection, but the sky’s the limit.”

1. Chin RI, Chen K, Usmani A, et al. Detection of solid tumor molecular residual disease (MRD) using circulating tumor DNA (ctDNA). 

. 2019;23(3):311-331. doi:10.1007/s40291-019-00390-5 

2. Tan X, Yan H, Chen L, Zhang Y, Sun C. Clinical value of ctDNA in hematological malignancies (lymphomas, multiple myeloma, myelodysplastic syndrome, and leukemia): a meta-analysis. 

. 2021;11:632910. doi:10.3389/fonc.2021.632910 

3. Pellini B, Pejovic N, Feng W, et al. ctDNA MRD detection and personalized oncogenomic analysis in oligometastatic colorectal cancer from plasma and urine.

. 2021;5:PO.20.00276. doi:10.1200/PO.20.00276 

4. Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling.

. 2017;7(12):1394-1403. doi:10.1158/21598290.CD-17-0716

5. Moding EJ, Liu Y, Nabet BY, et al. Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer. 

. 2020;1:176-183. doi:10.1038/s43018-019-0011-0 

6. Henriksen TV, Tarazona N, Reinert T, et al. Circulating tumor DNA analysis for assessment of recurrence risk, benefit of adjuvant therapy, and early relapse detection after treatment in colorectal cancer patients. 

. 2021;39(suppl 3):11. doi:10.1200/JCO.2021.39.3_suppl.11 

7. Anandappa G, Starling N, Begum R, et al. Minimal residual disease (MRD) detection with circulating tumor DNA (ctDNA) from personalized assays in stage II-III colorectal cancer patients in a U.K. multicenter prospective study (TRACC). 

. 2021;39(suppl 3):102. doi:10.1200/JCO.2021.39.3_suppl.102 

8. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. 

. 2021;595(7867):432-437. doi:10.1038/s41586-021-03642-9

Articles

The future is rapidly approaching; several hundred trials are using circulating tumor DNA detection and quantification for either intervention or observation.

Currently Relegated for Use in Clinical Trials,  MRD Is Poised to Expand Further

In 2017, the American Society of Clinical Oncology (ASCO) and the Ontario Health-Cancer Care Ontario (OH-CCO)’s non–small cell lung cancer (NSCLC) expert panel published a guideline with recommendations for systemic therapy for patients with stage IV NSCLC.

Soon after publication, clinicians clamored for another update. With the fast pace of discovery of new immunotherapies and targets, the standard of care was changing so rapidly that “it left clinicians in a lurch about how to incorporate these, in what order, and in what patient population,” Bryan J. Schneider, MD, clinical professor of internal medicine in the Division of Hematology/Oncology at the University of Michigan in Ann Arbor, expert panel member, and guidelines coauthor said in an interview with 

. “More than most of the other tumor types, we’ve seen exponential leaps and bounds in the positive trials that have led to new standards of care in NSCLC.”

The topic became so broad and deep, with different subsets of NSCLC, that the committee divided the guidelines into 2: one for NSCLC with driver gene alterations and one without. “We thought it would be better for providers if we divided them among the first decision point they face when you have a patient with advanced NSCLC. Is there an actionable gene alteration or not? It drives all the treatment decision-making downstream,” Schneider said.

The update for treating for patients without driver alterations

 was published in 2020, and the guideline for patients with driver alterations

Advanced NSCLC Without Driver Gene Alterations 

These nondriver alteration guidelines include more data about incorporating immune checkpoint inhibitors, Schneider said. Prior to 2017, immune checkpoint inhibitors were typically used as monotherapies in second-line treatments for patients who progressed on chemotherapy. Since that 2017 update, additional clinical trial data became available for using immune checkpoint inhibitors in combination with chemotherapy and as monotherapy in the frontline setting.

These new recommendations are based on the degree of PD-L1 tumor expression, ie, tumor proportion score (TPS) test results. This was challenging, Schneider said, because the trials used different assays and different cutoff points for what was considered positive PD-L1. For this set of guidelines, “we tried to simplify recommendations based on consistent cut-off points,” he said. “If there’s a newly diagnosed patient with metastatic NSCLC and they do not have any actional driver gene alterations, what is the optimal treatment approach based on their PD-L1 status?”

