Darcy Lewis

The kinase inhibitor regorafenib (Stivarga) showed high levels of anti-tumor activity in patients with advanced or recurrent thymic cancers, including advanced or recurrent B2-B3 thymoma and thymic carcinoma previously treated with platinum-containing chemotherapy. These results from the phase 2 Resound trial were published recently in 

Patients in this single-arm trial had an 8-week progression-free survival (PFS) rate of 78.9% (15 of 19 patients). This result rejected the null hypothesis of an 8-week PFS rate ≤ 25% with a type I error of 0.10 and a statistical power of 80% at the alternative hypothesis of an 8-week PFS rate of ≥ 50% (≥ 8 of 19 evaluable patients remaining progression-free at 2 months).

The authors, led by Matteo Perrino, MD, of Humanitas Research Hospital, Milan, Italy, noted that the study met its primary endpoint. “The activity and toxicity profile of regorafenib observed in this small series of thymic epithelial tumors seem to be encouraging and, therefore, should be better evaluated in subsequent larger and specific study phases,” they wrote.

Conducted at two hospitals in Italy, this study enrolled 19 patients, 11 of whom had thymoma and 8 of whom had thymic carcinoma. The patients were divided nearly evenly between those for whom regorafenib was their second-line therapy vs. therapy beyond the second line. All study patients received 160 mg of regorafenib daily in a 4-week cycle (3 weeks on, 1 week off).

According to RECIST criteria, 1 patient achieved a partial response (PR), while 14 patients experienced stable disease (SD). Two patients had progressive disease (PD). Overall, 15 patients (78.9%) experienced disease control (95% Confidence Interval [CI], 54.4%-94.0%).

According to CHOI criteria, 13 patients had a PR, while 2 patients each had SD and PD. Overall, the disease control rate (DCR) was 78.9% (95% CI, 54.4%-94.0%).

In explaining their use of both RECIST and CHOI criteria, the authors wrote,

“The ability to differentiate between response or SD and PD early during therapy is crucial for allowing adjustment of therapy. The CHOI criteria, taking into account the tumor density as well as the diameters, seem to be able to better evaluate those cases in which the cystic change of the lesions is not associated with their significant size reduction.”

The median follow-up was 39.1 months (range, 0.9-43.9 months). The median PFS was 9.6 months (95% CI, 3.6-12.8 months). The 3-month PFS rate was 79%; at 6 months the PFS rate was 57.9%. At 12 months, the PFS rate had dropped to 33.8%.

The median overall survival (OS) was 33.8 months (95% CI, 10.2 months to not evaluable). The 1-and 2-year OS rates were 73.7% and 63.2%, respectively.

About half the patients (52.6%) experienced grade 3-4 treatment-related adverse events (AEs). Hypertension was the most common grade 3-4 AE, affecting 2 patients (10.5%). One patient had a grade 4 increase in lipase values, probably due to concurrent azathioprine use. About two-thirds of patients developed stomatitis (68.4%) and hand-foot skin reaction and asthenia (63.2%). Nearly half the patients (47.3%) required dose reduction; 3 of these patients required the dose reduction to address hand-foot skin reaction. Seven patients stopped treatment temporarily due to side effects.

The authors concluded, “Disappointingly, we are not able to identify a subset of patients potentially benefiting from this drug. In fact, no difference was observed in terms of DCR, PFS, or OS stratifying for age, histology, sex, response to the previous line, and line of therapy.”

Resound (NCT02307500) is a screening trial that investigates the potential role of regorafenib in different cancers after conventional therapies have failed. In addition to thymic malignancies, the trial also examines regorafenib’s effectiveness in pancreatic cancer, ovarian cancer, melanoma, and soft-tissue sarcomas. Thus, the authors characterized this substudy’s primary endpoint as “exploratory only” because it was not specifically targeted toward thymic neoplasms.

Perrino M, De Pas T, Bozzarelli S, et al. Resound Trial: A phase 2 study of regorafenib in patients with thymoma (type B2-B3) and thymic carcinoma previously treated with chemotherapy. 

Articles

As part of the larger Resound trial, regorafenib met its primary endpoint in thymic cancer but no patient subset received greater benefits from the drug.

Regorafenib Shows High Anti-Tumor Activity as Monotherapy in Advanced, Pre-Treated Thymic Cancer

The experimental small-molecule VEGFR inhibitor surufatinib yielded modest clinical benefits for patients with unresectable or metastatic biliary tract carcinoma, according to a report published recently in 

Notable results from the multicenter, single-arm, open-label phase 2 study included a 16-week progression-free survival (PFS) rate of 46.33% (95% Confidence Interval [CI], 24.38-65.73). In addition to this primary endpoint, results related to secondary endpoints included a median PFS of 3.7 months and a median overall survival (OS) of 6.9 months.

The best overall response was stable disease (SD) at week 16, achieved by nearly 1 in 4 patients (8 of 33; 24.2%). All patients were evaluable, and no patients had achieved a complete response (CR) or partial response (PR) by that time.

“When applied in the treatment of patients with BTC, surufatinib monotherapy has offered moderate clinical efficacy and shown expected tolerability and safety profiles,” wrote the authors, led by Jianming Xu, MD, of the Fifth Medical Center, General Hospital of the People’s Liberation Army, Beijing, China

This trial enrolled 39 patients in multiple centers in China. Nearly all patients (97.4%) had stage 4 disease at diagnosis. Intrahepatic cholangiocarcinoma was the most common malignancy, diagnosed in 29 patients (74.4%). Five patients each had extrahepatic cholangiocarcinoma (12.8%) and gallbladder cancer (12.8%). All patients received surufatinib at a dose of 300 mg, administered once a day, in 28-day cycles until disease progression or other event. The study ended when the last patient completed their 6-month follow up assessment. By this time, all surviving patients had discontinued the study drug, with about a third citing intolerable toxicity (35.9%). Nearly as many patients had experienced disease progression by that time (28.2%).

