Data regarding clinical, pathologic, and molecular features of 

 fusion–positive lung cancers are relatively limited given the rarity of 

 aberrations and their recent discovery in this tumor type.

 fusions first discovered in lung cancers in 2014,

 limited data exist on tumors harboring these oncogenes. Therefore, effectiveness of systemic therapies to treat patients with 

 fusion–positive lung cancers is also limited when compared with other lung cancer subtypes.

 presentation hosted by CancerNetwork®, 

, discussed details from the eNRGy1 Global Multicenter Registry, which sought to contribute pertinent data to a central registry on patients with 

“Here we are in the 21st century and we are describing new diseases,” Camidge, director of the Thoracic Oncology Clinical and Clinical Research Programs at the University of Colorado in Aurora, explained. “[Research] is showing that 

 fusion–positive small cell lung cancer is out there, it’s real, it’s super rare, but it’s not Bigfoot.”

“We need a lot more information,” Spira, director of Virginia Cancer Specialists Research Institute and the Phase I Trial Program in Alexandria, Virgina, emphasized. “The [sample sizes in trials] are really small, and as some of these newer studies develop, I think we’ll certainly learn a lot more.”

Spira and Camidge spoke about this lung cancer subtype in the context of findings from the eNRGy1 registry, which collected data from over 22 centers across 9 countries to evaluate clinical, pathologic, molecular, and response data for patients with 

Patient eligibility for the eNRGy1 registry required a pathologically confirmed 

 fusion–positive lung cancer diagnosis. The investigators set out to collect data across different disease features including clinicopathologic characteristics and tumor immunophenotype.

Data for 110 patients were included in the research. Patients had a median age of 64 years (range, 29-88) and 59% of patients were female. Most patients were either Asian (52%) or White (46%), and 57% were never smokers. Most patients (71%) had nonmetastatic disease. For the 44 patients with metastatic disease diagnosed at any time, the most common sites of metastases were the lung (71%), bone (34%), or lymph nodes (23%).

When evaluated by disease stage, median overall survival (OS) was not reached (95% CI, 51.5-undefined) for patients with stage I disease (n=26), 52.9 months (95% CI, 38.8-undefined) with stage II disease (n=19), 78.2 months (95% CI, 11.0-undefined) with stage III disease (n=13), and 15.5 months (95% CI, 10.3-64.5) for patients with stage IV disease (n=24).

 fusions were mostly detected using RNA-based testing (74%), with DNA-based tests used in only about one-quarter of the registrants (26%). Specifically, the most frequently used RNA-based assay was an anchored multiplex polymerase chain reaction (PCR) test (62%), followed by reverse transcription-PCR (27%). Next-generation sequencing (NGS; 52%) was the most commonly used DNA-based assay.

Camidge is a proponent of RNA-based testing and said a combination approach could help identify more patients with these extremely rare fusions. “Using an RNA- in addition to a DNA-based extraction to do your next-generation sequencing really boosts the sensitivity for picking up these rare fusions,” he explained.

Of note, tumor PD-L1 status was known for only 42% of the 110 patients included in the study, but Spira said this was probably due to a data set that’s a bit older. “It’s almost unheard of now that you would have PD-L1 unknown,” he said.

High PD-L1 expression, defined as 50% or greater, was observed in only 4% of patients with known PD-L1 status (2 of 46). Most tumors had either no PD-L1 expression (72%) or PD-L1 expression of 1% to 49% (24%).

 fusion–positive lung cancers was 0.9 mutations/megabase (range, 0-2.6), which is low when compared with different fusion statuses (TABLE).

Camidge continued, “If I have a never smoker with adenocarcinoma who has PD-L1 [expression] of 100%, that’s a red flag that they have a driver oncogene. You have to resist the temptation to rush [to treating with] single-agent immunotherapy and wait for the molecular [testing] to come back, if possible.”

When activity of systemic therapies was evaluated among eligible patients with metastatic disease, response rates were low. Targeted therapy with afatinib induced responses in 25% of the treatment patients (5 of 20) and represented the greatest efficacy, followed by single-agent immunotherapy (20%; 1 of 5), taxane-based chemotherapy (14%; 1 of 7), platinum doublet–based chemotherapy (13%; 2 of 15), and chemoimmunotherapy (0%; 0 of 9) (FIGURE).

“The implication here is that these patients, at least in this data set, are not really responding to many of the standard therapies,” Camidge explained.

