ASCO 2020-TUMOR MARKERS FOR INTRACRANIAL GERM CELL TUMORS

Tumor markers can be used to detect relapse with a high degree of sensitivity in patients with central nervous system nongerminomatous germ cell tumors (CNS-NGGCTs), according to a pooled analysis of cooperative group trials.

The findings suggest a role for the routine use of tumor markers for surveillance in CNS-NGGCT patients, said Adriana Fonseca, MD, a pediatric neuro-oncology fellow at the Hospital for Sick Children in Toronto.

She presented these findings as part of the American Society of Clinical Oncology virtual scientific program.

This pooled analysis represents the largest prospective cohort to date of relapsed intracranial germ cell tumors, Dr. Fonseca said. The analysis included 483 patients enrolled in five prospective CNS-NGGCT trials between 1989 and 2016. There were 106 patients who relapsed after the end of therapy; the relapsed patients had a median age of 13 years (range, 1-30 years) at diagnosis and 82% were male.

Tumor Marker Utility

There were 86 patients with tumor marker assessments at diagnosis, and 83 had tumor marker elevations in serum, cerebrospinal fluid (CSF), or both.

The three patients without tumor marker elevations at diagnosis had mixed GCT, choriocarcinoma, and yolk sac tumor, which are usually associated with tumor marker elevation, so this will be investigated further, Dr. Fonseca said.

The sensitivity of tumor markers at diagnosis was 94% for serum, 83% for CSF, and 97% for either serum or CSF.

The median time to relapse was 15.5 months. Relapses were local in 45 patients (44%), distant in 32 (33%), and combined in 22 (21%). Three intracranial relapses were located outside of the radiation field and were classified as distant.

Only two patients presented with isolated tumor marker elevations as the sole evidence of relapse, and the elevations usually preceded the presence of macroscopic disease, Dr. Fonseca said.

At the time of relapse, 88% of patients (n = 73) had tumor marker elevations. The sensitivity of tumor markers was 82% in serum, 85% in CSF, and 88% in either.

To better understand if tumor markers can be used for surveillance, the researchers analyzed data from patients who had either serum or CSF tumor marker levels available at both diagnosis and relapse.

Of the 74 evaluable patients who had elevated tumor markers at diagnosis, 68 had elevated tumor markers at relapse as well. This means 92% of relapsed patients were detectable by tumor markers, Dr. Fonseca said.

"Only six patients had tumor marker–negative relapses, and interestingly, one patient who was tumor marker negative at diagnosis relapsed with tumor markers positive," she added.

Rationale and Next Steps

CNS-NGGCTs are rare and heterogeneous tumors that respond best when treated using multimodal approaches, including surgical resection, chemotherapy, and radiation, according to Dr. Fonseca. The 5-year event-free and overall survival rates range from 72%-84% and 82%-93% respectively.

"GCTs are unique as they express tumor markers, such as AFP and beta-HCG, which we know are sensitive and specific and used for diagnostic and monitoring purposes," Dr. Fonseca said.

Current surveillance strategies use a combination of brain and spine MRI and serum tumor markers with declining frequency over time.

"CSF tumor markers are not performed during follow-up, and they are usually obtained only at the time of relapse," Dr. Fonseca said. "But what is the best surveillance strategy? We have to remember that some of our patients require sedation to undergo MRI, and recurrent sedations in children have been recently associated with potential detrimental neurocognitive effects."

Similarly, the administration of gadolinium used for MRI has been associated with an increased risk of renal fibrosis and negative neurological outcomes.

"Additionally, nonspecific areas of enhancement are commonly encountered and can lead to unnecessary further investigations," Dr. Fonseca said, adding that this can contribute to patients' and parents' anxiety and to increased overall health care costs and resource utilization.

Recent Children's Oncology Group data showed that 98% of patients with extracranial germ cell tumors who relapsed were detectable by tumor markers alone, and this led to a change in surveillance guidelines for those patients. This raised the question as to whether a similar approach could be used in CNS-NCCGTs, Dr. Fonseca explained.

"We hypothesized that tumor markers alone may be sufficient for relapse detection in children and adolescents treated for CNS-NGGCT, and hence, the frequency and associated risk with serial MRIs could be safely avoided," she said.

Though this study was limited by missing data in some cases, the inclusion of trials from different eras, and the use of different detection techniques across trials, the findings confirm the sensitivity of tumor markers in this setting.

"Tumor markers represent a valuable surveillance strategy with the potential to reduce MRI frequency in these patients," Dr. Fonseca said. "Additionally, the higher proportion of tumor marker–negative relapses, compared to extracranial GCTs, suggests a different biological behavior. Further studies to investigate the biology of the primary versus relapsed samples in GCTs are currently needed."

Dr. Fonseca and colleagues are "currently undertaking some correlative outcomes analyses to try to understand if the elevation or nonelevation to tumor markers is correlated with survival. We also would like to elucidate the optimal MRI frequency required for surveillance," she said.

Dr. Fonseca reported having no disclosures, and the researchers disclosed no funding for the study.

SOURCE: Fonseca A et al. ASCO 2020, Abstract 2503.

ASCO 2020-TREATMENT FOR HER2+ COLORECTAL CANCER

Having recently gained approval in metastatic breast cancer, fam-trastuzumab deruxtecan-nxki (T-DXd) is now proving its worth in metastatic colorectal cancer, according to results of the phase II DESTINY-CRC01 study in patients with HER2-positive disease.¹ 

T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor.