The panel conducted a systematic review of randomized controlled trials (RCTs) from December 2015 to 2019, ultimately using 5 RCTs as the evidence base: KEYNOTE-042 (NCT02220894), KEYNOTE-189 (NCT02578680), KEYNOTE-407 (NCT02775435), IMpower150 (NCT02366143), and IMpower130 (NCT02367781). Interventions include immune checkpoint therapy, chemotherapy, and antiVEGF agents. The panel addressed the most effective therapies for first line, second line, and potentially third line/beyond.

The following highlights the notable changes in the guidelines.

These recommendations focus on patients with high PD-L1 expression (TPS ≥ 50%) and nonsquamous cell carcinoma (non-SCC) in the absence of contraindications to immune checkpoint therapies. The panel recommended single-agent pembrolizumab (Keytruda) in the first-line setting. Additional treatment options include pembrolizumab/carboplatin/pemetrexed, atezolizumab (Tecentriq)/carboplatin/ paclitaxel/bevacizumab (Avastin), or atezolizumab/carboplatin/nab-paclitaxel.

The 2017 guidelines include monotherapy pembrolizumab as an option, but the 2020 guidelines present this as the preferred choice, based on new evidence from the KEYNOTE-042 trial and updated results from KEYNOTE-024 (NCT02142738). These trials showed an overall 2-year survival improvement on pembrolizumab, along with a superior toxicity profile compared to chemotherapy.

“All things being equal, the preference is single-agent pembrolizumab,” Schneider said, adding that a patient with a high tumor burden and a lot of symptoms may benefit from combination therapy however, as chemotherapy can elicit a response more rapidly than immunotherapy alone.

These recommendations focus on patients with non-SCC and either negative (0%) or low positive (1%-49%) PD-L1 expression. The 2.2 pembrolizumab/carboplatin/pemetrexed recommendation is based on a subset analysis of the KEYNOTE-189 study, which demonstrated an improvement in 1-year survival when pembrolizumab was added to carboplatin and pemetrexed. The 2.3 atezolizumab/carboplatin/paclitaxel/bevacizumab recommendation is based on the IMpower150 study, given the response rate and interim median overall survival (OS) improvement. The panel noted that it is a good option for patients with a contraindication to pemetrexed.

The 2.4 atezolizumab/carboplatin/nabpaclitaxel recommendation is based on the IMpower130 trial, which showed clinical benefit over carboplatin/nab-paclitaxel alone.

For the 0% to 49% PD-L1 expression group, “looking at the quality of evidence, chemotherapy needs to be part of the treatment plan because the clinical benefit of immunotherapy alone is there, but it’s low,” Schneider said. Only one-third of patients have high PD-L1 expression, he said, and the other two-thirds will need chemotherapy in addition to an immune checkpoint inhibitor. “There are a lot of different regimens out there, and they haven’t been compared head-to-head, but they have meaningful clinical benefits for the patients. The guidelines leave some of that to the discretion of the clinician.”

These recommendations focus on patients with negative (TPS 0%) and low positive (TPS 1%-49%) PD-L1 expression, SCC, and ECOG performance status 0 to 1, with 4.1 recommending pembrolizumab/carboplatin/paclitaxel or nab-paclitaxel. This is based on KEYNOTE-407, in which PFS and OS results were better than chemotherapy alone.

Recommendation 4.2 includes patients with contraindications to immunotherapy; clinicians should offer standard chemotherapy with platinum-based 2-drug combinations per the 2015 update. Recommendation 4.3 is also for patients with contraindications to immunotherapy who are not deemed candidates for platinum-based therapy; clinicians should offer standard chemotherapy with non–platinum-based 2-drug combinations, per the 2015 update.

Advanced NSCLC With Actionable Genomic Alterations This guideline, published in 2021, is almost completely new due to the identification and development of more targeted therapies to address specific actionable gene alternations, Schneider said. It includes 7 targets, 4 of which were covered in the 2017 update: 

 exon 19 deletion, exon 21 L858R, and exon 20 

 V600E. This update also covers driver alteration targets: 

Approximately 25% of patients with lung cancer tumors have driver alterations,4 but data presented at 2021 American Society of Clinical Oncology Annual Meeting suggested that not all lung cancer patients received driver testing, though they should, Schneider said. “Patients need to have this full biomarker profile, not just with PD-L1, 

, but the other drivers, since there are FDA-approved drugs that target these that could potentially spare the toxicity of chemotherapy.”