“It’s the beginning,” Camidge emphasized, regarding the emergence of 

and the need to further develop testing capabilities for this specific fusion. For greater precision approaches, clinicians should examine testing panels used at their centers to ensure they are checking their patient’s tumors for these fusions ahead of agents becoming available for treatment.

Future research is needed to further explore the impact of 

 fusions and to identify effective systemic therapeutic options for patients.

 fusion–positive lung cancers is only 0.2%, as Camidge explained, that rate is significant for the patients whose tumors harbor these oncogenes. Spira continued, “The only challenge of this journey is this is rare. We say 

 is rare, but that’s 4%. Here, we’re [talking] less than 1%.”

“Even if it’s only that small percentage, we don’t need to remind everybody the difference it makes for those individual patients,” Spira explained. “Even if it’s a fraction of a percent, for that 1 patient, it’s a game-changer, and I think that’s the important thing.” 

1. Drilon A, Duruisseaux M, Han JY, et al. Clinicopathologic features and response to therapy of 

 fusion-driven lung cancers: The eNRGy1 Global Multicenter Registry. 

. 2021;39(25):2791-2802. doi:10.1200/JCO.20.03307

2. Drilon A, Somwar R, Mangatt BP, et al. Response to ERBB3-directed targeted therapy in 

. 2018;8(6):686-695. doi:10.1158/2159-8290.CD-17-1004

3. Jonna S, Feldman RA, Swensen J, et al. Detection of NRG1 gene fusions in solid tumors. 

. 2019;25(16):4966-4972. doi:10.1158/1078-0432.CCR-19-0160

4. Fernandez-Cuesta L, Plenker D, Osada H, et al. CD74-NRG1 fusions in lung adenocarcinoma. 

. 2014;4(4):415-422. doi:10.1158/2159-8290.CD-13-0633

Articles

D. Ross Camidge, MD, PhD, and Alexander I. Spira, MD, PhD, discussed the use of NRG1 fusions as being a driver for patients with lung cancer. 

Recap: Experts Discuss NRG1 Fusions as Key Oncogenic Drivers for Certain Patients With Lung Cancer

With approximately 50% of patients with oligometastatic colorectal cancer (CRC) relapsing following surgical resection, effective prognostic biomarkers that can identify residual disease are needed in this patient population.

Similarly, the efficacy of postoperative systemic treatment is currently limited for patients with stage IV CRC, and patients may benefit greatly from a reliable biomarker to identify minimal residual disease (MRD).

, discussed the potential of circulating tumor DNA (ctDNA) as an effective biomarker for patients with CRC in a recent 

“As of right now, the only biomarker that we typically use in the setting is CEA [carcinoembryonic antigen], which we typically check before and after surgery,” explained Kim, who is service chief of Medical Gastrointestinal Oncology and senior member in the Gastrointestinal Oncology Department at the Moffitt Cancer Center in Tampa, Florida. “Now we’re trying to figure out the prognostic role of the circulating tumor DNA in this setting, which is a very novel idea.”

“Circulating tumor DNA is something that we can easily get that could help guide us in knowing how the patient is going to do and hopefully guide our treatments going forward,” Bustamante, a hematologist and medical oncologist at Florida Cancer Specialists in Fort Myers, Florida, added.

During the discussion, Kim and Bustamante examined the use of ctDNA for MRD detection in the context of the PREDATOR trial, which featured patients with metastatic CRC who underwent metastatic resection with curative intent. After resection, 39.2% of patients received systemic therapy.

A total of 112 patients with metastatic CRC who underwent metastatic resection were enrolled, with ctDNA drawn after surgery and at the time of radiologic evidence of progressive disease or last follow-up. In total, 82 patients experienced disease progression.

Analysis of ctDNA was performed on 192 samples from this cohort, with a
median follow-up of 10.7 months (range, 0.9-53.8 months). The median age of patients was 60.1 years, and disease progression was observed in 73.2% of patients (

Patients with MRD positivity characterized 54.4% of the total cohort, or 61 patients. Of these, 59 patients (96.7%) had disease progression at the data cutoff (HR, 5.8; 95% CI, 3.5-9.7; 

 < .001). MRD positivity at 2 time points, baseline and follow-up, was a strong indicator of outcome, with those having 2 ctDNA-positive tests having a high likelihood of disease progression without systemic therapy (

“There’s a clear separation telling us that [ct]DNA positivity is associated with a poor prognosis in terms of disease-free survival [DFS] and overall survival [OS] where patients who are circulating tumor DNA–negative tend to do well and their disease-free survival is much longer than the patients who are circulating tumor DNA–positive,” Kim explained.

