Snapshots of Studies of Interest Presented at ASCO 2022

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The 2022 ASCO Annual Meeting was filled with important science, engaging data, and several practice-changing abstracts, many of which have been covered in detail on other pages or in earlier issues of The ASCO Post. There were numerous high-impact studies and attendees, whether present at the meeting in Chicago or participating remotely, took home important information to help optimize care for their patients with cancer. Here, we offer a glimpse at additional clinical trial data—in breast cancer, small cell lung cancer, intrahepatic cholangiocarcinoma, and colorectal cancer—presented at ASCO 2022.

Breast Cancer: Adjuvant Denosumab Protects Bone, Improves Survival

In the final analysis of the phase III ABCSG-18 trial, the addition of the bone-protective agent denosumab to aromatase inhibitors extended disease-free survival, overall survival, and bone metastasis–free survival and continued to improve bone health.1 In the study, 3,420 patients with hormone receptor–positive early-stage breast cancer being treated with aromatase inhibitors received denosumab at 60 mg twice a year or placebo.

The study had already met its primary endpoint—time to first clinical fracture—which was significantly delayed with the use of denosumab (hazard ratio [HR] = 0.50; P < .0001). Fractures were observed in 176 patients on the placebo arm and in 92 patients on the denosumab arm.2

Michael Gnant, MD, FACS

Michael Gnant, MD, FACS

At ASCO 2022, principal investigator Michael Gnant, MD, FACS, Professor of Surgery at the Medical University of Vienna, presented the long-term outcomes, all favoring denosumab. These benefits were observed despite crossover once the primary results were revealed. Denosumab vs placebo resulted in the following results:

  • Improvement in disease-free survival: 74.4% vs 69.0% (HR = 0.83; P = .02)
  • Improvement in bone metastasis–free survival: 85.7% vs 81.3% (HR = 0.81; P = 0.05)
  • Improvement in overall survival: 88.8% vs 83.6% (HR = 0.80;
    P = .06).

Denosumab continued to show a good safety profile. Investigators observed no new cases of osteonecrosis of the jaw and one case of atypical fracture.

“We already knew that denosumab markedly reduces fractures, but what is new is that we have demonstrated long-term improvements in survival. With minimal toxicity and at its low cost, denosumab should be considered for routine clinical use,” said Dr. Gnant. “This is the only trial of its kind that has this type of long-term follow-up, which is reassuring in terms of the validity of the results,” he added.

Nancy E. Davidson, MD

Nancy E. Davidson, MD

The invited discussant of the ABCSG-18 trial, Nancy E. Davidson, MD, of Fred Hutchinson Cancer Research Center, Seattle, called the study a “very large, very comprehensive, beautifully designed trial,” for which the long-term follow-up provides us with “further information about outcomes that we really need” in a hormone receptor–positive early-stage breast cancer population.

Oligometastatic Breast Cancer: Systemic Treatment Alone Is Enough

In patients with oligometastatic breast cancer, local treatment of lesions added no benefit to standard-of-care systemic therapy, according to the results of the randomized phase II/III NRG-BR002 trial.3 The study assessed the benefit of stereotactic body radiation therapy or surgical resection, and it was halted after the disappointing results became clear, as reported by Steven J. Chmura, MD, PhD, Director of Clinical and Translational Research for Radiation Oncology at University of Chicago Medicine.

Steven J. Chmura, MD, PhD

Steven J. Chmura, MD, PhD

The addition of local therapy to metastatic lesions did not improve progression-free survival or overall survival for the 125 patients with controlled locoregional breast cancer and four or fewer metastases. Eighty percent of patients had hormone receptor–positive, HER2-negative disease, and 60% had a single metastasis. Patients were randomly allocated to metastasis-directed therapy plus systemic therapy or systemic therapy alone.