Subgroup analysis showed that the intrahepatic cholangiocarcinoma subgroup had a slightly longer median PFS of 3.7 months (95% CI, 2.1-6.5), compared with 2.9 months (95% CI, 1.9 to not reached [NR]) in the extrahepatic cholangiocarcinoma/gallbladder cancer subgroup (HR, 0.537; 95% CI, 0.200-1.440]. Median subgroup OS was similar, with 6.9 months (95% CI, 5.1-8.7) in the intrahepatic group and 6.4 months (95% CI, 2.4-NR) in the extrahepatic/gallbladder group (HR, 0.850; 95% CI, 0.375-1.923).

All 39 patients were included in the safety analysis and all but one experienced at least one treatment-related adverse event (AE) of any grade. The most common grade ≥ 3 treatment-related AEs were blood bilirubin increased (20.5%), hypertension (17.9%), and proteinuria (12.8%). These treatment-related AEs were observed at similar rates between subgroups: 72.4% in the intrahepatic disease group and 60.0% in the extrahepatic/gallbladder disease group. Two patients died during the trial; of these, investigators determined that one patient’s fatal cerebral hemorrhage was related to surufatinib treatment. The other patient’s fatal metabolic acidosis and cachexia were deemed unrelated to treatment.

In a post hoc analysis, the authors observed different clinical effects when patients with the CA 19-9 serum tumor marker received surufatinib as a second-line treatment. Patients with lower baseline values of CA 19-9 (≤ 1000 IU/mL) showed a higher 16-week PFS rate compared with patients who had higher baseline CA 19-9 levels: 52.4% (95% CI, 23.9-74.7) vs. 21.9% (95% CI, 1.2-59.3). The same was also true for median PFS: 3.3 months (95% CI, 1.6-4.1) versus 5.1 months (95% CI, 2.1-7.4).

“Results from subgroup and post hoc analyses revealed that patients with the proper [intrahepatic] tumor locations or appropriate levels of serum biomarkers might receive greater clinical benefits,” they wrote.

The same authors are currently running a larger phase 3 study of surufatinib in a larger biliary tract carcinoma population (NCT03873532).

Xu J, Bai Y, Sun H et al. A Single-Arm, Multicenter, Open-Label Phase 2 Trial of Surufatinib in Patients with Unresectable or Metastatic Biliary Tract Cancer. 

A phase 2 study of surufatinib in patients with biliary tract carcinoma showed some benefit and a larger phase 3 study is underway.

Surufatinib Monotherapy Shows Moderate Efficacy in Biliary Tract Carcinoma

Adding the PD-1 monoclonal antibody toripalimab to standard chemotherapy for patients with nasopharyngeal carcinoma boosted progression-free survival (PFS) compared to chemotherapy alone in the phase 3 JUPITER-02 trial.

When added to standard-of-care gemcitabine plus cisplatin, toripalimab (Tuoyi) outperformed standard of care plus placebo in patients with metastatic nasopharyngeal carcinoma as a first-line treatment, findings from the phase 3 JUPITER-02 trial showed.

Patients who received the investigational anti-PD-1 monoclonal antibody experienced a median progression-free survival (PFS) of 11.7 versus 8.0 months (Hazard Ratio [HR], 0.52; 95% Confidence Interval [CI] 0.36–0.74), 

 =.0003). Key subgroups, including the roughly 75% of patients with PD-L1 expression, displayed improved PFS, too. These interim results were published recently in 

Led by Hai-Qiang Mai, MD, PhD, of Sun Yat-Sen University Cancer Center in Guangzhou, China, the authors concluded, “The addition of toripalimab to GP [gemcitabine plus cisplatin] chemotherapy as a first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma provided superior PFS compared to GP alone, and with a manageable safety profile.”

In JUPITER-02, an international, double-blind phase 3 trial (NCT 03581786), 289 chemotherapy-naïve patients with recurrent or metastatic nasopharyngeal carcinoma were randomized. A total of 146 patients were assigned to the toripalimab combination arm, while 143 were assigned to the placebo arm. 

The trial design called for at least 6 treatment cycles on a 3-week schedule. Following chemotherapy completion, nearly 80% of patients continued with maintenance therapy of either toripalimab or placebo. At data cutoff in May 2020, patients in the experimental group had received a median of 12 cycles, while those in the placebo group had received a median of 11 cycles.

JUPITER-02’s primary end point was PFS as assessed by a blinded central review committee. Secondary end points included overall survival (OS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and safety. OS data remain immature, but, as of February 2021, investigators observed a 40% reduction in risk of death in the toripalimab arm compared to the placebo arm (HR, 0.603; 95% CI, 0.364-0.997). 

A notable number of patients in both arms achieved a complete response (CR): 28 in the toripalimab group (19.2%) and 16 in the placebo group (11.2%). A slight majority of patients achieved a partial response: 85 patients in the toripalimab arm (58.2%) and 79 (55.2%) in the placebo arm. The ORR was significantly higher in the toripalimab arm (77.4%; 95% CI, 69.8–83.9) than in the placebo arm (HR, 66.4%; 95% CI, 58.1-74.1; 

 =.0335). The DCR was 87.7% (95% CI, 81.2-92.5) in the toripalimab arm and 79.7% (95% CI, 72.2–86.0) in the placebo arm.

All patients experienced at least one treatment-related adverse event (TRAE). Leukopenia, anemia, and neutropenia were the most common and likely, the investigators wrote, stemmed from the chemotherapy. TRAEs seen more frequently in the experimental arm include hypothyroidism (30.8% vs 16.8%), pruritis (16.4% vs 7.0%) and pneumonia (16.4% vs 6.3%). Serious AEs were comparable between the two arms, but immune-related AEs (39.7% versus 18.9%) and grade ≥3 infusion reactions (7.5% versus 0.7%) were seen more frequently in the toripalimab arm.

