Tony Berberabe

The HER2 receptor represents a prototypical molecular abnormality that is detectable in several common solid tumors including breast, ovarian, endometrial, colon, non–small cell lung, prostate, and cervical cancer. HER2 is an established target in breast cancer, but success in other solid tumors, remains elusive. Anti-HER2 agents in breast cancer have helped inform further development of agents in other tumor types moving forward.

 At the recent 2020 American Society of Clinical Oncology Virtual Scientific Program (2020 ASCO), key research evaluating the use of anti-HER2 agents were highlighted across multiple solid tumors, including gastric or gastroesophageal junction (GEJ) adenocarcinoma, colorectal cancer (CRC), and non–small cell lung cancer (NSCLC).

Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor.

In the DESTINY-Breast01 trial (NCT03248492), which evaluated patients with HER2-positive metastatic breast cancer who had previously been treated with ado-trastuzumab emtansine (T-DM1; Kadcyla), T-DXd demonstrated strong efficacy, with an objective response rate (ORR) of 60.9% and median progression-free survival (PFS) of 16.4 months.2 These data were simultaneously published in the 

Further analysis of the DESTINY-Breast01 trial was presented during 2020 ASCO. Investigators explored the association between 15 clinical predictor variables and efficacy using logistic regression models and Cox proportional hazard models. Efficacy was demonstrated in all clinical subgroups analyzed; subgroups had ORRs ranging from 46.4% to 74.5% and PFS values ranging from 12.3 to 18.1 months, similar to the results reported for the overall cohort. Variables associated with improved efficacy included hormone receptor–positive status, fewer previous treatments, pertuzumab (Perjeta) given in the first or second line, and normal renal and hepatic function.

Additional DESTINY trials were presented during 2020 ASCO, as well as stand-alone trials with other HER2-directed therapies that are summarized herein.

Gastric cancer is proving to be an important setting for the use of anti-HER2 therapies in general and for T-DXd specifically, demonstrated by positive results from the DESTINY-Gastric01 trial (NCT03329690). Results from the primary analyses in patients with HER2-positive status were presented. HER2-positive status was determined by an immunohistochemistry (IHC) score of 3+. In cases with a borderline IHC result (score of 2+), a positive in situ hybridization (ISH) result confirming 

gene amplification could also indicate HER2-positive status.

“Chemotherapy plus trastuzumab [Herceptin] is a standard treatment for HER2-positive gastric cancer,” Kohei Shitara, MD, staff physician in the Department of Experimental Therapeutics and Gastrointestinal Oncology, National Cancer Center Hospital East, in Kashiwa, Japan, said during a recorded presentation of the poster. “However, several phase 3 studies with other HER2- targeting agents have failed to show survival benefit. Therefore, there is still an unmet need for patients with HER2-positive gastric cancer.”

This phase 2 study enrolled 187 patients with HER2-expressing advanced gastric cancer (AGC) or GEJ adenocarcinoma at 66 sites: 48 in Japan and 18 in South Korea. Patients had progressed on 2 or more prior regimens. The primary cohort was randomized to receive 6.4 mg/kg of T-DXd every 3 weeks (n = 125) or physician’s choice of chemotherapy (n = 62; irinotecan or paclitaxel). The primary end point was ORR determined by independent central review using RECIST version 1.1, and secondary end points were overall survival (OS), duration of response, PFS, disease control rate (DCR), and safety.

Shitara said the study met its primary end point, with ORR for patients treated with T-DXd (51.3%) over patients in the physician’s choice arm (14.3%; 

<.0001). Median duration of response was 11.3 months (95% CI, 5.6-not estimable) for T-DXd versus 3.9 months (95% CI, 3.0-4.9) with physician’s choice.

The investigators reported a significant improvement in median OS that favored the T-DXd arm (12.5 months) compared with 8.4 months for the physician’s choice arm (HR, 0.59; 95% CI, 0.39-0.88; 

= .0097) (TABLE 1).4 Additionally, the OS 

value crossed the prespecified boundary of .0202. OS rates at 6 and 12 months also favored T-DXd versus physician’s choice, at 80.3% versus 66.4% and 52.1% versus 28.9%, respectively.

Forty-eight percent of patients in the T-DXd arm received poststudy treatment, with 31.2% receiving a PD-1/PD-L1 inhibitor, versus 74.2% of patients in the physician’s choice arm, with 45.2% receiving a PD-1/PD-L1 inhibitor.