For the primary endpoint, at a median follow-up of 35 months, median progression-free survival was not improved with metastasis-directed therapy: 19.5 months vs 23.0 months with systemic therapy alone (P = .36). At 24 months, progression-free survival was 46.8% vs 45.7% with systemic therapy alone, and at 36 months, these rates had dropped to 38.1% and 32.8% with systemic therapy alone, Dr. Chmura reported. The 24-month progression-free survival rates were quite high in both arms, he added, “likely reflecting improvement in systemic therapy for estrogen receptor–positive/HER2-negative breast cancer.” At 36 months, overall survival was 68.9% with metastasis-directed therapy, compared with 71.8% with systemic therapy alone (P = .54).

Gaorav P. Gupta, MD, PhD

Gaorav P. Gupta, MD, PhD

The results offer clarity that stereotactic body radiation therapy does not improve outcomes over the standard of care, said Gaorav P. Gupta, MD, PhD, of the University of North Carolina at Chapel Hill, who served as discussant of the study. Dr. Gupta noted the findings diverge from the positive results seen in other phase II trials (that lacked stratification of histology) of metastasis-directed therapy in solid tumors, “which highlights the need to conduct disease-specific randomized trials for metastasis-directed treatment in oligometastatic disease.”

Extensive-Stage Small Cell Lung Cancer: Tiragolumab Misses the Mark

The addition of tiragolumab to standard first-line therapy with atezolizumab plus carboplatin and etoposide failed to show a survival benefit compared with standard atezolizumab plus chemotherapy alone in patients with treatment-naive, extensive-stage small cell lung cancer (SCLC), according to the phase III SKYSCRAPER-02 trial.4 Tiragolumab is an investigational monoclonal antibody that targets the inhibitory receptor T-cell immunoglobulin and ITIM domain (TIGIT).

Excluding patients with brain metastasis at baseline for the primary analysis, at a median of follow-up of 14.3 months, the median progression-free survival was 5.4 months with tiragolumab/atezolizumab/chemotherapy compared with 5.6 months with atezolizumab/chemotherapy. The treatment did not cross the statistical boundary of significance. Additionally, median overall survival among patients in the primary analysis set was 13.6 months and 13.6 months, respectively.

“From a clinical standpoint, based on these data, our conclusion is that targeting TIGIT in extensive-stage small cell lung cancer does not appear to be therapeutically relevant.”
— Charles M. Rudin, MD, PhD

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“From a clinical standpoint, based on these data, our conclusion is that targeting TIGIT in extensive-stage SCLC does not appear to be therapeutically relevant,” said Charles M. Rudin, MD, PhD, Chief of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, New York. “There doesn’t appear to be any subgroup that selectively benefits from the addition of tiragolumab.”

These findings emphasize that improved treatment of extensive-stage SCLC over the current standard of care (atezolizumab plus chemotherapy) remains an unmet need, he said. Investigators will continue to follow patients and conduct biomarker analyses to determine whether there are subgroups who may benefit. The manufacturer plans to continue to study the novel agent in non–small cell lung cancer.

SKYSCRAPER-02 randomly assigned a total of 490 patients to receive tiragolumab (600 mg intravenously once every 3 weeks), atezolizumab (1,200 mg intravenously once every 3 weeks), and carboplatin/etoposide chemotherapy or placebo plus atezolizumab and the same chemotherapy. Overall survival and investigator-assessed progression-free survival were the co-primary endpoints in the primary analysis set.

A secondary endpoint was outcome in all patients, including those with brain metastasis. In this population, median progression-free survival was 5.1 months in the experimental arm vs 5.4 months with standard therapy, and median overall survival was 13.1 months vs 12.9 months, respectively. Approximately 19% of the population had brain metastasis. For these patients, median overall survival was also not statistically significant: 11.7 months with tiragolumab vs 10.4 months with placebo.

Among all patients, the objective response rate was 70.8% in the investigational arm vs 65.6% in the control arm. The median duration of response was 4.2 months and 5.1 months, respectively.

The addition of tiragolumab was reported to be well tolerated, and safety was consistent with previous reports. Grade 3 or 4 treatment-related adverse events were observed in 52.3% of the tiragolumab arm and 55.7% of the control arm; grade 5 events occurred in 0.4% and 2.0%, respectively. Approximately 5% of each arm discontinued treatment because of treatment-emergent adverse events.