“I know it can be challenging to obtain enough tumor tissue for analysis and not all driver alterations may be assessed based on the platform used. Plus, many of these are exceedingly rare. But if they’re found, it’s a significant game changer for patient prognosis and treatment options,” he said.

Recommendations 1.1-1.9 These recommendations focus on patients with 

 driver alterations with an ECOG performance status of 0 to 2. Recommendation 1.1 suggests that in the first-line setting, patients with 

, or exon 19 deletion mutations should be offered osimertinib (Tagrisso). This is based on evidence in the FLAURA trial (NCT02296125), which showed PFS and OS improvement and fewer adverse events compared with first-generation EGFR tyrosine kinase inhibitor (TKI) comparators like gefitinib (Iressa) or erlotinib (Tarceva) as well as improved PFS compared with platinum-based doublet chemotherapy. In the 2017 guidelines, osimertinib was only recommended as second-line therapy for people with 

If osimertinib is unavailable, recommendations 1.2-1.3 suggest using gefitinib with chemotherapy or dacomitinib (Vizimpro) monotherapy. These options will improve PFS and OS compared with a first-generation EGFR-TKI monotherapy option, based on several RCTs. The ARCHER1050 (NCT01774721) trial supported using dacomitinib monotherapy over gefitinib, although some adverse events increased. Other options in recommendations 1.4-1.5 include afatinib (Gilotrif) or erlotinib/bevacizumab or erlotinib/ramucirumab (Cyramza) or gefitinib, erlotinib, or icotinib (Conmana).

The most common mutation identified is EGFR. Those with access to osimertinib receive it as first-line therapy. “The [adverse] effect profile for osimertinib is very manageable, which is important, as this medication is taken on a daily basis, potentially for years,” he said.

Recommendation 1.6 includes patients with a ECOG performance status of 3; panelists suggest an EGFR-TKI. “Oftentimes, treatment decisions are based on performance status of patients.” Schneider said. “If patients are symptomatic from cancer and have mutation like EGFR, utilizing one of these TKIs can afford rapid improvement of symptoms in days to a couple of weeks. For those with a marginal performance status, you can still offer this with the hopes it can help improve the quality of life.”

Recommendation 1.7 applies to patients with 

 mutations other than exon 20 insertion mutations, 

, or exon 19 deletion alterations. The panel recommends afatinib or osimertinib or treatments outlined in the ASCO/OH-CCO nondriver mutation guideline. “Ninety percent of these 

 or exon 19 deletions. Afatinib has been shown to have some clinical benefit.”

Recommendation 1.8 applies to patients with any activating 

 mutation, including exon 20 insertion mutations, regardless of PD-L1 expression levels. In these situations, single-agent immunotherapy should not be used. Schneider said the panel felt this was important because some patients get biomarker testing done in one fell swoop. “It’s not uncommon to have high PD-L1 expression and an 

 mutation. It led to confusion in the community,” he said. Clinicians were unsure whether to offer osimertinib because of the 

 mutation or single-agent pembrolizumab because of the high PD-L1 expression level. “I think the data really [support] that in our patients who have an 

 mutation, PD-L1 expression has not been a very good biomarker to predict response to immunotherapy. Regardless of PD-L1 status, if the patient has an 

 mutation, that drives treatment options, not PD-L1 status,” he said, noting that they’ve seen more concerning data that patients who start with a PD-L1 inhibitor and are subsequently treated with an EGFR inhibitor are at much higher risk for adverse events, particularly pneumonitis.

Recommendation 1.9, the final one in this section, is for those with driver alterations causing resistance to first- and second-generation EGFR-TKIs. The panel recommends doublet chemotherapy with or without bevacizumab or standard treatment outlined in the ASCO/ OH-CCO nondriver mutation guideline for patients with 

“Oftentimes providers want to know the current standard of care if the patient has progressed on an EGFR-TKI,” Schneider said.

“Most of the clinical trials that are investigating immune checkpoint inhibitors, with the exception of IMpower150, excluded patients with 

-positive mutations. So we don’t know the role of incorporating immune checkpoint TKIs after they progress. It’s still an area of active investigation.” If a patient runs out of EGFR-TKI options, they would receive platinum-based chemotherapy.