“Interestingly, more patients were on treatment at the time of data cutoff in the T-DXd arm than in the physician’s choice arm [22.4% vs 4.8%],” Shitara said.

Median PFS was 5.6 months (95% CI, 4.3-6.9) with T-DXd versus 3.5 months (95% CI, 2.0-4.3) with physician’s choice (HR, 0.47; 95% CI, 0.31- 0.71; 

= .0003). In subgroup analyses, ORRs also favored T-DXd and were consistent within each treatment arm across subgroups.

Regarding safety, the most common grade 3 or greater treatment-emergent adverse effects (TEAEs) were decreased neutrophil count, observed in 51.2% of patients who received T-DXd and 24.2% of patients who received physician’s choice, followed by anemia (37.6% vs 22.6%), decreased white blood cell count (20.8% vs 11.3%), and decreased appetite (16.8% vs 12.9%). Among patients in the T-DXd arm, 9.6% developed interstitial lung disease (ILD)/pneumonitis, with a median time to onset of 84.5 days (range, 36-638 days). Most cases were grade 1 or 2 in severity, although there were 2 patients with grade 3 and 1 patient with grade 4.

“In summary, T-DXd demonstrated statistically significant and clinically meaningful improvements in objective response rate and overall survival compared with the standard chemotherapy in patients with HER2-positive gastric cancer, with separation [of the Kaplan-Meier curves] and [with] intestinal lung disease as notable toxicity,” Shitara said. “Based on these findings, T-DXd may be an effective treatment option for patients with advanced HER2-positive gastric/GEJ adenocarcinoma who have progressed after trastuzumab.”

Further research in the gastric setting is examining combination therapies. The following phase 1 and 2 trials often combine anti-HER2 agents with immunotherapies.

Significant tumor shrinkage was observed in the phase 1b/2 PANTHERA trial (NCT02901301) of the triplet combination of pembrolizumab (Keytruda), trastuzumab, and chemotherapy as first-line therapy for HER2-positive AGC.

Investigators from Yonsei Cancer Center of Yonsei University College of Medicine in Seoul, South Korea, reported tumor shrinkage of 95.3%, a median depth of response of 54.6%, and an ORR of 76.7% (TABLE 2).5 Further analysis revealed that the ORR consisted of 16.3% complete responses (CRs) and 60.5% partial responses (PRs), and the DCR was 97.7%. Median PFS was 8.6 months (95% CI, 7.2-22.0), and median OS was 18.4 months (95% CI, 17.9-not available).

Results of the open-label, phase 1b Ni-HIGH study to determine the safety and tolerability of adding an anti–PD-1 antibody to trastuzumab in patients with HER2-positive AGC were also presented at 2020 ASCO. The trial consisted of a safety portion and an expansion portion.

 Eligible patients had histopathologically confirmed HER2-positive AGC and measurable lesions.

In the safety portion, patients were randomized to receive nivolumab (Opdivo; 360 mg), trastuzumab (course 1, 8 mg/kg; course ≥2, 6 mg/kg), and oxaliplatin (130 mg/m2) once every 3 weeks plus either S-1 (a prodrug of 5-fluorouracil at 40 mg/m2 twice per day) or capecitabine (1000 mg/m2 twice per day) for 14 days of every 3-week cycle until disease progression or unacceptable toxicity.

Both the S-1– and capecitabine-containing regimens were shown to be well tolerated. The investigators reported that this ongoing study demonstrates favorable efficacy for these combinations.

Another trial evaluated pembrolizumab with trastuzumab, fluoropyrimidine, and platinum chemotherapy in HER2-positive metastatic esophagogastric cancer using plasma and tumor-based biomarker analysis.

The objectives were to evaluate circulating tumor DNA (ctDNA) as a possible early predictor of therapeutic response and resistance and to identify genomic mutations leading to resistance. Tumor biopsies and serial blood samples were collected from patients. To be eligible for this first-line regimen, patients had to have a diagnosis of stage IV, HER2-positive metastatic esophagogastric cancer.

Tumor-matched ctDNA was detected at baseline in 84% of patients. Median PFS was longer in patients who cleared ctDNA at 9 weeks (12.3 months; 95% CI, 7.44-not available) than in those who did not (3.9 months; 95% CI, 2.01-not available). Activating 

alterations were found in 10 patients upon progression.