In discussing the importance of their work, Mai et al. emphasized that, although nasopharyngeal carcinoma is a rare malignancy in most of the world, its incidence rate in China is 3.0 per 100,000 people. All of JUPITER-02’s study patients were Asian and nearly all had nonkeratinizing nasopharyngeal carcinoma, the predominant subtype in Asia and the most common form of this malignancy in North America. They noted that this subtype’s strong association with Epstein-Barr virus and nonsurgical treatment paradigm has led to its frequent exclusion from clinical trials of head and neck cancer, resulting in unmet need for these patients. “We believe the results observed in JUPITER-02 can be extrapolated to Western populations, because the majority of patients with NPC in the West and China/Southeast Asia have the nonkeratinizing histology,” they wrote.

granted toripalimab a breakthrough therapy designatio

Toripalimab first received approval for the second-line treatment of metastatic melanoma the National Medical Product Administration (NMPA) in China in December 2018. Then the NMPA awarded conditional approval of toripalimab for the third-line

treatment of recurrent and metastatic nasopharyngeal carcinoma in February 2021 by the NMPA.

1. Mai HQ, Chen QY, Chen D, et al. Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial. Nat Med. Published online August 2, 2021. 

https://doi.org/10.1038/s41591-021-01444-0

2. News Release: NMPA Approves Toripalimab in Patients with Recurrent or Metastatic Nasopharyngeal Carcinoma after Failure of at Least Two Lines of Prior Systemic Therapy. Global Newswire. February 21, 2021. Accessed November 29, 2021. 

https://www.globenewswire.com/en/news-release/2021/02/21/2179175/0/en/NMPA-Approves-Toripalimab-in-Patients-with-Recurrent-or-Metastatic-Nasopharyngeal-Carcinoma-after-Failure-of-at-Least-Two-Lines-of-Prior-Systemic-Therapy.html

Results from the phase 3 JUPITER-02 trial show that oncologists can extend progression-free survival in patients with nasopharyngeal carcinoma by adding toripalimab to chemotherapy.

Toripalimab Added to Chemotherapy Extends PFS in Nasopharyngeal Carcinoma

The investigational ALK-inhibitor ensartinib (X-396) outperformed standard-of-care crizotinib (Xalkori) in patients with advanced ALK-positive non–small cell lung cancer (NSCLC), findings from the phase 3 eXalt3 show. 

Patients who received ensartinib experienced a median progression-free survival (PFS) of 25.8 months compared to only 12.7 months in the crizotinib group. The Hazard ratio (HR) was 0.51, meaning that ensartinib was associated with a 49% lower risk of disease progression or death (95% Confidence Interval [CI], 0.35-0.72). These interim results from the phase 3 eXalt3 randomized clinical trial were published recently in 

Ensartinib also had a confirmed intracranial response rate of 64% among patients who had baseline brain metastases. This compares with a 21% intracranial response rate among patients in the crizotinib group.

Led by Leora Horn, MD, MS, Vanderbilt-Ingram Cancer Center, Nashville, Tenn., the authors concluded: “In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with 

The open-label eXalt3 trial was conducted at 120 centers in 21 countries. It enrolled 290 patients with advanced, recurrent, or metastatic 

-positive NSCLC who had not received prior treatment with an ALK inhibitor. Patient sex distribution was well balanced, and the median patient age was 54, with an age range of 25 to 90 years.

Participants were randomized 1:1 to receive either 225 mg of oral ensartinib once daily or 250 mg of crizotinib twice daily. The trial design called for patients to receive treatment until disease progression or unacceptable toxicity, but no crossover was permitted. At the physician’s discretion, treatment could continue beyond progression.

The primary end point was blinded independent review committee–assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival (OS).

At the July 2020 data cutoff, many more patients in the ensartinib group continued to receive treatment: 64 patients (44.8%) versus 25 patients (17.0%) in the crizotinib group. The median follow-up was 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group.

EXalt3 also included a prespecified modified intention-to-treat (mITT) group that consisted of 

-positive patients whose status was confirmed by central testing. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; HR, 0.45; 95% CI, 0.30-0.66; log-rank 

Progression-free survival for patients without brain metastases was not reached with ensartinib. “[This compares with] 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95%CI, 0.16-0.63; 

The safety profiles of each drug were manageable and consistent with previous studies. About two-thirds of patients in the ensartinib group experienced a grade 1, 2, or 3 rash. Of these, 16 patients (11.2%) had a grade 3 rash; all responded when the study drug dose was withheld or reduced. Additionally, about half the patients in the ensartinib group developed elevated alanine aminotransferase levels and about one third developed elevated transaminase levels.

Only 3 patients in the ensartinib group developed grade 4 treatment-related adverse events (AEs): one each with increased bilirubin level, increased creatine phosphokinase level, and hyponatremia. In the crizotinib group, the most common AEs were liver toxic effects, nausea, edema, and constipation. There were no treatment-related deaths in either group.

Horn et al. noted some limitations with the study. One concern is that eXalt3 included some patients whose ALK status was confirmed only at the local level, which could have affected efficacy outcomes in the ITT population. Additionally, the OS data may be confounded by the fact that study participants could have received other ALK inhibitors when their disease progressed. Finally, the OS data are not yet mature; when they are, they may“help to better contextualize the role of ensartinib compared with other next-generation 

Additionally, Horn et al. believe that researchers should look more closely at drug resistance in this disease setting: “A more precise understanding of primary and acquired resistance mechanisms is warranted to establish the optimal sequence of ensartinib and other available second- and third-generation ALK inhibitors in the first-line setting.”

Horn L, Wang Z, Wu G et al. Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase−Positive Non–Small Cell Lung Cancer: A Randomized Clinical Trial. 

. doi:10.1001/jamaoncol.2021.3523. Published online September 2, 2021.