These recommendations include second-line treatment for patients with 

 mutation at the time of progressive disease who did not receive osimertinib, osimertinib should be offered. Patients with any 

 mutation who progressed on EGFR-TKIs and did not have 

 mutations or those who progressed on osimertinib should receive treatment based on the ASCO/OH-CCO nondriver mutation guideline.

“Osimertinib, when under development, was looked at as a means to salvage patients who progressed on a first- or second-generation TKI,” Schneider said.

“They found that up to 60% of patients who progressed on early generation EGFR TKIs had a resistance mutation, 

, and osimertinib actually still had activity [in these patients]. We wanted to stress that if a patient was treated in the front line with an earlier-generation TKI and progressed, repeat [next-generation sequencing] testing to look for 

 and if positive, to treat with osimertinib.”

This recommendation covers patients with 

 driver alterations and a ECOG performance status of 0 to 2. Guidelines recommend offering alectinib (Alecensa) or brigatinib (Alunbrig) in the first-line setting, and if these are not available, offering ceritinib (Zykadia) or crizotinib (Xalkori).

High-quality data are available for this recommendation, especially for alectinib, Schneider said. The agent is well tolerated and with a good central nervous system penetration, “so it actively treats brain metastases, which is a common site of failure for the initial drug approved for 

 rearrangement for patients with an ECOG performance status of 0 to 2 who previously received alectinib or brigatinib. These patients can be offered lorlatinib (Lorbrena) in second-line treatment. If crizotinib was given in the first-line setting, alectinib, brigatinib, or ceritinib should be offered. If crizotinib was given in the fi rst-line setting and alectinib, brigatinib, or ceritinib was given in the second-line setting, the guidelines recommend lorlatinib as the third-line setting or standard treatment based on the ASCO/OH-CCO nondriver mutation guideline. While developing the guidelines, lorlatinib, the newest generation of ALK inhibitor was being developed and had some activity in patients who progressed, Schneider said.

For patients with ROS1 rearrangement, crizotinib, or entrectinib (Rozlytrek) should be offered in the first-line setting or standard treatment based on the ASCO/OH-CCO nondriver mutation guideline. They can also be offered ceritinib or lorlatinib. Patients should be tested for ROS1, Schneider said. “Crizotinib and entrectinib have low-level data but durable responses to these therapies are commonly achieved and should be offered to these individuals,” he said.

These recommendations focus on second-line treatments for patients with ROS1 rearrangement and ECOG performance status of 0 to 2. If the patient received first-line 

-targeted therapy, they should receive standard treatment based on the ASCO/OH-CCO nondriver mutation guideline for second line. If given nontargeted therapy in the first-line setting, they should be offered crizotinib, ceritinib, or entrectinib in the second line. The EUROCROSS trial (NCT02183870) and METROS trials (NCT02499614) were used for these recommendations. The review identifi ed no RCTs com-paring targeted agents like crizotinib, entrectinib, ceritinib, or lorlatinib with chemotherapy or chemotherapy/immunotherapy. They found no RCTs directly comparing 2 ROS1 inhibitor therapies.

 V600E mutations. In the first-line setting, the guidelines recommend dabrafenib (Tafi n-lar)/trametinib (Mekinist) or standard first-line treatment based on the ASCO/OH-CCO non-driver mutation guideline.

The guidelines for BRAF V600E and the remain-ing gene alterations recommend targeted therapy either before or after platinum-based chemotherapy. Many of the trials investigated these agents after progression on frontline chemotherapy so data on use of these agents as initial therapy is very limited, Schneider said. “Sometimes clinicians are unsure of the optimal frontline treatment.”

The panel filt it was reasonable to start with a targeted agent or start with standard platinum-based chemotherapy. Either way, you should offer the other treatment in the second-line setting.

 V600E mutation is started on platinum-based chemotherapy but is responding and tolerating the chemotherapy, it’s reasonable to continue on that and consider dabrafenib/trametinib as second-line therapy. This would be a similar approach for 

 fusions and their respective targeted therapies., Schneider noted.

This set of recommendations focuses on patients with 

 exon 14 skipping mutations. Patients should be offered either 

-targeted therapy of capmatinib (Tabrecta) or tepotinib (Tepmetko) as first-line treatment or standard treatment based on the ASCO/OH-CCO nondriver mutation guideline.