Loss of HER2 overexpression/amplification was noted in 44% of patients with postprogression samples, as determined by IHC or fluorescence ISH. The reappearance of ctDNA preceded radiographic progression in 56% of patients with serial ctDNA. The investigators concluded that reappearance of ctDNA may serve as an early predictor of progression.

The open-label, phase 2 DESTINY-CRC01 study (NCT03384940) evaluated T-DXd in patients with HER2-expressing, unresectable, and/or metastatic CRC. Eligible patients had progressed on 2 or more lines of therapy and had wild-type 

“Importantly, patients who received prior anti-HER2 therapies were allowed to enroll, [whereas] patients with a history of or suspected interstitial lung disease were excluded,” lead investigator Salvatore Siena, MD, a professor of medical oncology at Università degli Studi di Milano in Italy, said during a recorded presentation of the data.

Three cohorts were evaluated. Cohort A comprised 53 patients with HER2-positive tumors, defined as IHC 3+ or IHC 2+/ISH positive. Siena said that futility monitoring was conducted after at least 20 patients in cohort A had undergone 12 weeks of follow-up to inform the opening of cohorts B and C, which both had low HER2 expression. Cohort B comprised 7 patients whose tumors were HER2 IHC 2+ and ISH negative. Cohort C contained 18 patients who had HER2 IHC 1+ tumors.

The primary end point was confirmed ORR by independent central review in cohort A. In the overall study population, the median age was 58.5 years. The median sum of target lesions was 8.4 cm in cohort A and 8.8 cm for all patients. The primary tumor site was the left intestine in almost 90% of patients, both in cohort A (88.7%) and in the overall study population (89.7%). About 80% of patients had microsatellite-stable tumors; the remainder had unknown status.

Regarding previous treatments, 100% of patients in cohort A had received either panitumumab (Vectibix) or cetuximab (Erbitux), which are both anti-EGFR antibodies. About 30% of patients in cohort A had received anti-HER2 agents, such as pertuzumab, trastuzumab, T-DM1, lapatinib (Tykerb), or tucatinib (Tukysa).

The ORR in cohort A was 45.3% (24 of 53 patients) and consisted of 1 CR and 23 PRs. An additional 20 patients in cohort A had stable disease, resulting in a DCR of 83%.

“Interestingly, median duration of response was not reached,” Siena said. “There were no confirmed responses in cohorts B and C.”

The median treatment duration was 4.8 months (range, 1-11) in cohort A and 3.5 months (range, 1-11) in all patients.

Drug-related TEAEs of grade 3 or higher occurred in 50.9% of patients in cohort A and 48.7% of all patients. Serious drug-related TEAEs were reported in 22.6% of patients in cohort A and 17.9% of all patients. There were 2 deaths related to the study drug, including 1 death of pneumonitis and 1 caused by ILD; both occurred in cohort A.

“[ILD] was an adverse effect of special interest,” Siena said. “Among 78 patients treated with T-DXd, ILD occurred in 5 patients, with a median time to onset of 80 days, ranging from 22 to 132 days.” He added that ILD is an important risk that requires careful monitoring and proper intervention.

Interim results of DESTINY-Lung01 (NCT03505710) revealed a high response rate that was durable in 42 patients with 

- mutated NSCLC who were treated with T-DXd.9 Findings were presented in a prerecording by Egbert Smit, MD, PhD, professor of pulmonary medicine (pulmonary oncology) at the Netherlands Cancer Institute and in the Department of Pulmonary Diseases of Vrije Universiteit Medical Centre in Amsterdam, the Netherlands.

Eligible patients had unresectable, metastatic NSCLC that was relapsed or refractory to standard treatments. The primary end point was confirmed ORR by independent central review.

Cohort 1 enrolled patients with HER2-expressing tumors, defined as IHC 2+ or 3+. Cohort 2 consisted of patients whose tumors harbored an activating 

mutation. All patients were treated with T-DXd (6.4 mg/kg) every 3 weeks. The authors presented results for cohort 2 in this report.

The median age of patients at baseline was 63.0 years, and the majority (64.3%) were women. ECOG performance status was 0 (23.8%) or 1 (76.2%). Central nervous system metastases were present in 45.2%. Median prior lines of treatment was 2 and included platinum-based therapy (90.5%), a PD-1/PD-L1 inhibitor (54.8%), and docetaxel (19.0%).