Ensartinib, an investigational ALK inhibitor, significantly extended progression-free survival versus crizotinib in patients with advanced disease in the phase 3 eXalt3 randomized clinical trial.










Next-Generation ALK Inhibitor Ensartinib Outperforms Crizotinib in ALK-Positive NSCLC

As targeted anticancer therapies proliferate, companion diagnostics have become an equally indispensable part of the clinician’s tool box. This effective combination helps determine the genetic makeup and protein expression status of a patient's tumor, while informing the oncologist's treatment choices.

Genomic testing appropriate to the type and stage of tumor is the way forward to ensuring that patients receive maximum benefits from targeted therapies. This increased focus on the use of biomarker and genomic testing to guide treatment for patients with cancer has found wide acceptance in comprehensive cancer centers and large research-based institutions. But by all accounts, testing uptake still lags among community-based oncology practices, although the situation does appear to be improving.

, chief scientific officer at US Oncology Research, points out that drug development is what is driving genomic testing. As new targeted therapies become the standard of care, testing rates are increasing, albeit more slowly than he would like.

“For many tumors, whether or not you test depends on what you can do with the information. Look at how PARP inhibitors have affected my field of ovarian cancer: The only approval for a PARP inhibitor we had in 2014 was for patients with germline BRCA-positive recurrent ovarian cancer,” he says. “Then we studied [and got approval] as a third-line therapy, and then as a maintenance therapy for recurrence, and then as a maintenance therapy for primary. As we’ve gotten approval as a frontline indication, we now need to know the BRCA mutation status at the time of diagnosis, and clinicians do need to adapt to that.”

, a molecular geneticpathologist and associate director of genomic and molecular pathology services for PathGroup/PBM in Dallas, Texas, says that message seems to be getting through to clinicians. “Since 4 out of every 5 patients with ovarian cancer present with advanced disease, they should get broad genomic profiling instead of testing just for BRCA1 and BRCA2 mutations,” she says. “Most orders we see are indeed for the broad panel, so that’s a good development.”

In general, Shiller finds that clinicians are getting better about ordering testing. “There’s still a gap between what the guidelines or FDA approvals say and what we actually see in the field,” she says. “Too often, a clinician doesn’t test until after a patient has progressed or escaped a prior therapy.”

Testing for non–small cell lung cancers (NSCLCs) has been a relative bright spot. “Testing uptake has been the best with NSCLCs but we’re still not seeing enough,” Shiller says. “All advanced NSCLCs should receive broad genomic profiling at diagnosis, and all early-stage lung cancers should get screened for the presence or absence of an EGFRmutation at diagnosis. We’re not seeing enough early-stage testing yet, not even in lung cancer.”

An analysis of testing patterns with next-generation sequencing (NGS) for patients with advanced NSCLC (n = 29,572) as well as for patients with metastatic breast cancer (n = 12,175) from January 2015 to May 2020 showed significant improvements in NGS testing rates for NSCLC over 5 years (22% in 2015 vs 60% in 2020) and more moderate improvements in testing rates for breast cancer (17% in 2015 vs 27% in 2020) (

Shiller also notes that most—but not all—institutions are ordering mismatch repair testing by immunohistochemistry on all colon and endometrial cancers. “This gap needs to be closed, because aside from screening for the potential to respond to an immune-based therapy, it also screens a patient for hereditary predisposition. For colon, only about 75% to 80% of all-comers [have those orders], either in diagnostic biopsy or a resection,” she says. “In endometrial [cancer], it’s a bit lower at about 70%. But these are part of the NCCN [National Comprehensive Cancer Net-work] guidelines and there’s a lot of data to drive this practice, so testing rates should be at 100%.”

Possible Barriers to TestingTrends in real-world genomic testing have become a subject of widespread interest in oncology. A glance at the programs from the 2021 American Society for Clinical Oncology (ASCO) Annual Meeting and the 2021 ASCO Quality Care Symposium hints at both insufficient community-based genomic testing and optimism that testing is on the upswing. Dozens of ASCO abstracts this year focused on some aspect of documenting—and then improving—genomic testing at the community-practice level.

Some commonly perceived barriers to full testing include:

Here’s a closer look at some questions these studies are asking and attempting to answer.

For years, technology development has followed a familiar pattern: initial to-market iterations are prohibitively expensive and relatively limited in performance. Then, within a few years, price drop dramatically even as features increase. 

Genomic testing is no different. Everyone agrees that genomic testing prices have decreased even as they have become able to offer testing panels of 450 to 500 genes. In Coleman’s experience, genomic testing can range from about $250 to $2500 per testing panel. “It’s clear that pricing is on a downward trend, and, of course, the actual cost of testing varies from what is charged,” he says. “Reimbursement trends are improving because drug payment approvals are tied into knowing [a patient’s genetic status].”

Tracking genomic testing pricing in detail has been challenging because of all the variables involved. At ASCO 2021, one Merck-funded study set out to describe historic trends in the average allowed cost for NGS testing.

The retrospective database study looked at 4 years of patient claims for tumor and/or germline sequencing tests. The authors, led by Merck’s Kaushal Desai, PhD, found that average allowed amounts for NGS tests varied from $1269 to $2058 per test during the study period, which concluded in 2019. They found even greater variability in subgroup analyses that included the patients’ region, age, gender, and cancer type. For hereditary cancers, the average allowed amounts varied from $1722 to $2249 per test. Pricing and utilization were more consistent over time, with prices gradually decreasing.

Tests that focused on the newer biomarkertumor mutation burden showed an even larger range: $438 to $3700 each.

“Currently, coverage and reimbursement of NGS tests is one of the key policy challenges that needs to be addressed,” wrote Desai et al. “Hence, development and adoption of policies is needed to ensure efficient integration of NGS testing into the US healthcare system.”