Positive results for T-DXd, including an overall survival benefit, were recently shown in gastric cancer in the DESTINY-Gastric01 trial, as reported in The New England Journal of Medicine.² In the open-label nonrandomized DESTINY-CRC01 trial, 45% of heavily pretreated patients with HER2 positivity (3+ IHC) responded to this single agent, and 83% achieved disease control.

“In our opinion, these data demonstrate the potential of T-DXd as a treatment option for patients with advanced HER2-positive colorectal cancer,” said Salvatore Siena, MD, of Niguarda Cancer Center and Università degli Studi di Milano, Milan, Italy, who presented the study during the ASCO20 Virtual Scientific Program.

Salvatore Siena, MD

Michael S. Lee, MD

Although there remain some unanswered questions regarding the use of T-DXd in patients with HER2-expressing metastatic colorectal cancer, “these data are promising for subsequent anti-HER2 therapy in HER2-positive metastatic colorectal cancer,” said study discussant Michael S. Lee, MD, Assistant Professor of Medicine at Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.

DESTINY-CRC01 Details

The trial was conducted in 78 patients with previously treated unresectable and/or metastatic colorectal cancer that was HER2-expressing and RAS/BRAF wild-type. Patients had received at least two prior regimens, which in 30% included prior anti-HER2 treatment. The median number of prior regimens was four (range, 2–11). Patients with current or suspected interstitial lung disease (a known toxicity of T-DXd) were excluded.

Three cohorts were based on the degree of HER2 positivity:

• HER2-positive with immunohistochemistry (IHC) scoring 3+ or IHC 2+/in situ hybridization (ISH)+ (cohort A, n = 53)
• HER2 IHC 2+/ISH– (cohort B, n = 7)
• HER2 IHC 1+ (cohort C, n = 18).

All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was objective response by blinded central review in cohort A, who had the highest HER2 expression.

Key Findings

In cohort A, objective responses were observed in 45.3%, with one patient demonstrating a complete response. Responses were seen equally for patients with prior anti-HER2 treatment (43.8%) and no prior anti-HER2 treatment (45.9%). The median duration of response was not reached, Dr. Siena reported.

Stable disease was also achieved by 37.7% of patients in cohort A, yielding a disease control rate of 83.0%. Median progression-free survival was 6.9 months in cohort A, and median overall survival was not reached. There were no confirmed responses in cohorts B and C, who had lower HER2 expression.

Interstitial Lung Disease in 6.4%

The median treatment exposure was 4.8 months. Over that time, the safety profile was consistent with what has been seen in other tumor types, with most adverse events being low grade. Interstitial lung disease, however, occurred in 5 patients (6.4%). Of these cases, two were grade 2, one was grade 3, and two were grade 5; the median time to reported onset was 80 days.

“Of note, the study protocol recommendations included monitoring for symptoms of interstitial lung disease and to halt T-DXd and start corticosteroids if it is suspected,” explained Dr. Siena. All five patients, therefore, received steroids; two recovered, two died, and one did not recover and later died of progressive disease.

“Interstitial lung disease is an important risk [with T-DXd] and requires careful monitoring and proper intervention,” Dr. Siena emphasized.

Approximately half the patients in cohort A and also in the overall study population experienced a treatment-related adverse event; they were considered serious in 23% and 18%, respectively. The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite. 

DISCLOSURE: The study was funded by Daiichi Sankyo. Dr. Siena reported owning stock and other interests with Guardant Health and Myriad Genetics; has served as a consultant or advisor to Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, and Seattle Genetics; has received institutional research funding from MSD Oncology; has patents, royalties, and other intellectual property from Amgen; and has received travel accommodations and expenses from Amgen, Bayer, and Roche. Dr. Lee has received travel support from Genentech/Roche and institutional research support from several companies.

REFERENCES

1. Siena S, Di Bartolomeo M, Raghav KPS, et al: A phase II, multicenter, open-label study of trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer: DESTINY-CRC01. ASCO20 Virtual Scientific Program. Abstract 4000. Presented May 29, 2020.

2. Shitara K, Bang YJ, Iwasa S, et al: Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. May 29, 2020 (early release online).

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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ASCO 2020-IMMUNOTHERAPY RECHALLENGE FOR RENAL CELL CARCINOMA

In a study reported in the Journal of Clinical Oncology, Gul et al found that salvage therapy with nivolumab/ipilimumab was capable of producing a response after prior programmed cell death 1 (PD-1) pathway inhibitor therapy in some patients with metastatic renal cell carcinoma.

Study Details

The retrospective analysis included 45 patients from five U.S. centers who had not received prior anti–CTLA-4 antibody treatment. Overall, 76% had received an anti–PD-1 antibody and 24% received an anti–programmed cell death ligand 1 (PD-L1) antibody either alone or in combination with other therapies. Best overall response on anti–PD-1 therapy was partial response in 53% of patients, stable disease in 27%, and progressive disease in 20%.

Key Findings

Median follow-up was 12 months. Among 44 evaluable patients receiving salvage nivolumab/ipilimumab, partial response was observed in 9 (20%), stable disease in 7 (16%), and progressive disease in 28 (62%). 

Among 24 patients with a partial response to prior therapy, partial response was observed in 4, stable disease in 2, and progressive disease in 17 with salvage therapy. Among 12 patients with stable disease on prior therapy, 3 had partial response, 5 had stable disease, and 4 had progressive disease. Among nine patients with progressive disease on prior therapy, two had a partial response and seven had progressive disease.

Median duration of response was 7 months (range = 2–17 months) and median progression-free survival was 4 months (range = 0.8–19 months). Among nine patients with partial response, six had ongoing response and five were receiving maintenance nivolumab at the time of analysis.