Intrahepatic Cholangiocarcinoma: Benefit of Futibatinib Upheld in FOENIX-CCA2

The final analysis of the FOENIX-CCA2 trial, with an additional 8 months of follow-up since the last report, confirmed the efficacy and safety of futibatinib for patients with intrahepatic cholangiocarcinoma and FGFR2 fusions/rearrangements.5

FGFR2 fusions and rearrangements appear to play a key role in the development and growth of intrahepatic cholangiocarcinoma. Futibatinib is an oral tyrosine kinase inhibitor that inhibits all four FGFR subtypes and has received Priority Review designation by the U.S. Food and Drug Administration.

The phase II nonrandomized FOENIX-CCA2 trial evaluated the drug in 103 patients who had received one to three prior treatments for advanced disease. In the updated analysis, median progression-free survival was 8.9 months, with 35% of patients free of disease progression at 12 months. Mature median overall survival was 20.0 months, with 73% of patients alive at 12 months. Responses were observed in 41.7%, and the median duration of response was 9.5 months, said Lipika Goyal, MD, of Massachusetts General Hospital.

“Exploratory ctDNA analysis results may herald a change in practice for intrahepatic cholangiocarcinoma as a potential additional means of detecting FGFR2 fusions.”
— Lipika Goyal, MD

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FOENIX-CCA2 also incorporated an exploratory analysis of the use of circulating tumor DNA (ctDNA) in detecting FGFR2 fusions or rearrangements. This test identified alterations in 83 of 95 patients who provided samples, leading to an 87% positive percentage agreement between tissue-based analyses collected at baseline and ctDNA. “Exploratory ctDNA analysis results may herald a change in practice for intrahepatic cholangiocarcinoma as a potential additional means of detecting FGFR2 fusions,” Dr. Goyal said.

The study’s invited discussant, Marina Baretti, MD, of Johns Hopkins University School of Medicine, noted that the results “beat any previous historical benchmark in this setting.” Although she acknowledged the limitations of cross-trial comparisons, Dr. Baretti suggested the numerical trend for progression-free survival may favor futibatinib over two other FGFR inhibitors approved in the second-line setting.

Marina Baretti, MD

Marina Baretti, MD

The challenge now will be optimizing the use of this class of drugs, Dr. Baretti said. “This is truly an exciting era in the management of cholangiocarcinoma, with a whole new arsenal of drugs from which to choose. In this expanding horizon, treatment selection can be guided by increased knowledge of the molecular and biological characterization of cholangiocarcinoma.”

Metastatic Colorectal Cancer: Triplet No Better Than Doublet in Combination With Panitumumab

Intensive first-line treatment for metastatic colorectal cancer did not result in better outcomes in the 57-center Italian TRIPLETE trial, presented by Chiara Cremolini, MD, PhD, of the University of Pisa, Italy.6

“The primary endpoint was not met: the intensification of the upfront chemotherapy backbone with modified FOLFOXIRI was not associated with improved response rates as compared with modified FOLFOX6 when both regimens were combined with panitumumab in patients with RAS and BRAF wild-type metastatic colorectal cancer,” Dr. Cremolini announced.

Chiara Cremolini, MD, PhD

Chiara Cremolini, MD, PhD

The study evaluated the benefit of first-line intensified chemotherapy—FOLFOXIRI (leucovorin, fluorouracil, oxaliplatin, irinotecan) vs modified FOLFOX6 (leucovorin, fluorouracil, oxaliplatin), both given with panitumumab—in RAS/BRAF wild-type metastatic colorectal cancer. Patients received a maximum of 12 cycles followed by fluorouracil plus leucovorin and panitumumab until disease progression. The primary endpoint was objective response rate.