In the second-line setting, patients with 

 abnormalities other than exon 14 skipping mutations or those given 

-targeted therapy in the frontline setting should receive standard treatment based on the ASCO/OH-CCO nondriver mutation guideline.

Just as the 2017 guidelines needed updating soon after they were published, research continues to move quickly. For this reason, ASCO is piloting a living guideline program for NSCLC and immunotoxicity guidelines.

“We’re looking to update these in real time, or potentially quarterly, when practice-changing data emerge like the recent approval of sotorasib for 

 G12C positive advanced NSCLC,” Schneider said. Ideally the guidelines would be updated on the ASCO website.

“Then eventually when there are a critical mass of changes, there would be a normal guideline update in 

, like we have here. The goal of the living guideline program would be to provide current treatment recommendations in a world where standard of care may change every few months.”

1. Hanna N, Johnson D, Temin, S, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical prac-tice guideline update. 

. 2017;35(30):3484-3515. doi:10.1200/JCO.2017.74.6065

2. Hanna NH, Schneider BJ, Temin S, et al. Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update. 

 2020;38(14):1608-1632. doi:10.1200/JCO.19.03022

3. Hanna NH, Robinson AG, Temin S, et al. Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO and OH (CCO) joint guideline update. 

. 2021;39(9):1040-1091. doi:10.1200/JCO.20.03570

4. Lung cancer genomic testing (EGFR, KRAS, ALK). Memorial Sloan Ket-tering Cancer Center. Accessed June 16, 2021. https://bit.ly/3gHKAxI

In 2017, the American Society of Clinical Oncology and the Ontario Health-Cancer Care Ontario's non–small cell lung cancer expert panel published a guideline with recommendations for systemic therapy for patients with stage IV NSCLC.

New Guidelines Divide Recommendations for Driver and Nondriver NSCLC

Although there is resistance to use the word “cured” to describe patients with long-term progression-free survival (PFS) in renal cell carcinoma (RCC), “that word sometimes gets whispered around the meetings,” Christian Thomas, MD, director of clinical research at New England Cancer Specialists in Scarborough, Maine, said in an interview with 

. “Sometimes patients are on the drugs for 5 years with no evidence of disease. But we don’t think we can routinely cure kidney cancer yet.”

Although curing advanced RCC is an admirable goal, there are many treatment options available on the horizon that result in substantial improvements in long-term outcomes. A handful of novel combination therapies have been approved for the frontline setting in the past few years, with others now in trials. These regimens mark a shift away from monotherapy, as seen in data shared at the 2021 Genitourinary (GU) Cancers Symposium, which highlighted a move toward combinations of immuno-oncology (IO) agents or an IO agent combined with a tyrosine kinase inhibitor (TKI), including VEGF inhibitors.

“I never use monotherapy anymore, like sunitinib [Sutent] or pazopanib [Votrient],” said Michael Humeniuk, MD, a hematologist/oncologist at the SMC Center for Hematology/Oncology in Spartanburg, South Carolina. “There are a lot of new first-line therapies.” If the patient has no contraindications, Humeniuk said he uses double IO or IO/VEGF-TKI combination therapies.

Advanced RCC, although a fairly loose descriptor, is unlikely to be surgically curable, so patients with metastatic RCC in the favorable-risk category based on the International Metastatic RCC Database Consortium (IMDC) scale may be just observed initially, Thomas said. For those in the intermediate- or poor-risk categories, Thomas would consider debulking nephrectomy. But he would also consider frontline double-IO combinations or an IO/TKI combination, a big change from treatment a decade ago, he said.

The current standard of care for someone with intermediate- or poor-risk disease is a combination of IO agents, such as ipilimumab (Yervoy)/nivolumab (Opdivo), or an IO/TKI combination, such as pembrolizumab (Keytruda)/axitinib (Inlyta), said Pooja Ghatalia, MD, assistant professor, Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“[Although] a combination of dual checkpoint inhibitors, [like] ipilimumab/nivolumab, isn’t the wrong answer based on data seen more recently, there is a greater number of treating physicians who prefer an IO/TKI combination for these patients,” Ghatalia said.

Based on data presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 and 2021 GU Cancers Symposium, a patient with intermediate or poor risk can also receive frontline cabozantinib (Cabometyx)/nivolumab.