Teasing out the ways in which health disparities interact with genomic testing trends in community oncology is even more challenging than analyzing pricing trends. And yet, for Coleman, the issue has a certain simplicity: “If NGS testing is tied to insurance coverage, there are going to be disparities because there’s a massive amount of disparity built into insurance coverage in the United States,” he says. “Anecdotally, I’ve found that patients who have Medicare can usually get testing covered.”

One study at ASCO 2021 that garnered attention was a retrospective observational study led by Debora Bruno, MD, of University Hos-pitals in Cleveland, Ohio, that investigateddifferences in Black vs White race among patients with NSCLC undergoing biomarker testing and clinical trial enrollment. Conducted using the Flatiron Health database, the study found that comparable numbers of White patients (76.4% of 9800) and Black patients (73.6% of 1300) underwent at least 1 single molecular test or comprehensive genomic analysis (P = . 0 3).

Bruno et al found that the use of NGS-based testing, which is recommended by the NCCN Clinical Guidelines in Oncology for patients with advanced/metastatic NSCLC,

 reflects the most notable disparity between Black and White patients. NGS was performed among 50.1% of White patients and only 39.8% of Black patients (P < .0001).

 “Black patients had more than a 10 percentage-point difference in receiving this testing vs White counterparts,” they concluded. “Also, Blacks were 55% less likely to be treated within a clinical trial...as many second line and beyond trials utilize molecular targets as inclusion criteria.”

An ASCO 2021 poster from the Association of Community Cancer Centers (ACCC) and the LUNGevity Foundation used a mixed-methods approach to identify barriers to equitable precision medicine access among underserved patients with NSCLC. Using a national survey of clinicians and one of patients, the authors triangulated survey data with data from clinician and patient focus groups to probe issues of concern.

A total of 78% of clinicians said they were “very” or “extremely” likely to discuss biomarker testing with patients; less than 7% of clinicians said they would not discuss testing with their patients at any point during the management of their disease. Further, only half of community clinicians ordered testing at the time of initial biopsy, while nearly three-quarters of academic clinicians did. Eighty-five percent of LUNGevity-connected patients received biomarker testing, yet only about half of the underserved population did (

“Notably, more than a quarter (27%) of underserved patients who have undergone biomarker testing do not know their results,” wrote the authors, led by Leigh Boehmer, PharmD, BCOP, chief medical officer of the ACCC.

There were also differences observed in the study for the likelihood of ordering biomarker testing for a patient with NSCLC based on socioeconomic status and health literacy. “[We] identified disparities in offering biomarker testing and results to patients with known or presumed low socioeconomic status [SES] and/or health literacy. This was supported by patient survey data, which showed biomarker testing was proactively offered to only 40% of low-SES patients,” Boehmer et al wrote.

Clinicians surveyed responded that they were extremely (57%) likely to order testing for a high SES patient, compared with 32% for low SES or homeless patients. Sixty-three percent of clinicians were extremely likely to order testing for a patient with a high perceived health literacy, compared with 32% for patients with a low perceived health literacy.

As for genomic testing, tumor tissue is a finite resource. Shiller believes running a broad sequencing panel is the best way to make use of the limited tissue obtained in a biopsy. “It’s better tissue stewardship to choose the broad profiling because you have less likelihood of running out of tissue before you answer the clinical question,” she says. “Some doctors start by ordering individual genes, but then after 3 or 4 additions to the order, you’ve paid for the NGS that would actually tell you more and you may have run out of tissue to boot.”

However, tissue requirements may become less of an issue in the future as liquid biopsy tests can gather ever-increasing amounts of data from a simple blood draw.

 According to Shiller, an industry standard for turnaround time is 10 days from when the specimen arrives at the lab.

In Coleman’s opinion, genomic sequencing turnaround times can be a major imped-iment for starting patients on targeted therapies. “That’s particularly true if the patients are too ill to wait,” he says. “That often leads us to do a more general treatment like chemotherapy, so the turnaround time is key for increasing testing uptake in the community. Liquid-based assays currently have a leg up in timing, but it would be great to reduce turnaround even more.”

ASCO recently funded a study that probed the issue of turnaround time in managing patients’ treatment. An ASCO task force, including representatives from the American Cancer Society National Lung Cancer Roundtable and patient advocates, conducteda study to assess opinions on biomarker testing and treatment practices for patients with advanced NSCLC among US oncologists. Nearly 2400 ASCO members who treat at least 1 patient with NSCLC per month, including lung cancer specialists and general oncologists (59% were academic physicians and 41% were community based), received a survey.

Nearly all respondents (98%) believed they should receive biomarker results within 1 or 2 weeks of ordering, yet 37% waited an average of 3 or 4 weeks for results. About a third of respondents who usually wait 3 or 4 weeks said they initiate a non-targeted systemic treatment while waiting. Respondents from community practices were more likely to initiate non-targeted, systemic treatment if results were not available after 2 weeks (59%, compared with 40% of academic respondents). Additionally, oncologists with fewer years since training were more likely to express concerns and delay treatment while waiting for biomarker testing results.

“Respondents indicated that treatment decisions are impacted by delays in bio-marker test results,” wrote the authors, led by Kathryn Finch Mileham, MD, chief of the Section of Thoracic Medical Oncology at Levine Cancer Institute/Atrium Health, Charlotte, NC. “Clinicians should be informed about when it is safe and appropriate to defer treatment while biomarker testing is pending. Respondents suggest that diagnostic biomarker testing companies should strive to expedite results.”

Comparatively in the LUNGevity survey, the turnaround process for receiving testing results took over 2 weeks for 23% of community clinicians vs for 3% of academic clinicians.

In order to fully understand the scope of genomic testing in community settings, large organizations are conducting research projects to document current trends in testing.

Educational programs and policies are being created to move toward better testing uptake, including to ensure that all relevant genes are tested for across tumor types and to stay up to date with the latest recommendations.