Immune-related adverse events of any grade were observed in 64% of patients, with the most common being diarrhea (16%), rash (13%), hepatotoxicity (9%), and pneumonitis (7%). Grade 3 or 4 immune-related adverse events were observed in 13%, with the most common being hepatotoxicity (7%) and pneumonitis, rash, diarrhea, thrombocytopenia, and colitis (2% each). No treatment-related deaths were reported.

The investigators concluded, “Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic renal cell carcinoma who had prior treatment with checkpoint inhibition.”

Brian I. Rini, MD, of Vanderbilt University Medical Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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ASCO 2020-BIOLOGY OF CUP

Next-generation sequencing (NGS) of tumor tissue and cell-free DNA (cfDNA) analysis of blood samples are identifying potentially actionable targets in patients with cancer of unknown primary (CUP), although it is not yet clear whether the use of drugs to exploit those will improve outcomes, warn experts.

During a special session of American Society of Clinical Oncology (ASCO) 2020 annual meeting, F. Anthony Greco, MD, Tennessee Oncology, Nashville, and Karim Fizazi, MD, PhD, Institut Gustave Roussy, Villejuif, France, led the audience through a series of presentations on the state of the art for genomics in CUP.

They showed that decades of improvements in molecular and genetic profiling are beginning to bear fruit in CUP, a relatively rare disease that affects 50,000 to 60,000 patients a year in the United States.

Among the included studies was NOMINATOR, which investigated the feasibility of NGS in more than 120 patients with rare cancers. In that study, 56% of patients had at least one actionable finding that could be subject to targeted treatment.

Another study investigated cfDNA. That study, which was led by Shumei Kato, MD, assistant clinical professor, Moores Cancer Center of the University of California, San Diego, found that in almost 2000 patients with CUP, 46% had genomic alterations associated with either response or resistance to therapy.

These patients included a 62-year-old man with poorly differentiated CUP who underwent cfDNA because of a lack of tissue for NGS.

This revealed KRAS and ARID1A gene alterations, which the researchers targeted with trametinib (Mekinist, GlaxoSmithKline) and olaparib (Lynparza, AstraZeneca), respectively.

"After 16 weeks of therapy, the tumor was nearly gone, and the patient is doing well to date," Kato said.

Social Media Responds

Following the presentations, in a live discussion at ASCO 2020, Greco said that molecular assays such as NGS and cfDNA have already made their way into the clinic, particularly for patients for whom classic immunohistochemical labels are not available.

Fizazi pointed out that although the data for NGS, for example, are "quite compelling," it is still not clear "whether we're doing some good to the patients, and we need randomized data to make sure" that the approach improves outcomes more than just on an individual patient basis.

He said that he would still probably perform NGS for his next patient who has a CUP, because it has the "potential to identify a target for which we can indeed use a drug that we would not use in the natural management of a patient with CUP."

The session generated a great deal of interest among clinicians. Pashtoon Kasi, MD, from the University of Iowa Hospitals and Clinics, in Iowa City, said on Twitter that CUP "should have mandatory tumor-based genetic testing as part of [the] upfront algorithm"However, one physician who watched the session live on the ASCO website commented that although the presentations were "excellent," the "great difficulty is how to access these diagnostic methods."

Opening the session, Greco said that in more than 800 autopsy studies published over the past 50 or 60 years, 75% of CUPs were found to have a small anatomic primary, often less than a centimeter in diameter. These primaries occurred in more than 25 locations and included diverse tissues, such as the intestinal tract, lung, breast, and urinary tract. It is therefore "clear that CUP is not one single cancer type.

"It represents a clinical syndrome with more than 30 types and subtypes, but all present with clinically undetectable anatomical primary sites," Greco said, adding: "If one finds a primary site, it's not CUP."

Although the etiology remains "obscure and unknown," he said it is "very likely" that genetic and/or epigenetic mechanisms lead to the development of detectable metastatic cancers from undetectable occult primaries.

Until 2008, during the "era of empiric chemotherapy," the survival of the most "unfavorable" groups of CUP patients was around 9 months. These accounted for 80% of cases.

Since then, clinicians have entered "the era of increased sophistication in diagnostic techniques, mainly immunohistochemistry and molecular cancer classifier assays."

As a result, the tissue of origin "became obvious in many of these patients with CUP." Up to 90% of tissue types are now identifiable. The majority are found to be carcinomas, primarily adenocarcinomas, as well as sarcomas and melanomas.

This has allowed patients to receive site-specific therapies based on molecular assay diagnosis, leading to improvements in survival.

"The era of involving improved therapies for many metastatic cancer has really been in the last decade, including precision-targeted therapies and immune checkpoint blockers," Greco said, "so the recognition of the specific cancer type in CUP is becoming more and more important."

The recognition of the specific cancer type in CUP is becoming more and more important. Dr Anthony Greco

This is best achieved, in his opinion, with comprehensive NGS or liquid biopsy, which in many cancer types is "necessary to plan appropriate therapies."

He cautioned, however, that "without knowledge of the cancer type or cellular context," NGS is "often misleading and may suggest inappropriate first-line therapy for several cancer types" that are "otherwise quite treatable with standard approaches."

The most recent NCCN guidelines recommended the "judicious use" of molecular cancer classifier assays. Greco said that "until more robust outcomes and comparative effectiveness data are available, pathologists and oncologists must collaborate on the judicious use of these modalities on a case-by-case basis."

NGS in Rare Cancers

Investigations into the effectiveness of these techniques continues apace. The first study of the session investigated the feasibility of NGS in rare cancers to match the cancer to its most appropriate treatment.