The newer, orally administered TKI agents have now been successfully combined with IO agents. “The first wave of IO drugs including nivolumab, pembrolizumab, and avelumab [Bavencio] are being combined with an oral agent,” Thomas said.

The FDA approved the ipilimumab/nivolumab combination for frontline treatment of advanced, intermediate or poor risk RCC in 2018.1 Approval was based on superior efficacy in this patient population compared with sunitinib monotherapy in the CheckMate 214 trial (NCT02231749).

“Ipilimumab/nivolumab was the first [IO combination] to make a significant overall survival impact in this space, and it certainly changed our standards on treatment selection for patients with metastatic kidney cancer,” said Tian Zhang, MD, MHS, assistant professor of medicine at Duke Cancer Institute in Durham, North Carolina. “It is really improving outcomes in terms of targeting patients to get them to live longer and without progression for longer.”

For patients in the favorable-risk category, however, the advantages of ipilimumab/nivolumab over sunitinib are more questionable. In fact, exploratory analyses in CheckMate 214 revealed that sunitinib produced a significantly better objective response rate (ORR) and PFS for patients with favorable-risk disease, although the complete response (CR) rate was higher with ipilimumab/nivolumab.

The FDA approved the pembrolizumab/axitinib combination for frontline treatment of advanced RCC in 20193 based on data from the KEYNOTE-426 trial (NCT02853331). Updated data were presented at GU Cancers Symposium 2021.

 A poster showed that per the KEYNOTE-426 protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent because of toxicity. However, pembrolizumab was stopped for all patients at 2 years, whereas axitinib could be continued until the patient progressed or experienced toxicity.

Results in patients treated with pembrolizumab showed that extended follow-up of the combination of pembrolizumab/axitinib continued to demonstrate clinically significant improved efficacy when compared with sunitinib for previously untreated patients with advanced RCC.

The pembrolizumab/axitinib combination and the axitinib/avelumab regimen from the JAVELIN Renal 101 trial (NCT02684006) were the first IO/VEGF-TKI combinations for frontline treatment of advanced RCC, Zhang said. The axitinib/avelumab combination was approved in 2019.5 A poster presentation at the 2021 GU Cancers Symposium shared JAVELIN Renal 101 efficacy data from the second interim overall survival (OS) analysis of axitinib/ avelumab compared with sunitinib, based on various IMDC risk factors and target tumor sites at baseline.

Although OS data were still immature, the results showed that with extended follow-up, the combination generally showed efficacy benefits compared with sunitinib. Specifically, median follow-up for OS for the axitinib/ avelumab arm was 19.2 months versus 19.3 months for the sunitinib arm. Median PFS was 16.8 months for the axitinib/avelumab arm versus 15.2 months for the sunitinib arm.

Data from the CheckMate 9ER trial (NCT03141177) investigating the nivolumab/ cabozantinib combination in patients with previously untreated clear cell RCC were also presented at GU Cancers Symposium 2021 and ESMO 2020.7,8 Results published in the New England Journal of Medicine9 showed that the combination had a significant OS and PFS improvement compared with sunitinib. “I’ve switched everyone over to cabozantinib/ nivolumab [based on the study] if I have to use an IO/VEGF[-TKI] combination. Cabozantinib is just a better overall inhibitor of kidney cancer because there are more off-target hits. I think it’s a better drug,” Humeniuk said. The combination gained an FDA approval on January 22, 2021.

CheckMate 9ER also analyzed qualityof-life data, with patients reporting better health-related quality of life in the combination arm compared with sunitinib. “I haven’t seen quality-of-life data in the other studies yet,” Ghatalia said, adding that this study included a greater number of patients in the poor-risk category versus the KEYNOTE-426 or CLEAR study (NCT02811861), which evaluated lenvatinib (Lenvima)/pembrolizumab versus lenvatinib/everolimus (Afinitor) versus sunitinib.

The pembrolizumab/lenvatinib combination has not yet been approved by the FDA; however, “the data presented at [GU 2021 were] encouraging,” Ghatalia said, noting “It had a very good response rate and improvement in all efficacy end points.” Ghatalia said she would consider using this combination and anticipates it will receive FDA approval based on the CLEAR study results: 71% ORR compared with 53.5% for lenvatinib/everolimus and 36% for sunitinib; and 16.1% CR rate compared with 9.8% for lenvatinib/everolimus and 4.2% for sunitinib.10 Pembrolizumab/ lenvatinib “demonstrated significant progression-free survival benefit and overall survival benefit compared with sunitinib,” Zhang said.