The investigators reported that 45.2% of patients in cohort 2 remained on treatment at the data cutoff in November 2019. The other 54.8% discontinued treatment, with the primary reasons being progressive disease (21.4%) and adverse events (AEs; 21.4%).

The confirmed ORR by independent review was 61.9% (95% CI, 45.6%-76.4%). One patient (2.4%) had a CR, 59% had PRs, and 28.6% had stable disease as their best outcome.

Median PFS was 14.0 months (95% CI, 6.4- 14.0), and median OS was not reached (95% CI, 11.8-not evaluable).

- mutated NSCLC was generally consistent with what was previously reported, said Smit. Low-grade gastrointestinal and hematological AEs were most commonly observed. TEAEs that occurred in more than 15% of patients were mainly nausea, alopecia, anemia, decreased appetite, decreased neutrophil count, and vomiting. The majority of the TEAEs were either grade 1 or 2.

“Of note, the median duration of exposure of patients to the study drug was 7.8 months,” Smit said. The most common TEAEs associated with dose reduction were fatigue and nausea. The most common TEAEs associated with dose interruption were decreased neutrophil count and lung infection. Five patients with TEAEs died, but investigators noted that none of the deaths were considered to be related to the treatment.

“In this analysis, there were 5 patients [who] experienced grade 2 interstitial lung disease, but there were no patients [who] had interstitial lung disease of higher grades,” said Smit.

“However, ILD remains an important identified risk for patients treated with T-DXd and requires careful monitoring and management,” Smit said. “The study was expanded with an additional 50 patients to better characterize the risk-benefit ratio of T-DXd in patients with 

-mutated non–small cell lung cancer,” Smit concluded.

1. Wang J, Xu B. Targeted therapeutic options and future perspectives for HER2-positive breast cancer. 

. 2019;4:34. doi:10.1038/s41392-019-0069-2

2. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. 

. 2020;382(7):610‐621. doi:10.1056/NEJMoa1914510

3. Modi S, Andre F, Krop IE. Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis. 

38: 2020 (suppl 15):1036. doi:10.1200/JCO.2020.38.15_suppl.1036

4. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS- 8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: a randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). 

. 2020;38: (suppl 15): 4513. doi:10.1200/JCO.2020.38.15_suppl.4513

5. Rha SY, Lee CK, Kim HS, et al. Targeting HER2 in combination with anti-PD-1 and chemotherapy confers a significant tumor shrinkage of gastric cancer: A multi-institutional phase Ib/II trial of first-line triplet regimen (pembrolizumab, trastuzumab, chemotherapy) for HER2-positive advanced gastric cancer (AGC). 

2020;38(suppl 15):3081. doi:10.1200/ JCO.2020.38.15_suppl.3081

6. Takahari D, Shoji H, Minashi K, et al. A phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2-positive advanced gastric cancer (Ni-HIGH study): safety evaluation. 

2020;38(suppl 15):4525. doi:10.1200/JCO.2020.38.15_suppl.4525

7. Maron SB, Chatila WK, Millang BM, et al. Pembrolizumab with trastuzumab and chemotherapy (PTC) in HER2-positive metastatic esophagogastric cancer (mEG): plasma and tumor-based biomarker analysis. 

38;2020(suppl 15):4559. doi:10.1200/JCO.2020.38.15_suppl.4559

8. Siena S, Di Bartolomeo M, Raghav KPS, et al. A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01. 

2020;38(suppl 15):4000. doi:10.1200/ JCO.2020.38.15_suppl.4000

9. 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

Articles

At the recent 2020 American Society of Clinical Oncology Virtual Scientific Program, key research evaluating the use of anti-HER2 agents were highlighted across multiple solid tumors, including gastric or gastroesophageal junction adenocarcinoma, colorectal cancer, and non–small cell lung cancer.

Anti-HER2 Agents Explored Further in Gastric, Colorectal, and NSCLC Settings

New guidelines issued jointly by the American Urological Association (AUA), American Society for Radiation Oncology (ASTRO), and Society of Urologic Oncology (SUO) focus on men withadvanced stage disease and now include new treatments, including the use of PARP inhibitors in the metastatic castration-resistant (mCRCP) setting. The guidelines were co-presented by William T. Lowrance, MD, MPH, and Michael S. Cookson, MD, MMHC, during the 2020 American Urological Association Virtual Experience.