The US Oncology Network MYLUNG consortium is a step in that direction, according to Coleman, the program’s principal investigator. “We want to understand what’s happening now and eventually push our clinicians to improve upon current testing rates,” he says.

MYLUNG is an ambitious 3-protocol study that ultimately will include some 12,000 patients with NSCLC in the US Oncology Network over a 5-year period. The first results of protocol 1 were presented at ASCO 2021.

This retrospective, observational chart review included nearly 3500 patients with metastatic NSCLC who started first-line therapy between 2018 and early 2020. Investigators led by NicholasJ. Robert, VP of Medical Affairs for Ontada, assessed testing rates for 

, and PD-L1; use of full NGS panels; time from diagnosis to therapy initiation; turnaround time from biomarker orders to results; and time from diagnosis to test results.

Robert et al found that 90% of patients had at least 1 biomarker tested, but only 46% had all 5 tests. NGS testing increased from one-third to 45% over the time of the analysis (P < .0001). The median time to starting therapy was 35 days (range, 22-55) and median turnaround time from orders to results received ranged from 10 to 15 days for individual biomarkers. The median time from diagnosis to biomarker results ranged from 13 to 21 days by biomarker.

Guidelines for genomic testing in NSCLC have changed since 2018, however, based on now available targeted therapies for 

, and other alterations. “When we wrote the initial MYLUNG protocol, we focused on just the metastatic recurrent incurable patients, but while we were writing the protocols, additional drugs became available and approved in the frontline setting,” Coleman says. “We realized the study and protocols needed to evolve to reflect the temporal changes happening in practice. We’ll be looking at curable patients who are getting testing for adjuvant therapy.”

 will be a prospective observational trial at 11 US Oncology sites that will enroll 1000 patients. “We will monitor the real-world patient journey from presentation through their first line of cancer therapy,” says Coleman. “This will help to understand the types of patients presenting and the barriers to molecular testing across different types of practices with varying levels of expertise, not only in lung cancer but also in molecular diagnostics.”

Protocol 3, to conclude in 2026, will be a series of prospective trials in 20 practices that will look at ways to improve upon the data gathered in the earlier protocols. “Eleven of these sites will be serving as their own controls for the introduction of new standard operating procedures or new testing methodologies,” Coleman notes.

But how can community oncologists who are not part of larger organizations ensure that they remain up to date in their genomic testing protocols? Shiller advocates forging closer ties between pathologists and clinicians to increase genomic testing to appropriate levels.

“As pathologists, we make that final diagnosis. There’s a clinical impression, there’s a radiologic impression, but we seal the deal. So we’re the key to helping clinicians get comfortable with newer testing protocols,” she says. “I would tell clinicians to find a lab that will partner with them and make themselves readily available for discussion.”

Alternatively, she says, community oncologists can ask their current pathologists to make the connection. “Call them and say, ‘Hey, I want you to own genomic testing. Please do the research and let us know what you recommend,’” she advises.“I also recommend working with your pathologists to set up standard delegated orders for genomic testing. That helps ease the burden on clinicians while ensuring that patients receive optimal care.”

Both Shiller and Coleman see participation in a molecular tumor board as an important educational opportunity for community clinicians. “PathGroup runs a few molecular tumor boards with different institutions throughout each month,” Shiller says. “We’re seeing clinician interest go through the roof, which I think is hugely positive, especially since we’ve seen a fairly significant increase in testing since we started the tumor boards. We’re just trying to get everyone talking about what’s appropriate in genomic testing.”

1. Vanderwalde A, Ma E, Yu E, et al. NGS testing patterns in advanced non-small cell lung cancer (aNSCLC) and metastat-ic breast cancer (mBC): OneOncology (OO) sites compared to Flatiron Health Nationwide (NAT). J Clin Oncol. 2021;39(suppl 28):288. doi:10.1200/JCO.2021.39.28_suppl.288

2. Desai K, Hooker G, Gilbert K, et al. Real-world trends in costs of next generation sequencing (NGS) testing in U.S. set-ting. J Clin Oncol. 2021;39(suppl 15):e18824. doi:10.1200/JCO.2021.39.15_suppl.e18824 

3. Bruno DS, Hess LM, Li X, et al. Racial disparities in biomarker testing and clinical trial enrollment in non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):9005. doi:10.1200/JCO.2021.39.15_suppl.9005

4. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 6.2021. September 30, 2021. Accessed October 15, 2021. https://www.nccn.org/professionals/physi-cian_gls/pdf/nscl.pdf 

5. Boehmer L, Roy UKB, Schrag J, et al. Identifying barriers to equitable biomarker testing in underserved patients with NS-CLC: A mixed-methods study to inform quality improvement op-portunities. J Clin Oncol. 2021;39(suppl 28):123. doi:10.1200/JCO.2020.39.28_suppl.123 

6. Mileham KF, Roy UKB, Bruinooge SS, et al. Physician concern about delaying lung cancer treatment while awaiting biomarker testing: Results of a survey of U.S. oncologists. J Clin Oncol. 2021;39(suppl 15):9067. doi:10.1200/JCO.2021.39.15_sup-pl.9067 

7. Robert NJ, Nwokeji ED, Espirito JL, et al. Biomarker tissue journey among patients (pts) with untreated metastatic non-small cell lung cancer (mNSCLC) in the U.S. Oncology Network community practices. J Clin Oncol. 2021;39(suppl 15):9004. doi:10.1200/JCO.2021.39.15_suppl.9004

Genomic testing has grown in importance as the number of targeted anticancer therapies rises. Early genomic testing can help to guide treatment choices. 

Overcoming Barriers to Genomic Testing in Community Care Settings

FDA approvals of novel agents for molecularly defined subtypes of non–small cell lung cancer (NSCLC) are poised to change both patient outcomes as well as pretreatment testing requirements for those harboring these tumors.