He continued by stating that the sensitivity of baseline ctDNA was just above 70% but correlating findings from baseline ctDNA with that collected at 6 or 8 weeks of follow-up resulted in the sensitivity increasing to over 80%.

“If you look at the correlation between a one-time baseline blood draw and try to [connect] that with [survival outcomes], there’s a clear correlation between positive circulating tumor DNA and the worst prognosis in terms of the disease-free survival and overall survival. The patients who are negative for circulating tumor DNA at baseline tend to do much better,” Kim said.

MRD positivity was associated with inferior OS vs MRD negativity (HR, 16.0; 95% CI, 3.9-68.0; 

 < .001). At the data cutoff, 49 of 51 patients (96%) who were MRD negative were alive vs only about half of those who were MRD positive (32 of 61; 52.4%).

“The biggest takeaway is that the only variable that showed a statistically significant correlation with disease-free survival was the circulating tumor DNA,” Bustamante explained.

For patients with ctDNA negativity at both baseline and follow-up blood draws, the OS rate was 100% at 50 months of follow-up. Expanding on this, Kim explained “If you have a multiple draw, the sensitivity tends to go up as well, clearly telling us that there is a prognostic role of drawing tumor DNA in this setting in patients who undergo surgery [and do] not get chemotherapy in this study.”

A main takeaway from this study is the prognostic potential of ctDNA for detecting progression in CRC, especially over 2 time points postoperatively, according to Bustamante.

Bustamante emphasized that 2 negative tests at different points provides some reassurance that clinicians may safely observe their patients instead of treating them systemically. It also provides comfort to patients because there are data linking positive survival and testing negative twice by ctDNA.

Kim explained that questions remain regarding ctDNA, specifically around its predictive ability. “The dilemma that we will be facing after surgery if the circulating tumor DNA is positive is what to do at that time, understanding that there is no radiographic evidence of disease,” he said.

“Regardless,” Kim concluded, “this is a prognostic biomarker that we can use in conjunction with the radiographic imaging and CEA as well to help better guide patients [regarding treatment and monitoring] after surgery.”

“This paper showed that CEA levels do not have good sensitivity in predicting who’s going to progress or not as compared to this test. In this case, ctDNA will help us predict patients’ prognosis or risk of recurrence and hopefully help guide how we follow them and how we treat them,” Bustamante explained. 

1. Lin J, Peng J, Zhao Y, et al. Early recurrence in patients undergoing curative resection of colorectal liver oligometastases: identification of its clinical characteristics, risk factors, and prognosis. 

 2018;144(2):359-369. doi:10.1007/s00432-017-2538-8

2. Pan Z, Peng J, Lin J, et al. Is there a survival benefit from adjuvant chemotherapy for patients with liver oligometastases from colorectal cancer after curative resection? 

. 2018;38(1):29. doi:10.1186/s40880-018-0298-8

3. Loupakis F, Sharma S, Derouazi M, et al. Detection of molecular residual disease using personalized circulating tumor DNA assay in patients with colorectal cancer undergoing resection of metastases. 

. 2021;5(5):PO.21.00101. doi:10.1200/PO.21.00101

Richard Kim, MD, and Lilliana Bustamante, MD, discuss the potnetial for using ctDNA to treat patients with oligometastatic colorectal cancer. 

Recap: Prognostic Potential of ctDNA for Oligometastatic Colorectal Cancer

, a professor of medicine and the C.E. and Bernadine Laborde Professor of Cancer Research at Tulane University School of Medicine as well as the medical director of Tulane Cancer Center, in New Orleans, Louisiana, shared clinical experiences and perspectives regarding the use of PARP inhibitors to treat certain patients with prostate cancer.

To begin the discussion, Sartor talked about baseline testing strategies that he employs to match patients with the best systemic therapy. “In terms of molecular testing for metastatic disease, I always [want] to do germline testing. I may want to get additional genetics as well, [such as] somatic genetics within the tumor,” he said. “I also cover family history when I [begin] the analysis of a patient.”

Testing for both somatic and germline aberrations are important for the treatment of these patients, especially now that targeted therapies are becoming available in this space. “Findings like a 

 which can often be picked up on primary prostate tissue, [are] important to be able to identify because of [their] treatment implications.”