The more intensive regimen, modified FOLFOXIRI and panitumumab, did not significantly improve response rates. Responses were achieved by 73% of those given modified FOLFOXIRI/panitumumab vs 76% of those given modified FOLFOX6/panitumumab (odds ratio [OR] = 0.87; P = .526). The deepness of response, duration of response, and chance of early tumor shrinkage were all similar between the arms, as was median progression-free survival at 12.7 months and 12.3 months, respectively (HR = 0.88; P = .277).

The main grade 3 or 4 adverse events more common with modified FOLFOXIRI plus panitumumab were diarrhea (23% vs 7%) and neutropenia (32% vs 20%). However, modified FOLFOX6 plus panitumumab produced more skin rash (29% vs 19%).

Christina Wu, MD

Christina Wu, MD

Invited discussant of the TRIPLETE trial, Christina Wu, MD, of the Mayo Clinic in Arizona, called the study “very clinically relevant. We have patients for whom we must decide whether to offer triplet vs doublet chemotherapy. Doublet chemotherapy and panitumumab should be offered to this population. This has a great impact on patients, as we can decrease toxicities and costs by offering a doublet.” 

DISCLOSURE: Dr. Gnant reported financial relationships with Amgen, AstraZeneca, Lilly, MSD, Novartis, Pierre Fabre, Daiichi Sankyo, LifeBrain, Tolmar, and Veracyte. Dr. Davidson reported no conflicts of interest. Dr. Chmura reported financial relationships with Astellas Pharma, AstraZeneca, and Genentech. Dr. Gupta owns stock in Naveris. Dr. Rudin has served as a consultant to AbbVie, Amgen, AstraZeneca, Epizyme, Genentech/Roche, Ipsen, Jazz, Lilly, and Syros and has served on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. Dr. Goyal reported financial relationships with Agios, Alentis Therapeutics, Black Diamond, H3Biomedicine, Incyte, QED Therapeutics, Sirtex Medical, Exelixis, AstraZeneca, and Taiho Oncology. Dr. Baretti reported no conflicts of interest. Dr. Cremolini reported financial relationships with Amgen, Bayer, Merck, MSD, Organon, Pierre Fabre, Roche, and Servier. Dr. Wu reported financial relationships with Array BioPHarma, Daiichi Sankyo/Lilly, Natera, Nova Research Company, and Pfizer.


1. Gnant M, Frantal S, Pfeiler G, et al: Long-term outcomes of adjuvant denosumab in breast cancer: Fracture reduction and survival results from 3,425 patients in the randomised, double-blind, placebo-controlled ABCSG-18 trial. 2022 ASCO Annual Meeting. Abstract 507. Presented June 7, 2022.

2. Gnant M, Pfeiler G, Dubsky PC, et al: Adjuvant denosumab in breast cancer (ABCSG-18): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433-443, 2015.

3. Chmura SJ, Winter KA, Woodward WA, et al: NRG-BR002: A phase IIR/III trial of standard of care systemic therapy with or without stereotactic body radiotherapy and/or surgical resection for newly oligometastatic breast cancer (NCT02364557). 2022 ASCO Annual Meeting. Abstract 1007. Presented June 4, 2022.

4. Rudin CM, Liu SV, Lu S, et al: SKYSCRAPER-02: Primary results of a phase III, randomized, double-blind, placebo controlled study of atezolizumab + carboplatin + etoposide with or without tiragolumab in patients with untreated extensive-stage small cell lung cancer. 2022 ASCO Annual Meeting. Abstract LBA8507. Presented June 5, 2022.

5. Goyal L, Meric-Bernstam F, Hollebecque A, et al: Updated results of the FOENIX-CCA2 trial: Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma harboring FGFR2 fusions/rearrangements. 2022 ASCO Annual Meeting. Abstract 4009. Presented June 3, 2022.

6. Cremolini C, Rossini D, Lonardi S, et al: Modified FOLFOXIRI plus panitumumab versus mFOLFOX6/panitumumab as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer: Results of the phase III randomized TRIPLETE study by GONO. 2022 ASCO Annual Meeting. Abstract LBA3505. Presented June 6, 2022.