In 2020, the agency approved biomarker-specific therapies for patients whose NSCLC tests positive for 

 exon 14 mutations, marking a big breakthrough for patients with these aberrations. Although the proportion of patients with these genetic alterations is low—estimated at 1% for 

 exon 14 alterations—these groups are primed to experience significantly improved outcomes. In addition, data reported in 2020 about novel, investigational, target-specific therapies in NSCLC indicate that this list will continue to grow in the near future.

“The year 2020 has been phenomenal for us in NSCLC,” Vivek Subbiah, MD, an associate professor in the Investigational Cancer Therapeutics Department, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, told 

 in an interview. “In May, we had a new FDA approval every week. I think 2021 and 2022 will also be good in this space.”

 gene have been difficult to target for investigators, according to Edward B. Garon, MD, MS, a health sciences associate clinical professor of medicine at David Geffen School of Medicine at UCLA in Los Angeles, California. “Until now, our main agents for these patients have been multitargeted tyrosine kinase inhibitors [TKIs], with limited effectiveness and high toxicities. There wasn’t much enthusiasm [among investigators] until recently in terms of available therapy for this patient population. But now we do have good treatment options for this population.”

Selpercatinib In May, the RET inhibitor selpercatinib (Retevmo) became the first biomarker-specific therapy to earn FDA approval for 

 fusion–positive NSCLC. The approval was based on the results of the open-label phase 1/2 LIBRETTO-001 trial (NCT03157128), which were published in the 

 in August with Subbiah as senior author.

The trial explored selpercatinib in both pretreated and treatment-naive patients with advanced 

 fusion–positive NSCLC across 65 centers in 12 countries. The primary end point was the objective response rate (ORR) as determined by an independent review committee. Secondary end points included the duration of response (DOR).

Initial enrollment consisted of 105 patients with pretreated 

 fusion–positive advanced NSCLC who received treatment across both the phase 1 dose-escalation portion of the trial (n = 49) and the phase 1 dose-expansion or phase 2 portion of the trial (n = 56). Additionally, the investigators later enrolled 39 previously untreated patients with the same malignancy type.

 fusion–positive NSCLC, nearly two-thirds (64%) responded to treatment per blinded independent central review. Two patients achieved a complete response (CR), 62% had a partial response (PR), and an additional 29% had stable disease (SD). At a median follow-up of 12.1 months, 63% of the responses were ongoing. The median DOR was 17.5 months (95% CI, 12.0-not evaluable [NE]).

Among the 39 previously untreated patients, 85% responded to treatment (95% CI, 70%-94%), and 90% of these responses continued at 6 months. Responses in this cohort comprised PRs exclusively, and 10% of patients had SD. The median duration of response was not yet reached (95% CI, 12.0 months-NE).

Eleven patients had baseline central nervous system metastases at enrollment, and nearly all of them experienced an intracranial ORR (91%; 95% CI, 59%-100%). This included 3 patients with CRs (27%), as well as 7 patients with PRs (64%). The remaining patient had SD. The median CNS DOR was 10.1 months (95% CI, 6.7-NE).

“Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with 

 fusion–positive NSCLC,” Subbiah said. “Our data clearly show that patients benefitted from this treatment.”

 fusion–positive NSCLC may also be treated with the selective RET kinase inhibitor pralsetinib (Gavreto), which gained accelerated approval from the FDA in September for the treatment of patients with 

 fusion–positive NSCLC based on the global registrational phase 1/2 ARROW trial (NCT03037385), which is ongoing.

The trial is examining pralsetinib in patients with advanced solid tumors and 

 fusion–positive NSCLC. Of 179 patients with 

 fusion– positive NSCLC, 116 were evaluable at the data cutoff in November 2019, and results from this group of patients were presented at the American Society of Clinical Oncology 2020 Virtual Scientific Program (ASCO 2020).

According to blinded independent central review, response-evaluable patients had an ORR of 65% (95% CI, 55%-73%). Six percent of evaluable patients achieved a CR and 59% experienced a PR. Among treatment-naïve patients (n = 26), the ORR was 73% (95% CI, 52%-88%), with a 12% CR and a 62% PR rate. Among 80 patients who had been pretreated for NSCLC, the ORR was 61% (95% CI, 50%-72%), with 5% CRs and 56% PRs.

The investigators found that 96% of evaluable patients had tumor reductions, including 100% of patients who were treatment naïve.

The median duration of response was not reached (NR; 95% CI, 11.3 months-NR). Of the pretreated patients, 80% of responding patients had responses lasting at least 6 months. Among treatment-naïve patients, 58% of responding patients had responses lasting 6 months or longer. At the time of presentation, 75% of responding patients were still on treatment.

Nine patients had measurable central nervous system metastases at baseline. Blinded central reviewers found that the intracranial ORR was 56%. Additionally, 3 of these patients obtained an intracranial CR.

“Patients have had beautiful responses to pralsetinib characterized by the resolution of all lesions, regardless of the presence of brain metastases, which is extremely uncommon in NSCLC,” Subbiah said. “These patients had no good treatment options before this approval.”

In May, the FDA approved capmatinib (Tabrecta), a selective inhibitor of the MET receptor, for use in patients with NSCLC tumors harboring 

 amplifications. Approval was based on the multicohort phase 2 Geometry Mono-1 trial (NCT02414139), the results of which were published in the 

The trial evaluated capmatinib in 364 patients with 

-dysregulated advanced NSCLC. Investigators assigned patients to cohorts based on their previous lines of therapy and 

 status. ORR was the primary end point and DOR was a key secondary outcome measure, both assessed by blinded central review.

 exon 14 skipping mutations, reviewers identified a response in 41% of pretreated patients (n = 69; 95% CI, 29%- 53%). Among those who were treatment naive (n = 28), 68% (95% CI, 48%-84%) responded to treatment. The median DOR was 9.7 months (95% CI, 5.6-13.0) among pretreated patients and 12.6 months (95% CI, 5.6-NE) among treatment-naive patients.