Sartor said testing for HRR genes such as 

 in metastatic castration-resistant prostate cancer (CRPC) can assist clinicians in identifying patients who may be candidates for treatment with the PARP inhibitors olaparib (Lynparza) or rucaparib (Rubraca).

“In nongenomic manners, you can look at immunohistochemistry for things like 

—where, for the classic mismatch repair genes, you’ll get loss in protein staining. You can also pick it up genomically. It’s nice to do both,” Sartor said, adding that also testing for microsatellite instability and tumor mutational burden may be useful in determining which patients can receive pembrolizumab (Keytruda) in later lines of treatment.

Sartor noted, however, that various barriers may impede patient testing, such as reimbursement issues and inability to get adequate samples. “It’s not uncommon that we may have a patient who was seen and diagnosed in a community urology clinic 7 years ago, and then they show up to me with metastatic disease. If we’re trying to get archival tissue, then we must chase that community hospital sample from 7 years ago. That could be a substantial issue,” he said.

Selecting Treatment and Monitoring Metastatic CRPC

Sartor said selecting therapy for patients begins with a baseline assessment of a patient’s age and comorbidities. “The 49-year-old marathon runner [will be treated] differently from a 99-year-old patient. We must look at the basic parameters. Some people come in with a baseline thrombocytopenia, and some from chemotherapy may be particularly problematic,” he noted.

Physicians should also consider the possibility of treating their patients on a clinical trial. “There’s a big evolution going on,” Sartor said. “If you don’t have a particular clinical trial, then [being] cognizant of a center nearby that might be able to offer a good clinical trial is something to think about as well.”

Next, he advised looking at genomic alterations and prior treatments administered in the nonmetastatic setting to further help determine which agents are available to treat patients in later-line settings.

“You must look at a variety of parameters, including the cost of what you’re dealing with, affordability, the patient’s insurance, and their ability to pay. There are a lot of factors included in decision-making,” Sartor said.

For monitoring, Sartor said he emphasizes the need for communication between him and his patients often. “I explain it to patients this way: I need to know how you’re feeling,” he said.

Other important aspects for tracking disease progression include laboratory studies—such as complete blood count, comprehensive metabolic panel, liver function, and prostate-specific antigen (PSA) levels—plus imaging.

“By looking at these factors taken in total, we’re monitoring the disease of the patient and the toxicities of therapy. Then we’re putting it together in the context of good patient care and seeing the patient on a relatively frequent basis, particularly when we’re introducing new therapies,” Sartor said.

Role of PARP Inhibitors in Prostate Cancer

Although many are familiar with PARP inhibitor therapy in the context of treating ovarian cancer, 2 of these agents have indications for treating those with metastatic CRPC, Sartor said.

In May 2020, the FDA granted full approval to olaparib for the treatment of adult patients with deleterious or suspected deleterious germline or somatic HRR gene–mutated disease who have disease progression after either enzalutamide (Xtandi) or abiraterone (Zytiga).

Regarding HHR gene mutations, Sartor says the data are not clear on which genes outside 

 indicate the greatest response, but the olaparib indication does allow for treatment of these patients.

“You have a series of other genes, including 

, that can be indications for the treatment,” Sartor said (

 “It doesn’t have to be somatic. It turns out that germline 

Data for this approval came from the PROfound study (NCT02987543),
a phase 3 trial of olaparib or physician’s choice of enzalutamide or abiraterone in men with metastatic CRPC who had disease progression while receiving a new hormonal agent. Patients were evaluated in 2 cohorts having either 1 alteration in 

 (cohort A) or any of the other 12 prespecified HHR gene mutations (cohort B).

At the initial readout, olaparib demonstrated statistically significant boosts in radiographic progression-free survival vs the control group in cohort A (HR, 0.34; 95% CI, 0.25-0.47; 

 < .001).3In an updated assessment, statistically significant improvements in cohorts A (HR, 0.69; 95% CI, 0.50-0.97; 

 = .02) and numerical benefit in cohort B (HR, 0.96; 95% CI, 0.63-1.49) were noted for overall survival (OS) with the PARP inhibitor. In the overall trial population, olaparib resulted in a median OS of 17.

 months vs 14.0 months with control therapy (HR, 0.79; 95% CI, 0.61-1.03), with 66% of the control group crossing over to receive olaparib at progression.