“Men with advanced prostate cancer have exhausted local therapies and are now moving on to systemic options,” said Lowrance, who is an associate professor in the Division of Urology at the University of Utah School of Medicine and an investigator at the Huntsman Cancer Institute. “Specifically, these guidelines focus on men who experience biochemical recurrence, metastatic hormone-sensitive prostate cancer [mHSPC], non-metastatic castration-resistant prostate cancer [nmCRPC], or metastatic castration-resistant prostate cancer.”

The guidelines panel, made up of members from the 3 organizations, emphasized important principles in the early evaluation and counseling for these patients.

“In patients with suspicion of advanced prostate cancer and no prior histologic confirmation, clinicians should obtain a tissue diagnosis from the primary tumor or metastatic site,” Lowrance said. The guidelines recommend that counseling for patients with advanced prostate cancer should be based on the life expectancy, comorbidities, patient treatment preferences, and tumor characteristics. In addition, pain control and palliative care should be offered whenever possible.

In men who experience biochemical recurrence without metastatic disease, prostate-specific antigen (PSA) recurrence almost always precedes clinical detection of metastasis, Lowrance said. Therefore, clinicians should perform serial PSA measurements, clinical evaluation, and staging evaluations using standard-of-care imaging, including bone scans.

“Clinicians may use novel PET-CT scans in patients with PSA recurrence after failure of local therapy as an alternative to conventional imaging or in the setting of negative conventional imaging,” Lowrance said.

In this setting, a rising PSA after failure of local therapy and no metastatic disease demonstrated by conventional imaging, clinicians should offer observation or enrollment on to a clinical trial. Androgen deprivation therapy (ADT) should not be routinely initiated in this population. If ADT is initiated in the absence of metastatic disease, intermittent therapy may be offered in lieu of a continuous schedule.

In the setting of mHSPC, the guidelines recommend that patients receive genetic counseling and germline testing, regardless of age and family history. For treatment, the guidelines recommend that clinicians offer either chemotherapy (docetaxel) or continued ADT in combination with androgen pathway–directed therapy, including abiraterone plus prednisone, apalutamide (Erleada), or enzalutamide. The panel gave this treatment option a strong recommendation, with grade A evidence level data to support it. Another treatment option, but with a grade B evidence level, is to offer ADT with either luteinizing hormone–releasing hormone (LHRH) agonists or antagonists or surgical castration.

Evidence for these recommendations were based on findings from the CHAARTED (NCT00309985), STAMPEDE (NCT00268476), LATITUDE (NCT01715285), TITAN (NCT02489318), ARCHES (NCT02677896), and ENZAMET (NCT02446405) studies (

Recommendations in the Non-Metastatic Setting

Until recently, there were no agents available to treat men with nmCRPC, said Cookson, professor and chairman of the Department of Urology at the University of Oklahoma College of Medicine in Oklahoma City. Based on a new end point, metastases-free survival (MFS), 3 new androgen receptor antagonists—apalutamide, enzalutamide, darolutamide (Nubeqa)—have gained FDA approval based on phase 3 clinical trials SPARTAN (NCT01946204), PROSPER (NCT02003924), and ARAMIS (NCT02200614), respectively.

“Importantly, all men in this nonmetastatic CRPC group were at high risk for developing metastatic disease, with PSA doubling times of less than 10 months,” Cookson said. He also noted that the PROSPER study, whose survival data was subsequently published after the guidelines were finalized, demonstrated the benefit of enzalutamide in nmCRPC, with an overall survival of 67 months and a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.61-0.89; 

In the mCRPC setting, the use of a PARP inhibitor for men with metastatic castration-resistant prostate cancer (mCRPC) who have a deleterious or suspected deleterious germline or somatic homologous recombination repair mutation following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga), and/or a taxane-based chemotherapy (docetaxel) is now recommended. The recommendation has the potential to benefit nearly 20% of patients with mCRPC. It is estimated that 23% of these prostate cancer tumors harbor alterations to DNA damage response and repair (DDR) genes, with 8% having DDR germline mutations.

In the mCRPC setting, Cookson noted that DNA repair gene alterations are common and that among DDR alterations, 

 genes were the most frequently altered (12.7%).

Cookson spoke about data from the phase 3 PROfound trial that looked at men with mCRPC and homologous recombination repair mutations who had previously failed enzalutamide, abiraterone, or docetaxel-based chemotherapy.. Enzalutamide, abiraterone, or docetaxel-based chemotherapy had failed in these patients.