The study was not conducted with CUP patients. The session moderator, Melissa L. Johnson, MD, chair of ASCO's scientific program, explained that it was selected because it "highlighted some of the difficulty that patients with rare cancers and cancers of unknown primary may have gaining access to drugs that may be appropriate based on their molecular profile.Lead author Damian Kee, MD, Peter MacCallum Cancer Center, Melbourne, Australia, noted, "Collectively, rare cancers account for up one quarter of all cancer diagnoses."

Their low prevalence means that access to research and clinical trials is limited, and patients with rare cancers "often lack evidence-based treatment and have worse outcomes than patients diagnosed with more common cancers."

Kee described the shift to treatment guided by molecular biomarkers as "opportune" for patients with rare cancers. He said that for NOMINATOR, he and his colleagues recruited patients with a "compelling" rare cancer.

These were defined as cancers in which the incidence was less than six per 1000,000 population, that are associated with a poor prognosis, and for which there is no evidence-based treatment.

In all, 121 patients were included. The vast majority (91%) had metastatic disease, and 63% had received at least two prior lines of therapy.

A comprehensive cancer panel revealed that of 100 tumors successfully sequenced, the most common aberrant genes were TP53, in 44%; CDKN2A/B,in 14%; RB1, in 14%; PTEN, in 13%; and NF1, in 12%.

The team used the OncoKB database levels of actionability to assess the genomic results. These range from recognized biomarkers predictive of response to an approved drug in a specific tumor type to more hypothetical associations. In addition, two levels relate to biomarkers associated with drug resistance.

With this approach, the researchers identified 93 actionable events across 27 genetic markers, with 18 matched drug classes. The result was that for 56% of the patients, there was at least one actionable finding, and for 27%, there was a potentially "high-impact" finding.

The genomic testing led to a revised diagnosis in six patients and the identification of germ-line variants in 13.

Eight patients died before the NGS results were available. Kee said that 24% of patients now have access to a matched drug treatment, suggesting that NGS is both "feasible" and should be used "earlier to maximize the potential benefits, as well as minimizing patients attrition".

cfDNA in Patients With CUP

But what should clinicians do for a patient for whom NGS of tumor tissue samples is not feasible?

The next study, presented by Kato and colleagues, investigated at the utility of cfDNA in patients with CUP.

Kato explained that cfDNA relies on detecting in the bloodstream low levels of DNA shed by the tumor. He believes this is "especially relevant for CUP patients, because...it theoretically does not matter where the primary sites are."

Kato's team had previously conducted a preliminary study to demonstrate feasibility. In that study, which involved 442 CUP patients, the team examined 2022 samples from 1937 patients with CUP that were sent for commercially available cfDNA assay over a 3-year period.

The assay comprised a 73- or 74-gene NGS panel that assessed for sequence alterations, fusions, and applications. In addition, microsatellite instability analysis was available for a proportion of patients after its inclusion in the assay.

The assay was able to detect at least one cfDNA alteration on 1819 tests from 1743 patients, giving a detection rate of 90%.

Using the OncoKB database levels of actionability, the team found that 46% of patients had either a level 1 or 2 biomarker association with drug response or a level R1 association with drug resistance.

These included 396 (22%) patients with at least one level 1 cfDNA alteration, indicating the presence of a US Food and Drug Administration (FDA)–approved biomarker predictive of response to an FDA-approved drug in this indication.In addition, 381 patients (21%) had at least one level R1 cfDNA alteration, suggesting a standard care biomarker predictive of resistance to an FDA-approved drug in this indication.

However, Kato pointed out that this means that approximately 50% of patients "still have challenging alterations without ideal targets, and this requires further clinical investigation."

Checkpoint Inhibition in CUP

As an example of how the latest treatments are beginning to make their way into the management of CUP, Junko Tanizaki, MD, PhD, Kishiwada City Hospital, Kishiwada, Japan, presented findings from NivoCUP.

This is a phase 2 study on the impact of the programmed cell death–ligand-1 (PD-L1) inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) in CUP.

It was undertaken because the researchers had "recently found that the immune profile of a CUP is similar" to that in malignancies responsive to immune checkpoint inhibitors, and so CUP patients "might receive clinical benefit" from the drugs.

To be included in the study, patients had to have undergone a range of mandatory examinations, and tumor samples had to have been obtained less than a year previously. In addition, patients were required to have measurable disease on RECIST 1.1 criteria. Patients who were found to have melanoma, sarcoma, or lymphoma on pathologic examination were excluded.

In all, 56 patients, of whom 45 had been previously treated, were assigned to receive nivolumab twice weekly for a maximum of 52 cycles over 2 years or until disease progression or toxicity.

Patients who had been previously treated were slightly older than untreated patients (median age, 66 years, vs 64 years), and they were more likely to be women (62% vs 55%).

They were more likely to have ECOG performance status 1 rather than 2 (78% vs 46%) and were more likely to have three or more metastatic sites (38% vs 9%).

Of previously treated patients, 42% had received at least two prior lines of chemotherapy, and 22% had undergone radiotherapy.

During a median follow-up of 8.4 months, the objective response rate (ORR) among previously treated patients was 22%. Median progression-free survival (PFS) was 4.0 months, and median overall survival was 15.9 months.

Previously untreated patients were followed for a median of 17.2 months. Among these patients, the ORR was 18.2%, and the median PFS was 2.8 months. Median overall survival was not reached.

There was a trend for association between response rates and PD-L1 expression levels, although Karim Fizazi, MD, PhD, Institut Gustave Roussy, Villejuif, France, noted in his discussion of the presentations that it was not strong.