“The overall survival data [were] quite strong despite the crossover,” Sartor said. “The bottom line is, the FDA saw fit to include all the homologous recombination repair genes within the FDA approval.”

Another agent, rucaparib, became available under accelerated approval in the same month for patients with germline and/or somatic deleterious 

mutation–associated disease who had previously received treatment with androgen receptor–directed therapy and taxane chemotherapy.

 Continuation of this indication will be contingent upon confirmation from a randomized trial.

Data supporting this decision came from the phase 2 TRITON2 trial (NCT02952534), in which rucaparib was examined in men with metastatic CRPC with alterations in 

 who progressed after 1 or 2 prior lines of next-generation antiandrogen therapy and 1 prior taxane-based chemotherapy. Objective response rate by independent radiologic review was 43.5% (95% CI, 31.0%-56.7%) and by investigator assessment was 50.8% (95% CI, 38.1%-63.4%), with responses being similar regardless of germline or somatic mutations. Confirmed PSA response was at 54.8% (95% CI, 45.2%-64.1%).

With rucaparib, Sartor said there’s the potential to lower the treatment dose in patients who are responding well. “If you have a good response in a patient, then what you can do is create an even lower dosing and potentially have good activity. I have a patient right now on 300 mg once per day, and he’s having a great response. He had some significant anemia when he came into it, and he had a 

[mutation]. He just can’t tolerate the 300-mg twice-daily dosing; we had to dose-reduce him for anemia,” Sartor said.

Anemia is one of the more common adverse effects seen with this agent, along with fatigue and gastrointestinal effects, but “anemia is present in virtually all patients with metastatic CRPC, so not everybody is going to be affected to the same degree,” Sartor noted.

Up front, Sartor said he looks to using hormones first to treat his patients. “I’m trying to get the novel hormones [into treatment] first because we have an accumulation of data that earlier use of these results in better survival advantages,” he said. “In fact, we have lots of new data that demonstrate in the castration-sensitive space [that] if you’re treating with these novel hormones, you do have an amazing effect on overall survival.”

After that, treatment options are few, with clinicians relying on genomics and precision medicine to select the next therapy.

To conclude, Sartor said physicians should be cognizant of multiple factors when treating their patients, including the use of up-front novel hormonal therapy, appropriate use of taxanes, the possibility of clinical trials, and utilization of biomarkers. “There are [many] things that you need to be open to—one [being] the idea of precision medicine,” he said. 

1. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. Updated May 20, 2020. Accessed November 5, 2021. https://bit.ly/3bKgTKj

2. NCCN. Clinical Practice Guidelines in Oncology. Prostate Cancer, version 1.2022. Accessed November 5, 2021. https://bit.ly/3ES5gNQ

3. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. 

. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440

4. Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. 

. 2020;383(24):2345-2357. doi:10.1056/NEJMoa2022485

5. FDA grants accelerated approval to rucaparib for

BRCA-mutated metastatic castration-resistant prostate cancer.FDA. Updated May 15, 2020. Accessed November 5, 2021. 

6. Abida W, Patnaik A, Campbell D, et al; TRITON2 investigators. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a 

. 2020;38(32):3763-3772. doi:10.1200/JCO.20.01035

A. Oliver Sartor, MD, discussen treatment options for PARP inhibitor use in patients with prostate cancer. 

Recap: Recommendations for PARP Inhibitor Use in Prostate Cancer

, an assistant professor of medicine at Harvard Medical School and a lung cancer medical oncologist at Massachusetts General Hospital, in Boston, Massachusetts, discussed the identification and targeting of 

 exon 20 insertion mutations in non–small cell lung cancer (NSCLC).

Piotrowska opened the conversation with a background review of 

 exon 20 insertions in this space, emphasizing that “the landscape of 

 mutations in non–small cell lung cancer has gotten increasingly complex in recent years. It’s important not just to recognize that your patient may have an EGFR mutation on their molecular testing report, but specifically look at which type of mutation they have and think about what the implications are of that specific mutation for treatment.”

Piotrowska explained that many next-generation sequencing (NGS) assays being used in clinics today will detect 

 exon 20 insertion mutations. “The important thing is to be able to notice that an EGFR mutation has been discovered and that this specific mutation may not be the same as the more common exon 19 deletions and L858R point mutations. It’s important to read the report carefully and distinguish these different mutations.”