However, the 18-mg lenvatinib dose can cause significant adverse effects for patients, Ghatalia said. She expressed surprise that patients in the CLEAR study were given lenvatinib in a 20-mg dose along with pembrolizumab. “Investigators reassured us that in the frontline setting, patients can tolerate higher treatment doses because they’re not receiving prior treatment or prior toxicity,” said Ghatalia.

Choosing a Frontline RCC Treatment It is challenging to decide what to use for a first-line treatment in RCC, Zhang said. “We now have multiple trials that are showing the benefits of immunotherapy-based treatments in all comers, in particular in patients with IMDC intermediate- and poor-risk disease.”

Zhang said she thinks about the full continuum of treatment when considering frontline options. “We think about potential resistance patterns,” she noted. In addition to considering which frontline treatments are available, she takes the patient’s treatment goals into account. “Some of the treatment combinations have yielded higher response rates,” she said. For example, the ipilimumab/nivolumab combination or the pembrolizumab/lenvatinib combination have CR rates of more than 10%. That is meaningful if patients can get to CR and potentially consider discontinuing treatment a year or 2 after sustained CR. “Those are the type of things I think about when starting on first-line treatment and selecting from these options,” Zhang said

Zhang is pleased about the handful of immunotherapy-based combinations with positive OS impacts, which are all considered superior to more traditional treatments for patients with intermediate-risk disease. “We are looking at this era of checkpoint inhibitor–based combination strategies as the main go-to for most patients,” she said, adding that these combinations were all benchmarked against sunitinib as a control. Patients whose disease is more driven by angiogenesis may benefit more from IO/ VEGF-TKI combinations.

Both IO and VEGF-TKI are important classes of RCC therapies, said Humeniuk, but patients with autoimmune disease should not use a double-IO combination. He recommends going with a single IO or a VEGF-TKI agent for patients with severe autoimmune disease.

Despite the many options, clinicians still need longer-term OS data, Ghatalia said. “These are all studies with a median follow-up of about 18 to 30 months. More mature data will inform our decisions going forward.”

Data are more limited for patients with metastatic non–clear cell RCC (nccRCC), who represent a fraction of patients with RCC. A poster presented at GU Cancers Symposium 2021 shared results of a retrospective analysis of IMDC data from 1181 patients with nccRCC. Patient outcomes were compared based on type of frontline therapy: IO-based monotherapy or combination therapy, VEGF-TKI monotherapy, or mTOR inhibitor monotherapy. Data showed that for advanced nccRCC, frontline IO-based treatment produced the best OS result.

Currently in Trials Other trials are underway and producing data. What follows are a few to watch.

The PDIGREE trial (NCT03793166) is evaluating ipilimumab/nivolumab and cabozantinib in patients with intermediate- or poor-risk clear cell RCC.

“This adaptive phase 3 trial is based on induction with ipilimumab/nivolumab, and at the 3-month cutoff, response is assessed,” Zhang said. Patients with a CR then receive nivolumab alone, and those with disease progression receive cabozantinib alone. All other patients are randomized to receive nivolumab alone or combined with cabozantinib, she said. Investigators will examine optimal sequencing of drugs in this trial. “We’ll have some understanding of [which patients will be] complete responders and [whose disease] might recur. It’s an important study in terms of trying to benchmark treatments against the standard of ipilimumab/nivolumab,” Zhang said.

In the COSMIC-313 study (NCT03937219), patients are randomized to receive 4 doses of triplet therapy comprising ipilimumab/ nivolumab/cabozantinib or ipilimumab/ nivolumab/placebo (the CheckMate 214 regimen; FIGURE13), followed by nivolumab/ cabozantinib or nivolumab/placebo.13 Zhang said this trial is almost finished with enrollment. 

“Ipilimumab/nivolumab is a strong competitor in the IO/TKI space. So it will be interesting to see what the addition of the TKI to the combination will do,” Ghatalia said.