Although he said that nivolumab showed a clinical benefit, he disagreed with the researchers' assertion that it could become a new standard of care in CUP.

More Trials and the Frustrations of Being "Outside the Box"

Fizazi said that overall, the questions asked by the presentations regarded whether genomics are the "solution" to treatment in CUP and whether they can improve outcomes.

He said that the study by Kato and colleagues was "impressive" and that it was the largest to date to examine the feasibility and potential impact of cfDNA in CUP.

However, Fizazi pointed out that in NOMINATOR, NGS could not be performed in approximately 20% of patients and that the claims for actionable findings made by Kee and colleagues were "optimistic" and underline that the strategy is "challenging" in the real world.

He referred to his own GEFCAPI 04 randomized phase 3 trial, in which a diagnostic and therapeutic strategy that was based on molecular analysis and tailored therapy was compared to an empiric strategy in patients with CUP.

Fizazi underlined that this showed that overall survival was not improved with the tailored approach, even though some subgroups appeared to benefitThis trial was nonrandomized, but he referenced his own GEFCAPI 04 randomized trial, in which overall survival was not improved. Some subgroups did improve, but the numbers were small.

However, he pointed to the ongoing phase 2 CUPISCO study, which is comparing molecularly guided chemotherapy with standard platinum-based chemotherapy for patients with CUP whose prognosis is poor. He said that that trial could provide clearer direction.

Fizazi summarized that the NGS techniques employed in the studies led by Kee and Kato are "promising," but that currently, there is no level 1 evidence to support their use.

In the subsequent live discussion, Johnson asked about difficulties in accessing drugs that may be appropriate for a CUP patient, as determined on the basis of their molecular profile.

Fizazi replied that although there are benefits to working in a social health system such as that in France, it is not possible to be reimbursed for a drug if you go "outside the box" of its approved indication.

"Sometimes it's very frustrating, because we know that the disease behaves pretty much like something we know with a drug that works, but it's very hard to access to that."

Referring to the NOMINATOR trial, he added that "anything that can help better provide data and strong enough data to support access to treatments in a rational way for rare tumors ― and this also applies to CUP ― is obviously welcome."

NOMINATOR was funded by Melbourne Health. NivoCUP was funded by Ono Pharmaceutical Co, Ltd. The presenters have disclosed multiple relationships with industry.

American Society of Clinical Oncology (ASCO) 2020: Presentation: Redefining Cancer of Unknown Primary: Is Genomics the Answer?

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ASCO 2020-IMMUNOTHERAPY FOR METAPLASTIC BREAST CANCER

Metaplastic breast cancer (MpBC) is a rare form of triple-negative breast cancer (TNBC), accounting for fewer than 1% of all breast cancers, but it is very aggressive and responds poorly to chemotherapy. So new results with a combination of immunotherapies that resulted in significant tumor shrinkage and survival topping 2 years have led to some excitement, even though the results were seen in only 3 of 17 women who were treated.

"The impressive part is that these are very dramatic and durable responses in a cancer that is so resistant to chemotherapy," lead investigator Sylvia Adams, MD, professor of medicine at the Perlmutter Cancer Center at New York University Langone Health, New York City, told Medscape Medical News.

With chemotherapy, median survival of women with metastatic MpBC is typically 8 months. "Anything that is durable for 2 years is unbelievably exciting," said Adams.

There was one complete response and two partial responses with "very little tumor burden left. That gives us the hope that maybe there is a chance for cure in these three patients," she told Medscape Medical News. 

Adams presented the results as part of the virtual scientific program of the American Society of Clinical Oncology (ASCO) 2020 annual meeting.

Approached for comment, Natalie Berger, MD, assistant professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, New York City, was equally impressed with the results.

"Demonstrating durable responses in patients who have such an aggressive subtype of breast cancer is very exciting, hypothesis generating, and certainly warrants further investigation," said Berger, who wasn't involved in the study.

Aggressive Tumor Type

The results come from the Dual Anti-CTLA-4 & Anti-PD-1 Blockade in Rare Tumors (DART) trial (SWOG S1609), a phase 2, prospective, open-label, single-arm trial evaluating the combination immune checkpoint blockade with the CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb) plus the PD-1 inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) in patients with rare tumors.

One cohort in this trial comprised 17 women (mean age, 60 years) with histologically confirmed MpBC, measurable disease, and ECOG performance status 0 to 2. They all received the combination immunotherapy with ipilimumab 1 mg/kg IV on day 1 and nivolumab 240 mg IV on day 1, 15, and 29 of continuous 6-week cycles.

These women had experienced disease progression following at least one line of standard systemic therapy, and there was no other approved/standard therapy available that had been shown to prolong overall survival (OS). Patients who had undergone prior anti-CTLA4 or anti-PD-1/PD-L1 treatment (but not both) were permitted for inclusion, as well as those with treated stable brain metastases.

Chance for a Cure?

The overall response rate was 12% (2 of 17 patients) per RECIST 1.1 and 18% (3 of 17) per immune-related RECIST (iRECIST), with ongoing responses at 27, 25, and 23 months, respectivelyTwo or more responses among 16 patients were considered evidence that the drug combination warrants further study in this patient population.

Median follow-up among patients who are alive is 20 months. The cutoff date of data follow-up was May 7, 2020. Median progression-free survival was 2 months, and median OS was 12 months.

"The patients that progressed, unfortunately, didn't have a long survival, which is what we see with the majority of metaplastic patients," Adams said.