At the initial diagnosis, Piotrowska recommends doing molecular testing for patients. She explained, “It really is important to do testing for all of our patients, and ideally that testing should be done at the time of initial diagnosis so that we can help select the best first-line therapy.”

And although testing should be done for all patients with this disease, barriers to testing remain, according to Piotrowska. Specifically, she cites the lack of regular testing across treatment settings, struggles with performing the testing itself, and waiting times for results as common issues associated with testing.

There are several ways to increase access to testing. “Working closely with pathologists to make sure that the tissue is used carefully and as much as possible is saved for molecular testing, and then also thinking about the use of liquid biopsies are important steps that we can take to improve the rates of testing,” Piotrowska explained.

Furthermore, the ability to accurately interpret the results from these assays, and specifically identify which mutations are present, is an increasingly difficult challenge that care providers need to tackle, according to Piotrowska.

“The other big category is waiting for test results and being able to appropriately interpret NGS reports to identify which mutations are present and help ensure that we’re selecting the right treatment for patients,” Piotrowska explained. “I’ve seen in my own practice that has gotten more and more complicated in recent years as we have new targeted therapies available for patients.”

A current problem for treating patients with 

exon 20 mutations revolves around the ineffectiveness of commonly used first- and second-generation EGFR inhibitors, such as erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif), to treat this specific mutation, according to Piotrowska.

“The data that we have so far certainly seem to show that these drugs are not as effective as they are for exon 19 deletions and L858R point mutations,” Piotrowska continued.

Specifically in the first-line setting, standard chemotherapy remains a good option for patients with exon 20 insertion mutation–positive lung cancers. A gap in the field exists surrounding the benefit of immunotherapy for patients with 

 exon 20 mutations as it compares with that observed in other mutation subtypes, as well as the potential use of immunotherapy plus chemotherapy combinations.

“The jury is still out on the role of immunotherapy, but certainly chemotherapy remains an important treatment option, as it has been historically for these patients.”

One emerging agent in the second-line or later setting that recently received accelerated approval from the FDA for patients with 

 exon 20 insertion–positive NSCLC is the EGFR-MET bispecific antibody amivantamab (Rybrevant).

Amivantamab was approved based on the results of the phase 1 CHRYSALIS trial (NCT02609776).

 exon 20 insertion—mutant NSCLC who previously received platinum-based chemotherapy were treated with amivantamab. The overall response rate (ORR) for the efficacy population was 40% (95% CI, 29%-51%), including 3 complete responses. Median duration of response was 11.1 months (95% CI, 6.9 to not reached [NE]) and median progression-free survival (PFS) was 8.3 months (95% CI, 6.5 - 10.9).

The most common any-grade adverse effect (AE) was rash, seen in 86% of patients. Common grade 3 or higher AEs included hypokalemia (5%), rash (4%), pulmonary embolism (4%), diarrhea (4%), and neutropenia (4%).

“It’s great to have another option for patients with these mutations, and it’s a very good option for patients,” Piotrowska explained. “It’s approved for second-line and later use, so it doesn’t necessarily impact our first line of treatment for patients with 

Another targeted therapy for the second-line or later setting is the oral EGFR tyrosine kinase inhibitor mobocertinib (Exkivity), which was granted accelerated approval by the FDA in September 2021.

“Mobocertinib was the second drug approved for 

 exon 20 insertion mutations,” Piotrowska explained. “It’s great to have 2 different targeted therapeutic options for these patients.”

Approval was based on positive results from the phase 1/2 EXCLAIM trial (NCT02716116).

 A total of 114 patients with EGFR exon 20 insertion–positive NSCLC who progressed on prior platinum-based chemotherapy were included in the study’s population. The confirmed ORR was 28% (95% CI, 20% - 37%) by independent review committee assessment. Median duration of response was 17.5 months (95% CI, 7.4 - 20.3) and median PFS was 7.3 months (95% CI, 5.5 - 9.2).

Diarrhea was a common toxicity, seen in 91% of patients treated with mobocertinib, 21% of which were grade 3 or higher events. Rash was also a common AE (45%), but most cases were categorized as low-grade.

Although these 2 approvals are promising developments for treating this subset of patients, Piotrowska emphasized the existing need for an effective first-line therapeutic option.

“Although we now have 2 approved targeted therapies for these patients, unfortunately neither of them is approved in the frontline setting,” she explained. “There are some ongoing clinical trials looking at first-line treatment options for these patients, but as of today in 2021, the preferred first-line treatment for these patients is still platinum-based chemotherapy.”