 The investigators observed a median PFS of 7.4 months in those who were treated with olaparib (Lynparza) versus 3.6 months for the control of physician’s choice or enzalutamide or abiraterone. Results from the trial led to the approval of olaparib for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone.

 Cookson said rucaparib (Rubraca) is also approved following ADT and chemotherapy.

In patients who cannot use a PARP inhibitor, platinum-based chemotherapy may be offered, according to the guidelines. Further, in patients with mCRPC whose tumors have mismatch repair–deficient or microsatellite instability–high status, clinicians should offer pembrolizumab (Keytruda).

These guidelines are a welcome addition as prostate cancer is the most commonly diagnosed solid tumor malignancy in men in the United States and remains the second leading cause of cancer deaths for this population, said Lowrance.

1. Lowrance W, Breau R, Chou R, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline. Accessed June 26, 2020. 

https://www.auanet.org/guidelines/advanced-prostate-cancer

2. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. 

. 2018;36(11):1080-1087. doi:10.1200/JCO.2017.75.3657

3. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. 

. 2016;387(10024):1163-1177. doi:10.1016/S0140-6736(15)01037-5

4. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. 

. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174

5. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. 

. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307

6. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase iii study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. 

. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799

7. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. 

. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835

8. FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. News release. FDA. February 14, 2018. Accessed June 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-apalutamide-non-metastatic-castration-resistant-prostate-cancer

9. FDA approves enzalutamide for castration-resistant prostate cancer. News release. FDA. July 13, 2018. Accessed June 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-castration-resistant-prostate-cancer

10.FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. News release. FDA. July 30, 2019. Accessed June 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer

11. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. 

. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892

12. Zhang W, van Gent DC, Incrocci L, van Weerden WM, Nonnekens J. Role of the DNA damage response in prostate cancer formation, progression and treatment [published correction appears in 

. 2020;23(1):24-37. doi:10.1038/s41391-019-0153-2

13. 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

14. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. FDA. May 19, 2020. Accessed June 28, 2020. 

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer

15. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. News release. FDA. May 15, 2020. Accessed June 28, 2020. 

https://www.fda.gov/drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate

"Men with advanced prostate cancer have exhausted local therapies and are now moving on to systemic options."

Updated Guidelines Focus on Advanced Prostate Cancer

Even as he coronavirus disease 2019 has reached global pandemic levels, the time is right to encourage community oncology practices to expand their offerings by enabling clinical trial enrollment for their patients. 

“We’ve seen an expansion of telehealth capabilities and acceptance,” Howard “Skip” Burris III, MD said during the 2020 Community Oncology Conference, held virtually from April 23 to 24, 2020.1 “We’ve seen remote data monitoring and remote data capturing. We are in a situation to continue moving forward, even in the midst of the pandemic, and, in fact, accelerate our position,” he urged. For community oncology practices looking to expand their offerings, enrolling patients on clinical trials has 2 advantages. It allows more patients and treating oncologists to access exciting research by bringing early phase studies and novel trial designs to this setting and contributes to accelerated drug development by encouraging expansion cohorts. Opening up the community setting to clinical trial research allows greater access for patients with cancer to receive cutting-edge therapies where they are being treated and managed."

We’ve got to take the trials to the patients and to the physicians who are caring for them,” said Burris, chief medical officer and president of clinical operations at Sarah Cannon Research Institute in Nashville, Tennessee.

With this shift, Burris, who is also the current president of the American Society of Clinical Oncology (ASCO), said the advantages of enrolling patients on to clinical trials in the community setting has far-reaching opportunities.

Not only does it benefit the individual patient and promote drug development, it helps oncologists better understand the biology of cancer so that the aggregate data collected can reveal why certain patients are resistant to immunotherapy and identify subsets of patients who respond better or don’t respond well.

 mutations. A greater understanding of these aberrations, both difficult pathways to treat until recently, has resulted in the development of drugs to inhibit these proteins. For tumor-agnostic treatments, expansion of clinical trials into the community setting has real-world opportunities. Burris noted the larotrectinib (Vitrakvi) drug development story, citing 2 patient experiences.

In 1 case, after disease progression, it was discovered through molecular testing that the patient had a 

 fusion. This patient had an excellent response to larotrectinib.