The PROBE trial (NCT04510597) is exploring the effects of adding cytoreductive nephrectomy to standard-of-care immunotherapy. Patients with metastatic RCC are randomized to receive 4 cycles of an immunotherapy combination, either alone or followed by cytoreductive nephrectomy, Zhang said.

One criticism of current trials is that the studies have not been “totally clean in terms of using just patients with intermediate- or [poor-risk] disease,” Thomas said, noting that the trials often include patients with favorable-risk disease as well.

Another issue is that in studies such as CheckMate 9ER and CLEAR, the comparator arm used “a fairly ineffective old-style drug, [sunitinib],” Thomas said. He looks forward to seeing trials combining IO and new oral TKIs compared with new oral TKI agents as monotherapy. 

Fortunately, that process has already begun. “We’re phasing out sunitinib based on these phase 3 trials for metastatic kidney cancer,” Zhang said.

Treatment sequencing will be an even more important issue moving forward because of the lack of data on how to best sequence administration of these advanced agents. “That’s where the field is going now,” Thomas said. “What we clearly have now is a plethora of options relating to first-line treatment, especially for intermediate- and [poor]-risk disease.”

Future studies will include comparator arms using combination therapies, rather than single agents. “Randomizing patients to single-agent TKI as a comparator arm will probably be unethical” considering the robust data for combining 2 agents, Ghatalia said.

Research will also continue to search for treatments for RCC associated with specific genetic abnormalities, Thomas said. “We haven’t found a molecular Achilles’ heel for RCC yet.” Although the VHL tumor suppressor gene is lost or inactivated in most cases of clear cell RCC, it is not yet understood how to correct the resulting functional effects on the cell.

Although there is a lot of work to be done, Zhang said the kidney cancer field has blossomed recently with the addition of immunotherapy and novel targeted treatments. “It’s a really exciting time for GU oncology,” she said.

1. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. Updated April 16, 2018. Accessed March 18, 2021. 

2. Sheng IY, Ornstein MC. Ipilimumab and nivolumab as first-line treatment of patients with renal cell carcinoma: the evidence to date. 

. 2020;12:4871-4881. doi:10.2147/CMAR.S202017

3. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. Updated April 22, 2019. Accessed March 18, 2021. 

4. Plimack ER, Rini BI, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): updated analysis of KEYNOTE-426. 

. 2020;38(suppl 15):5001. doi:10.1200/JCO.2020.38.15_suppl.5001

5. FDA approves avelumab plus axitinib for renal cell carcinoma. FDA. Updated May 15, 2019. Accessed March 18, 2021. 

6. Tomita Y, Motzer RJ, Choueiri TK, et al. Efficacy of avelumab plus axitinib (A + Ax) versus sunitinib (S) by number of IMDC risk factors and tumor sites at baseline in advanced renal cell carcinoma (aRCC): extended follow-up results from JAVELIN Renal 101. 

. 2021;39(suppl 6):302. doi:10.1200/JCO.2021.39.6_suppl.302

7. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. 

. 2021;39(suppl 6):308. doi:10.1200/JCO.2021.39.6_suppl.308

8. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. 

. 2020;31(suppl 4):S1142-S1215. doi: 10.1016/j.annonc.2020.08.2257

9. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. 

. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

10. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

. Published online February 13, 2021. doi:10.1056/NEJMoa2035716

11. Graham J, Wells C, Dudani S, et al. Effectiveness of first-line immune checkpoint inhibitors (ICI) in advanced non-clear cell renal cell carcinoma (ccRCC). 

. 2021;39(suppl 6):316. doi:10.1200/JCO.2021.39.6_suppl.316

12. Zhang T, Ballman KV, Choudhury AD, et al. PDIGREE: an adaptive phase 3 trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704). 

. 2019;37(suppl 15):TPS4596. doi:10.1200/JCO.2019.37.15_suppl.TPS4596

13. Choueiri TK, Albiges L, Powles T, et al. A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk. 

. 2020;38(suppl 6):TPS767. doi:10.1200/JCO.2020.38.6_suppl.TPS767

14. Dizman N, Philip EJ, Pal SK. Genomic profiling in renal cell carcinoma. 

. 2020;16(8):435-451. doi:10.1038/s41581-020-0301-x

Although curing advanced RCC is an admirable goal, there are many treatment options available on the horizon that result in substantial improvements in long-term outcomes.

Deborah Abrams Kaplan | Authors

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