“It’s great to see the progress that we’ve made, but I would say there are still many unmet needs in this patient population,” Piotrowska explained.

Specifically, although the response rates observed with these targeted therapies are encouraging, Piotrowska emphasized that the data are still not as promising as response results seen with osimertinib (Tagrisso) for more common 

Moreover, toxicities exist with amivantamab and mobocertinib, including gastrointestinal and skin toxicities. Piotrowska suggests that alternative treatment options to minimize these AEs would be welcome.

Looking ahead, Piotrowska is excited for potentially more alternative targeted therapies for patients with NSCLC and mutations in 

“There are a number of drugs now in development that are trying to be more specific for that mutant 

, and a number of others that are in development that have the potential to be more effective and have a better safety profile,” Piotrowska concluded. 

FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed November 22, 2021. https://tinyurl.com/4s7phc9c

Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR Exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: Initial results from the CHRYSALIS phase I study. 

. 2021;39(30):3391-3402. doi:10.1200/JCO.21.00662

FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. News release. FDA. September 16, 2021. Accessed November 22, 2021. https://tinyurl.com/nr97hzwr

Zhou C, Ramalingam SS, Kim TM, et al. Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR Exon 20 insertion-positive metastatic non-small cell lung cancer: A phase 1/2 open-label nonrandomized clinical trial. 

. Published online October 14, 2021. doi:10.1001/jamaoncol.2021.4761

Zofia Piotrowska, MD, discusses potential therapies for patients with EGFR exon 20 insertion-positive non–small cell lung cancer. 

Recap: Targeted Therapies for EGFR Exon 20 Insertion-Positive NSCLC

Different oncology clinicians may diverge in their treatment approaches to advanced renal cell carcinoma (RCC) due to multiple options being considered standard-of-care therapies. Combination therapies have made great strides against the former standard of care, sunitinib (Sutent), and although investigators have not landed on a cure, many therapies are extending survival and sometimes improving patient quality of life as well.

 presentation hosted by CancerNetwork®, a panel of experts who were moderated by 

director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center at Dana-Farber Cancer Institute, and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School in Boston, Massachusetts, discussed these topics by reviewing available data from recent conferences as well as current challenges in the treatment of 2 patients with metastatic renal cell cancer.


Choueiri started the discussion reviewing recent clinical trials to change the treatment landscape in advanced RCC.

, associate professor in the Department of Internal Medicine at UT Southwestern Medical Center in Dallas, Texas, discussed the phase 3 CheckMate 9ER trial (NCT03141177), which examined the combination of nivolumab (Opdivo) plus cabozantinib (Cabometyx) vs standard of care sunitinib (Sutent), whose results were published in the 

 The primary end point of progression-free survival (PFS) in the intention-to-treat population showed a median of 16.6 months for patients receiving nivolumab plus cabozantinib compared with 8.3 months for the sunitinib arm, for a 49% reduction in the risk of disease progression or death (HR, 0.51; 95% CI, 0.41-0.64; 

 <.001). For the secondary end point of overall survival (OS), the rate at 12 months in the nivolumab plus cabozantinib arm was 85.7% vs 75.6% for the sunitinib cohort (HR, 0.60; 95% CI, 0.40-0.89; 

 = .001). The objective response rates (ORRs) were 55.7% and 27.1%, respectively (

Zhang also highlighted a trial update that was presented at the 2021 American Society of Clinical Oncology Annual Meeting (ASCO 2021), which looked at the International Metastatic RCC Database Consortium (IMDC) subgroups for risk status and found that all patient groups benefited from nivolumab plus cabozantinib over sunitinib, regardless of statuses in intermediate- or poor-risk disease groups. She said most subgroups saw a doubling of PFS along with OS improvements.

, looked at data from the CheckMate 214 trial (NCT02231749) of nivolumab plus ipilimumab (Yervoy) or sunitinib in patients with treatment-naive RCC, particularly the 42-month follow-up that was presented at ASCO 2021.