In a less common case, Burris described a juvenile patient with breast cancer who was identified as having a 

 fusion. After undergoing 4 lines of chemotherapy and repeated resections, the patient received larotrectinib as part of an expanded-access program.

 She had a positive response to the agent.

“The rapidity of response by the patient is how a targeted agent like larotrectinib is supposed to work,” said Burris.

 mutation and the subsequent discovery of druggable targets is another example of the benefit of expandable cohorts that include the community oncology setting. 

 appears prominently in a number of gastrointestinal and thoracic malignancies, Burris said.

, and as a result, there are a number of agents that are both in the clinic and in the laboratory undergoing development,” he said. “It’s the right time for community oncology practices to understand what specific 

 mutation patients have so that they can match the appropriate therapy,” Burris said.

The first step in expanding the community oncology practice is to begin understanding the power of aggregating data. This takes the form of molecular testing and the growing interest in liquid biopsy.

“We are seeing more oncologists [using] tumor tests for their patients at the time of diagnosis, as opposed to waiting for patients to undergo multiple lines of therapy,” Burris said.

A community practice that demonstrates an aptitude for aggregating data and understanding the importance of those data is looked upon favorably by biopharmaceutical companies, Burris said. “It helps these companies determine if your practice is a potential site for participating in a clinical trial.”

Burris cautioned that having the infrastructure in place to handle the amount of data generated from molecular testing and profiling is paramount to launching an effective clinical trials program in the community setting. A comprehensive program should include e-signature capabilities, document management, molecular profiling, electronic medical records, and clinical trial management systems (FIGURE).

Sarah Cannon Research Institute has adopted the GenoSpace platform, which helps to converge clinical research and clinical care that provides cohort-driven analyses. Data collected from the patient’s electronic medical records, along with molecular profile analysis carried out by Foundation Medicine and Caris Life Sciences, are aggregated in real time. Using these data, clinical insights are generated, which provide oncologists with an actionable item. “It is wisdom and understanding of what is best for your patients,” Burris noted.

“The ability to aggregate the data and have a conversation with the patient and biopharmaceutical company can move community oncology practices to the front of the line as we begin to bring these trials to our patients,” Burris said.

At the research institute, as clinical trials start in phase 1 and move on to expanding cohorts, Burris noted a few observations. He said the traditional phase 2 trial is going away because of expanding cohorts in phase 1 and noted that sometimes drugs are approved based on a large phase 1 effort. Second, expansion cohorts are enrolling rare tumor types, or patients with minimally invasive or untreated diseases. Third, multihistology studies are becoming increasingly common.

One criticism associated with clinical trial research is that the patient populations who participate don’t reflect real-world patients, Burris said. A real-world analysis carried out by R. Donald Harvey, PharmD, BCOP, and colleagues, noted that nearly double the number of patients with advanced non–small cell lung cancer would be eligible for clinical trial enrollment if a broader set of eligibility criteria proposed by ASCO and Friends of Cancer Research were implemented, according to data presented at the 2019 ASCO Annual Meeting.

The study used enrollment criteria proposed in 2017 to consider 10,500 patients whose records were drawn from ASCO’s CancerLinQ database. They found that 98.5% of patients would be accepted for a non–small cell lung cancer trial under the expanded criteria versus 52.3% under traditional criteria. This means that just 1.5% of the patients considered would be rejected for clinical trial participation.

“Broadening eligibility will enable patients to participate in clinical trials, make trial populations more representative, and results more generalizable, and accelerate drug approvals,” Burris concluded.

1. Burris H. The now and future of clinical trials in the community oncology setting. Presented at: 2020 Community Oncology Alliance Annual Conference; Virtual; April 23-24, 2020. https://bit.ly/2VZoDBd 

2. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. 

. 2020;21(4):531‐540. doi:10.1016/S14702045(19)30856-3 

. 2019;18(12):887‐891. doi:10.1038/d41573-019-00195-5 

4. Harvey RD, Rubinstein WS, Ison G, et al. Impact of broadening clinical trial eligibility criteria for advanced non-small cell lung cancer patients: real-world analysis. 

. 2019;37(suppl 18; abstr LBA108). doi: 10.1200/JCO.2019.37.18_suppl.LBA108

“We’ve seen remote data monitoring and remote data capturing. We are in a situation to continue moving forward, even in the midst of the pandemic, and, in fact, accelerate our position."