In her practice, Adams said, chemotherapy plus a PD-1 inhibitor have generated "dramatic but not durable" responses in women with MpBC. "The addition of the CTLA-4 antibody seems to make a big difference in terms of the durability and is crucial in this disease," Adams said.

The hope is that ongoing biomarker studies will provide a signal as to who will respond to this combination. "So far, clinically, patients who respond to this combination don't seem to be different from those that don't respond," Adams said.

In her comments to Medscape Medical News, Berger noted that MpBC is associated with a "poor prognosis [and that] novel treatments are needed to improve outcomes in patients with this rare tumor.

"While this study was small, it is hard to accrue a large number of patients, given the rarity of this subtype of breast cancer. These patients were all pretreated, so further investigation can consider testing this combination earlier in the disease process," said Berger.

With regard to toxicity, 11 of the 17 patients (65%) experienced some treatment-related adverse event (AE); four (24%) had AEs of grade 3 to 5, including one fatal AE (cardiac arrest potentially related to therapy). The most common AEs were liver function test abnormalities and fatigue.

"Patients on these medications need to be closely monitored for immune-related adverse events, and patients need to report side effects very early, and we have to be very aggressive in managing them and start steroids early when needed," Adams said.

In a recent article published in Nature Reviews Clinical Oncology, Adams and a coauthor review the published experience with immune checkpoint inhibitors in metastatic TNBC, with an emphasis on immune-related adverse events.

The study was funded by the National Cancer Institute (NCI). Bristol-Myers Squibb provided the nivolumab to support the study through a cooperative research and development agreement with NCI. Adams has served in a consulting or advisory role for Bristol-Myers Squibb, Genentech, and Merck. Berger has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2020: Abstract 1073

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ASCO 2020-TANSARTELIAL CHEMOPERFUSION FOR MESOTHELIOMA

A novel treatment for patients with advanced mesothelioma is safe and effective and may improve the quality of life for patients who have few treatment options, according to a research abstract presented during a virtual session of the Society of Interventional Radiology (SIR) 2020 Annual Scientific Meeting (Abstract 1). Transarterial chemoperfusion treatment for malignant pleural mesothelioma also showed minimal side effects.

“Malignant pleural mesothelioma is a devastating cancer of the pleura, the membranes surrounding the lungs, that is very difficult to treat,” said Bela Kis, MD, PhD, principal investigator on the study and an interventional radiologist at Moffitt Cancer Center. “The typical survival rate of patients with stage III and IV malignant pleural mesothelioma is around 12 months from diagnosis; but with this new treatment, we are hoping we might be able to extend patients’ lives beyond that—giving them more time with friends and family.”

Study Methods

Transarterial chemoperfusion delivers a relatively high concentration of drugs to diseased tissue in the lining of the lungs to maximize the treatment effect with limited side effects. Unlike other chemotherapy that is delivered intravenously and circulates through the entire body, interventional radiologists inject one-third of the triplet of of cisplatin, methotrexate, and gemcitabine directly into the internal mammary artery that supplies the pleura. The other two-thirds of the drugs are injected into the descending aorta, which reaches the intercostal vessels that also supply the pleura. The treatment is an outpatient procedure and typically lasts 1 hour, followed by another hour of recovery.

Twenty-seven patients with malignant pleural mesothelioma were enrolled in the phase II clinical trial and underwent chemoperfusion. All patients had received prior chemotherapy, and many had received multiple lines of chemotherapy. Four of the patients had prior radiation therapy and three patients had pleurectomy. All continued to have disease progression before enrollment.

Results

The interim results of the study show a 70.3% disease control rate and median overall survival rate of 8.5 months from the start of the chemoperfusion treatment. The treatment was well tolerated by patients, with a major complication rate of 1.4%. Most side effects were relatively minor, including mild nausea and chest pain.

“We were pleasantly surprised to find that this treatment doesn’t come with the same side effects of traditional intravenous chemotherapy,” said Dr. Kis.

The researchers are looking to expand their study to other cancer centers with larger malignant pleural mesothelioma patient populations, since the cancer is rare. They also hope to add flexibility to the study to allow for increasing the dosage and changing the combination of medications for individual patients to determine whether either approach could further improve outcomes.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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ASCO 2020-NO SURVIVAL BENEFIT WITH ADJUVANT GEFITINIB FOR EGFR+ NSCLC

Adjuvant gefitinib provides no overall survival (OS) benefit over standard chemotherapy for EGFR-mutant, resected, stage II-IIIA non–small cell lung cancer (NSCLC), according to final results from the phase 3 ADJUVANT trial.

The median OS was 75.5 months in patients randomized to adjuvant gefitinib and 62.8 months in patients randomized to vinorelbine plus cisplatin.

Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, reported these results as part of the American Society of Clinical Oncology virtual scientific program.

Prior results from this trial had shown a disease-free survival (DFS) benefit with gefitinib, but this did not translate to an OS benefit at the final analysis, Dr. Wu said.

He noted, however, that the median OS of 75.5 months in the gefitinib arm "was one of the best in resected EGFR-mutant non–small cell lung cancer, compared with historical data."

The findings also suggest a possible benefit with at least 18 months of gefitinib and show that adjuvant EGFR tyrosine kinase inhibitors (TKIs) should be considered the optimal therapy to improve DFS and achieve potentially better OS in this setting, Dr. Wu said.

Study Details and DFS 

The ADJUVANT trial (NCT01405079) randomized 222 patients, aged 18-75 years, with EGFR-mutant, stage II-IIIA (N1-N2) NSCLC who had undergone complete resection. Patients were enrolled at 27 sites between September 2011 and April 2014.