“CheckMate 214 really revolutionized the field of kidney cancer treatment in the first-line setting,” he said. “It was the first and only immune-oncology (IO)–based combination to be approved in this setting. The other combinations discussed in this presentation are IO/TKIs (immune-oncology/tyrosine kinase inhibitors),” he said. Published trial data from 2018 showed that at the 25.2-month median follow-up for intermediate- and poor-risk patients, the 18-month OS rate was 75% for the combination vs only 60% for sunitinib (HR, 0.63; 99.8% CI, 0.44-0.89; 

 The median OS was not reached with the combination and was 26.0 months with sunitinib. The ORRs were 42% vs 27%, and median PFS was 11.6 months vs 8.4 months, respectively (HR, 0.82; 99.1% CI, 0.63-1.05; 

“What is great about this combination and what really led to the approval in intermediate- and poor-risk [disease] is that these results seem to stand up over the test of time, both at the 25-month follow-up, which was the initial presentation, [and] the 42-month follow-up,” Ornstein said. “Approximately 30% of patients are still progression free at around 5 years. This is the only IO combination that is a standard of care in the frontline setting for treatment-naive patients.”

, physician at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School, to share an overview of the phase 3 KEYNOTE-426 trial (NCT02853331), which tested pembrolizumab (Keytruda) plus axitinib (Inlyta) vs sunitinib in the frontline setting for advanced RCC.

 This landmark study led the pack in combining IO plus tyrosine kinase inhibitor (TKI) therapy for RCC, with an anti–PD-1 antibody plus a specific VEGFR TKI. Initial findings, published in 2019, demonstrated superiority across the board, with an OS rate at 12 months of 89.9% for the combination group compared with 78.3% for the sunitinib group, for a total reduction in the risk of death of 47% (HR, 0.53; 95% CI, 0.38-0.74; 

 < .001). Corresponding median PFS was 15.1 months and 11.1 months, respectively (HR, 0.69; 95% CI, 0.57-0.84; 

 < .001). An interim analysis published in 2020 showed that the combination continued to have superior outcomes over sunitinib, supporting first-line treatment as standard of care.

Though Braun said it has a durable response, “the benefits have gotten a little bit smaller over time,” as the hazard ratio for OS was 0.73 at a median follow-up of 30.6 months, for a total risk reduction now of just 27%. At ASCO 2021, the 42-month follow-up data revealed no big changes and that OS results were within the range of benefit.

“The question in my mind is [whether these results are] a bit of a canary in a coal mine for IO plus TKI in terms of whether there’s that same durability that we see with the ipilimumab-based combination,” Braun said. However, he noted that it is an attractive first-line option for many with advanced clear cell kidney cancers.

Choueiri then discussed the phase 3 CLEAR trial (NCT02811861) that included 3 treatment arms: lenvatinib (Lenvima) plus pembrolizumab, lenvatinib plus everolimus (Afinitor), or sunitinib as the control arm.

 “This is the new kid on the block,” he said. The study showed the longest median PFS was with lenvatinib and pembrolizumab at 23.9 months vs 9.2 months with sunitinib (HR, 0.39; 95% CI, 0.32-0.49; 

 <.001); for lenvatinib and everolimus, the median PFS was 14.7 months (HR, 0.65; 95% CI, 0.53-0.80; 

 <.001). Median OS was significantly improved with lenvatinib plus pembrolizumab (HR, 0.66; 95% CI, 0.49-0.88; 

 = .005), but lenvatinib plus everolimus failed to result in the same benefit over sunitinib (HR, 1.15; 95% CI, 0.88-1.50; 

 = .3). As a result, the lenvatinib/pembrolizumab combination was approved in August 2021 as frontline systemic therapy for patients with RCC.

Choueiri brought the conversation to its practical application with a patient case.

CASE 1

A panel of experts reflect on how to treat patients with advanced renal cell carcinoma by reviewing clinical trial data and discussing patient cases.



ONCOLOGY® Companion, Volume 35, Supplement 2

Recap: Experts Discuss NRG1 Fusions as Key Oncogenic Drivers for Certain Patients With Lung Cancer

Recap: Prognostic Potential of ctDNA for Oligometastatic Colorectal Cancer

Recap: Recommendations for PARP Inhibitor Use in Prostate Cancer

Recap: Targeted Therapies for EGFR Exon 20 Insertion-Positive NSCLC

Recap: The Shifting Treatment Paradigmfor Advanced Renal Cell Carcinoma

Recap: Experts Review Management of Chronic GVHD

Recap: Optimizing Therapy in Frontline Multiple Myeloma Not Eligible for Transplant

Optimizing Therapy in Frontline Multiple Myeloma Not Eligible for Transplant