Global Pandemic Paves Way to Modernize Clinical Trials

For adult malignancies, potential therapeutic targets are identified using real-time comprehensive profiling, which provides valuable diagnostic information. For pediatric patients, however, the process is underutilized, which leaves a siginificant unmet need. With the INFORM (

alignancies in Childhood) registry, investigators in Heidelberg, Germany showed the utility of applying a large-scale multinational personalized oncology platform in decision-making to improve clinical benefit. Diagnostic refinement and targeted therapy options to pediatric patients was also provided with INFORM.


“This is the first time that such a large precision oncology platform [involving] pediatric patients was assessed for its clinical benefit,” Cornelis M. van Tilburg, MD, PhD, senior physician in Pediatric Oncology and Hematology, and head, Early Phase Clinical Trials at the Hopp Children's Cancer Center, in Heidelberg, Germany, said during a press program ahead of the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.1

Eight countries participated in the study by sending samples from pediatric patients for molecular analysis. The analyses were shared with an online interdisciplinary molecular tumor board that included the patient’s pediatric oncologist. A predefined algorithm using a 7-step scale that ranged from “very high priority” to “very low priority” target labels was implemented and was based on how druggable the target was, the alteration type, and any specific evidence. Treating physicians could access an online database to review the analyses.

“It is important to note that INFORM is not a clinical trial,” Tilburg said. “Treatment decisions made by the patient’s physician encompassed either enrolling the pediatric patient in a clinical trial, prescribing an off-label targeted drug, or treating with conventional therapy.” Any documentation follow-up was included in the online database.

In the analysis presented at ASCO, samples from 526 children were evaluated, of which 149 received a matching targeted drug. Twenty samples were determined to have the highest priority label. Children with higher-level targets more frequently received a matching targeted drug, said Tilburg. Seventeen children (3.2%) enrolled in clinical trials and 40 children (7.6%) with a potential cancer predisposition syndrome were detected, 17 of which were previously unknown. Families of these children were offered genetic counseling. “In approximately 8% of the brain tumors, we were able to provide diagnostic refinement of the original diagnosis,” Tilburg said.

Progression-free survival (PFS) rates in patients who received a matching targeted drug were similar to patients who did not receive a matching targeted drug. The survival curves overlap, said Tilburg.

An analysis of the highest priority level targets, however, reveals that those patients who had a very high priority level target and received a matching targeted drug had a median PFS rate of 204.5 days, compared with all other children, whose PFS rate was 114.0 days. “Children with very high priority level target show longer PFS,” Tilburg said.

In the initial INFORM study, 214 tumor samples of pediatric patients at high-risk were profiled and collected from 47 German centers.2 A breakdown of tumor types revealed that 39% were sarcomas, 30% were brain tumors, 13% were neuroblastomas, and 18% were hematological or other malignancies. On average, the turnaround time from tissue arrival to molecular results was 21 calendar days. In 14 of 214 patients (7%), the investigators identified an underlying germline predisposition syndrome. The investigators detected 1 or more potentially druggable alterations in 69% of samples (147 out of 214). Based on these findings, targeted therapeutics were incorporated into the therapy regimen in one-third of patients.

Tilburg said that pediatric precision oncology in a real-world, multinational setting is feasible. For the subgroup of children with very high priority level targets, the INFORM registry provided therapeutic opportunities and new diagnostic information.

“Looking to future research, there is an urgent need for biomarker-driven pediatric interventional clinical trials,” Tilburg said. “A significant group of patients didn't have very high-level targets and we should put our efforts in adding additional layers of diagnostics to allow them to benefit from new treatments,” he concluded.

1. Van Tilburg CM. The pediatric precision oncology study INFORM: Clinical outcome and benefit for molecular subgroups. 

 2020;38(suppl; abstr LBA10503). doi: 10.1200/JCO.2020.38.15_suppl.LBA10503

2. Worst BC, Pfaff E, Van Tilburg CM, et al. The INFORM personalized medicine study for high-risk pediatric cancer patients. 

. 2017;35(suppl 15):10509-10509. doi: 10.1200/JCO.2017.35.15_suppl.10509

<< View more of Targeted Oncology's coverage from the 2020 ASCO Virtual Annual Meeting

"This is the first time that such a large precision oncology platform [involving] pediatric patients was assessed for its clinical benefit."

Author | Tony Berberabe

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