The patients were randomized 1:1 to receive 250 mg of gefitinib once daily for 24 months, or 25 mg/m2 of vinorelbine on days 1 and 8 plus 75 mg/m2 of cisplatin on day 1 every 3 weeks for 4 cycles.

The intent-to-treat (ITT) population included 111 patients in each arm. The per-protocol population included 106 patients in the gefitinib arm and 87 patients in the chemotherapy arm.

Primary results from this trial showed a significant improvement in DFS with gefitinib (Lancet Oncol. 2018 Jan;19[1]:139-48). That improvement was maintained in the final analysis.

The median DFS was 30.8 months in the gefitinib arm and 19.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The hazard ratio (HR) was 0.56 (P = .001) in the ITT population and 0.51 (P < .001) in the per-protocol population.

In the ITT population, the 5-year DFS rates were 22.6% in the gefitinib arm and 23.2% in the chemotherapy arm. In the per-protocol population, the 5-year DFS rates were 22.6% and 22.8%, respectively.

OS Results 

The median OS was 75.5 months in the gefitinib arm and 62.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The HR was 0.92 in both the ITT (P = .674) and per-protocol populations (P = .686).

In the ITT population, the 5-year OS rates were 53.2% in the gefitinib arm and 51.2% in the chemotherapy arm. In the per-protocol population, the 5-year OS rates were 53.2% and 50.7%, respectively.Subgroup analyses by age, gender, lymph node status, and EGFR mutation showed trends toward improved OS with gefitinib, but the differences were not statistically significant.

The researchers conducted a post hoc analysis to assess the effect of subsequent treatment on patient outcomes. The analysis showed that patients who received gefitinib with subsequent EGFR-TKIs had the best responses and OS.

The median OS was not reached among patients who received gefitinib and subsequent EGFR-TKIs, whereas the median OS ranged from 15.6 months to 62.8 months in other groups. The shortest OS was observed in patients who received adjuvant chemotherapy without subsequent therapy.

The duration of gefitinib treatment also appeared to affect OS. The median OS was 35.7 months in patients who received gefitinib for less than 18 months, and the median OS was not reached in patients who received gefitinib for 18 months or longer (HR, 0.38; P < .001).

Implications and Potential Next Steps 

Despite the lack of OS improvement with gefitinib, "all of the patients on this study did much, much better than historical non–small cell lung cancer not specified by the EGFR mutation, with 70 months median survival compared to 35 months median survival for N2-positive disease," said invited discussant Christopher G. Azzoli, MD, director of thoracic oncology at Lifespan Cancer Institute at Brown University in Providence, R.I.

"But you can't avoid noticing how the curves come back together in terms of disease-free survival when your effective treatment is limited to 24 months," he added.

An apparent risk of late brain recurrence in the gefitinib arm is also a concern, Dr. Azzoli said. "So ... longer duration of treatment with a drug that has better control of CNS [central nervous system] disease, such as osimertinib, may improve both DFS and OS," he added.

Only about 50% of patients in the chemotherapy arm received a TKI at recurrence. The post hoc analysis showing that TKI recipients had the best outcomes raises the question of whether "the survival benefit could be conferred by delivering a superior drug merely at recurrence, or is there benefit to earlier delivery of an effective drug," Dr. Azzoli said.

Given the high cost of continuous therapy, biomarker refinement could help improve treatment decision-making, he said, noting that "early testing of blood DNA to detect cancer in the body as minimal residual disease is showing promise," and that many phase 3 studies of EGFR-TKIs are ongoing.

The current trial was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu disclosed relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Lilly, MSD Oncology, Pfizer, and Roche. Dr. Azzoli reported having no disclosures.

SOURCE: Wu Y et al. ASCO 2020, Abstract 9005.

This story originally appeared on MDedge.com.

ASCO 2020-WEEKLY CDDP ADDED TO RT FOR ADJUVANT TREATMENT OF HEAD-NECK CANCER-A NEW STANDARD OF CARE

For the first time, weekly cisplatin plus radiotherapy (CDDP+RT) has been shown to be not only less toxic than dosing once every three weeks but also achieves better outcomes in patients with postoperative squamous cell carcinoma of the head and neck (SCCHN), say Japanese researchers.

Consequently, the results of the JCOG1008 trial suggest that the weekly schedule should become the new standard of care in these patients, potentially settling what has been a "contentious" issue.

The research was presented the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.

Lead author Naomi Kiyota, MD, PhD, Medical Oncology and Hematology, Cancer Center, Kobe University Hospital, Japan, said that the study involving more than 160 high-risk patients with SCCHN demonstrated comparable overall survival in the weekly and three-weekly CDDP+RT groups.

Moreover, it showed that the weekly schedule was associated with better relapse-free and local relapse-free survival, and, in line with previous studies, had a more favorable safety profile.

"This phase II/III study is the first to show that weekly CDDP+RT is non-inferior to three-weekly CDDP+RT [and] is a new standard treatment option for these patients," Kiyota said.

Study discussant Hisham M. Mehanna, MD, PhD, Warwickshire Head and Neck Clinic, University of Birmingham, UK, described the study as a "significant achievement" that answers "an important question that we’ve been asking for a very long time."

He said that, despite three-weekly CDDP+RT being the standard treatment in the postoperative setting for SCCHN, there have been "lingering concerns," as 40% of patients don’t get all three CDDP cycles "and it is toxic."

Weekly CDDP is, on the other hand, "widely used, although the evidence for it is not as strong," and has a number of advantages, including that it can be delivered in the outpatient setting and it may be less toxic.