The investigators observed limited efficacy among previously treated patients with 

 amplification who had a gene copy number less than 10 (overall response in 7% to 12% of patients). Among pretreated patients with 

 amplification and a gene copy number of 10 or higher, nearly one-third of patients responded to treatment (29%; 95% CI, 19%-41%). Among patients without prior treatment, 40% experienced a response (95% CI, 16%-68%).

Garon, who was one of the investigators on the Geometry Mono-1 trial, appreciated the opportunity to study the role of MET as an oncogenic driver. “The fact that this trial evaluated both amplification as well as the exon 14 skipping mutation gave us a broader understanding of the role of MET as a biomarker in lung cancer,” he said. “One question that remains is whether this is an agent to use in the frontline setting. I would argue the data are not entirely clear, partly because we don’t know how well this patient population does with standard therapies.”

Meanwhile, work continues to explore the potential applicability of targeted therapies for oncogenes that do not currently have available options for biomarker-specific application. Promising trials abound, but no FDA approvals have yet materialized for either HER2- or 

Trastuzumab deruxtecan (T-DXd; Enhertu) is a novel antibody-drug conjugate that consists of 3 components: a humanized, anti-HER2, IgG1 monoclonal antibody and a topoisomerase I inhibitor payload that are connected by a tetrapeptide-based cleavable linker. Results of the open-label, multicohort phase 2 DESTINYLung01 trial (NCT03505710) exploring the agent in patients with HER-positive tumors were presented at ASCO 2020.

Patients enrolled in the trial must have received no prior HER2-targeted therapies, with the exception of pan-HER TKIs. ORR confirmed by an independent central committee was the primary end point. One cohort consisted of patients who had HER2-expressing tumors; the other included patients whose tumors harbored a HER2 mutation

At data cutoff in November 2019, the ORR in 26 patients confirmed by independent review was 61.9% (95% CI, 45.6%-76.4%). One patient had a CR (2.4%), 25 had a PR (59%), and an additional 12 patients had SD (28.6%). With only 2 patients either having progressive disease or being NE, the disease control rate was 90% (95% CI, 77.4%- 97.3%). The median DOR was not reached. The median follow-up was 8.0 months (range, 1.4-14.2 months) and the median duration of exposure to the drug was 7.8 months.

Investigators have expanded enrollment by 50 patients in the HER2-mutated cohort to better characterize the risk-benefit ratio of T-DXd. The FDA awarded T-DXd a breakthrough therapy designation in May for metastatic HER2-mutated NSCLC based on these data.

Garon noted that HER2 has been a difficult therapeutic target to date in NSCLC. “Unlike in breast cancer, [in which] HER2 tends to be amplified, in lung cancer there tends to be specific mutations. They tend to be in exon 20, which is somewhat structurally analogous to exon 20 mutations in 

, which have traditionally been a difficult target for drugs,” he said. “But the DESTINY-Lung01 data to date have been quite as promising in a population that is somewhat difficult to treat.”

 mutations are believed to account for about 13% of NSCLC cases. Sotorasib, a small molecule that selectively and irreversibly targets 

 G12C, is considered a promising therapy. A variety of clinical trials are currently underway under the CodeBreak clinical trial umbrella.

In the phase 1 CodeBreak 100 trial (NCT03600883), results of which appeared in the New England Journal of Medicine, investigators enrolled 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) in dose-escalation/-expansion cohorts.

The investigators observed no dose-limiting toxic effects or treatment-related deaths. In the subgroup with NSCLC, nearly one-third of patients (32.2%) had a confirmed objective response, whereas 88.1% of patients (n = 52) had disease control. The median progression-free survival was 6.3 months (range, 0.0-14.9).

More recently, Amgen has announced positive topline phase 2 results for sotorasib in a press release. Calling the trial “potentially registrational,” the company said that detailed results will be released at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer in January 2021.

Meanwhile, CodeBreak 200 (NCT04303780), a global, phase 3, randomized, active-controlled confirmatory study comparing sotorasib to docetaxel in 

 G12C–mutant NSCLC, has begun recruiting. Investigators shared complete study details in a poster at the European Society for Medical Oncology Virtual Congress 2020.

“The fact that KRAS is now druggable has opened up our field,” Subbiah said. “With the phase 3 trial enrolling more than 500 patients in its first 6 months, I won’t be surprised if there’s a 2021 approval in store for us.”

1. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. Updated May 11, 2020. Accessed November 14, 2020. https://bit.ly/2K7qf8n

2. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in 

 fusion–positive non–small-cell lung cancer. 

. 2020;383(9):813-24. doi:10.1056/NEJMoa2005653

3. FDA approves pralsetinib for lung cancer with RET gene fusions. FDA. Updated September 8, 2020. Accessed November 14, 2020. https://bit.ly/3kFME9w

4. Gainor JF, Curigliano G, Kim DW, et al. Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced 

 fusion+ non-small cell lung cancer (NSCLC). 

. 2020;38(suppl 15):9515. doi:10.1200/JCO.2020.38.15_suppl.9515

5. FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer. FDA. May 6, 2020. Accessed November 14, 2020. https://bit.ly/2Uy6hpm

6. Wolf J, Seto T, Han JY, et al; GEOMETRY mono-1 Investigators. Capmatinib in 

-amplified non–small-cell lung cancer. 

. 2020;383(10):944-957. doi:10.1056/NEJMoa2002787

7. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. 

. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504

8. Enhertu granted breakthrough therapy designation in the US for HER2-mutant metastatic non-small cell lung cancer. News release. AstraZeneca. May 18, 2020. Accessed November 16, 2020. https://bit.ly/3kMoDhe

FDA approvals of novel agents for molecularly defined subtypes of non–small cell lung cancer are poised to change both patient outcomes as well as pretreatment testing requirements for those harboring these tumors.