Mehanna said that there was "a surprise" to the current study, in that it was terminated early because it crossed the boundary for non-inferiority because  weekly CDDP has better survival than the three-weekly dose; notably, however, superiority was not achieved.

Mehanna also expressed some reservations over imbalances in the treatment groups that could have meant the three-weekly cohort had an unfavorable prognosis, and said questions remain over longer-term toxicity.

"Contentious Issue"

In a highlights session, Nabil F. Saba, MD, director of the Head and Neck Onology Program at Emory University's Winship Cancer Institute in Atlanta, Georgia, said that the dosing of CDDP in these patients has been "a contentious issue."

One issue has been whether scheduling of CDDP or the cumulative dose achieved is the key determinant of clinical outcome, and he suggested that the superior results seen in the current study can be attributed to the high cumulative dose that the investigators achieved in their patients compared with previous investigations.For Saba, the take-home message of the trial is that weekly cisplatin "is now, finally, an accepted standard of care in the postoperative high-risk setting, which is a major change at this ASCO meeting."

Presenting the trial, Kiyota said, in a recent study from the Tata Memorial Hospital, weekly CDDP at 30 mg/m² plus radiotherapy failed to achieve non-inferiority to a three-weekly regimen, "albeit with fewer toxicities."

He suggested that this could be because it was a single center trial, the use of two different treatment strategies, the majority of primary sites being in the oral cavity, and the dose being insufficient.

His team, on the other hand, undertook a randomized trial in which patients with postoperative high-risk SCCHN were recruited from 28 institutions.

The participants, who were aged 20 to 75 years and had ECOG performance status 0 to 1, all had pathological stage III/IV disease and a microscopically positive margin and/or extranodal extension.

They were randomly assigned to 100 mg/m² CDDP once every three weeks or weekly 40 mg/m² CDDP, plus radiotherapy at 66 Gy over 33 fractions.

For the intention-to-treat efficacy analysis, 132 patients received three-weekly CDDP+RT and 129 had weekly CDDP+RT, while the per protocol safety analysis included 129 and 122 patients, respectively.

The median age of the patients was 61 to 62 years and 110 patients in both treatment groups were male. Although there was a similar distribution of primary sites and high-risk factors in the two groups, more patients in the weekly group had pathological stage T2 disease (40) than in the three-weekly group (26).

The dose targets were met in both treatment groups. In the 3-weekly group, the cumulative dose of CDDP achieved was 280 mg/m² and in the weekly group it was 239 mg/m².

The second planned interim analysis showed that, over a median follow-up of 2.2 years, three-year overall survival was estimated at 71.6% in the weekly group vs 59.1% in the three-weekly group (hazard ratio [HR], 0.69).

As this was below the one-sided P value for non-inferiority, the data and safety monitoring committee recommended terminating the trial early.

The researchers also found that the 3-year relapse-free survival was higher with weekly CDDP+RT, at 64.5% vs 53.0% with three-weekly dosing (HR, 0.71).

Local relapse-free survival was also better with weekly dosing, at a three-year rate of 69.6% vs 59.5% for patients in the three-weekly group (HR, 0.73).

On a planned subgroup analysis, weekly CDDP+RT was nonsignificantly superior to the three-weekly schedule on almost every measure, whether looking at patient age, ECOG performance status, and primary site.

There were also differences in the occurrence of hematologic toxicities between the two groups, with fewer patients given the weekly schedule experiencing grade 3/4 neutropenia than those on the three-weekly dosing; however, there were more cases of any grade thrombocytopenia for patients getting the weekly dosing.

The weekly CDDP+RT regimen demonstrated its lower toxicity when looking at acute nonhematologic adverse events, with fewer occurrences of any grade dysphagia, nausea, hyponatremia, renal impairment, and hearing impairment vs the three-weekly schedule.

The weekly dosing schedule was also associated with lower rates of grade 3/4 dysphagia, nausea, and infection.

The study was funded by the National Cancer Center Research and Development Fund, Japan Agency for Medical Research and Development Fund.

Kiyota reports honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb Japan, Chugai Pharma, Eisai, Merck Serono, MSD, and Ono Pharmaceutical; speakers bureau fees from AstraZeneca, Bayer, Bristol-Myers Squibb Japan; Eisai, Merck Serono, MSD, and Ono Pharmaceutical; and receiving research funding from AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Ono Pharmaceutical (Inst), Pfizer (Inst), and Roche (Inst). Other study authors report potential conflicts of interest. The full list can be found here.

Mehanna reports stock and other ownership interests in Warwickshire Head and Neck Clinic; honoraria from AstraZeneca; speakers bureau fess from Merck, MSD, and Sanofi Pasteur; research funding from AstraZeneca, GlaxoSmithKline (Inst), MSD (Inst), Sanofi Pasteur (Inst), and Silence Therapeutics (Inst); and travel, accommodations, and expenses from Merck, MSD, and Sanofi Pasteur.

Saba reports honoraria from Aduro Biotech, Bristol-Myers Squibb, Cue Biopharma, Genentech/Roche, GSK, Kura, Lilly, Merck, and Pfizer; a consulting or advisory role with Biontech, Bluprint, Bristol-Myers Squibb, Lilly, Merck, and Pfizer; research funding from Bristol-Myers Squibb and Exelixis; travel, accommodations, and expenses from Bluprint, Bristol-Myers Squibb, Genentech/Roche, GSK, Lilly, Merck, and Pfizer.

American Society of Clinical Oncology 2020 Annual Meeting: Abstract 6502.

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