ASCO 2023 Insights: ADCS, Next-Generation TKIs, and More Lead Data Pack Ahead of Annual Meeting

Jane Meisel, MD

The 2023 ASCO Annual Meeting will once again be the premise for the unveiling of enticing clinical data from pivotal research across malignancies. With thousands of abstracts in oral and poster format slated to be presented over the 5-day meeting, attendees will gather to hear about study results that could once again shift practice in cancer care.

Therapeutics of interest comprise a novel IDH1 inhibitor and a pan-RAF inhibitor in glioma, novel chimeric antigen receptor products and bispecific T-cell engagers in hematologic cancers, and already-approved CDK4/6 inhibitors and antibody-drug conjugates being used in varying settings separate from their indications, among many other compounds.

OncLive^® spoke with experts in the field on the abstracts they found to be the most practice changing at this year’s meeting, which starts Friday, June 2 and is routinely held in Chicago, Illinois.

BREAST CANCER, PRECISION MEDICINE

Jane Meisel, MD, associate professor in the Department of Hematology and Medical Oncology, and in the Department of Gynecology & Obstetrics, Emory University School of Medicine

Phase III NATALEE trial of ribociclib + endocrine therapy as adjuvant treatment in patients with HR+/HER2 - early breast cancer (LBA500)

In March 2023, Novartis, the developer of ribociclib, reported that the combination of the CDK4/6 inhibitor ribociclib (Kisqali) added to endocrine therapy was found to significantly reduce disease recurrence risk vs endocrine therapy alone in the adjuvant setting for patients with hormone receptor (HR)–positive, HER2-negative early breast cancer.¹ The full data set of NATALEE (NCT03701334), which is the first phase 3 trial to show this type of activity in the stage II/III population at risk of recurrence, including those with no nodal involvement, will be released during the meeting.

“Adjuvant abemaciclib [Verzenio] is now standard of care along with endocrine therapy for high-risk early-stage HR-positive breast cancer patients, but can be difficult for some patients to tolerate. If NATALEE shows ribociclib to be an appropriate alternative in this setting, it will change the standard of care, allowing for a choice between CDK4/6 inhibitors in this vulnerable patient population, and likely allowing for more patients to take advantage of and gain benefit from these drugs in the high-risk early-stage setting.”

Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: DESTINY-PanTumor02 interim results (LBA3000)

In the phase 2 DESTINY-PanTumor02 trial (NCT04482309), fam-trastuzumab deruxtecan-nxki (Enhertu) is being explored in previously treated patients with locally advanced, unresectable, or metastatic HER2-expressing solid tumors that are ineligible for curative treatment. Interim results, which will zero in on response data, will be presented during the meeting. An announcement in March 2023 stated that the trial had met the prespecified criteria for objective response rate and duration of response.²

“Trastuzumab deruxtecan has revolutionized the treatment of [patients with] HER2-positive (and HER2-low) metastatic breast cancer, and this trial showing its efficacy in other types of HER2-positive cancers such as biliary tract, cervical, endometrial, ovarian and pancreatic cancer represents a huge, if easily, step forward for patients with these diseases.”

Effect of a telephone-based weight loss intervention on weight at 12 months in women with early breast cancer: results from the Breast Cancer Weight Loss (BWEL) trial (Abstract 12001)

This Alliance for Clinical Trials in Oncology study (NCT02750826) evaluated the impact of a weight loss intervention, conducted via phone, in women with early breast cancer and concluded that it was associated with clinically meaningful weight loss in patients with breast cancer who are overweight or obese. Investigators noted that further follow-up will determine whether disease outcomes will be improved, as well as enhanced weight loss in younger patients and Black patients, with this intervention.

“We know that being overweight or obese is associated with worse outcomes in early breast cancer. This telephone- and web-based intervention was successful at helping early-stage breast cancer patients lose weight at 12 months, and if this could be replicated on a larger scale, could not only help prevent breast cancer recurrences, potentially, but reduce the impact of other obesity-associated diseases as well.”

A cognitive behavioral digital therapeutic for anxiety and depression in patients with cancer: a decentralized randomized controlled trial (Abstract 1507)

The double-blind, randomized, controlled trial (NCT05227898) showed that patients with nonmetastatic, stage I to III hematologic cancers who used AttuneTM as a digital therapeutic, which is a 10-module digitized Cognitive Behavioral Stress Management app, had a greater reduction of anxiety and depression compared with the CerenaTM health education app. In the abstract, the benefit in improvement of symptoms was seen over 12 weeks and at end of study.

“Cancer patients experience high rates of anxiety and depression, and lack of access to mental health providers and psychological interventions is a very difficult problem. This study showed that participation in a digitized cognitive behavioral program significantly reduced anxiety and depression compared to a sham. This suggests that we may be able to harness technology to help compensate for the shortage of mental health providers and manage anxiety and depression in the vulnerable populations we see.”

HODGKIN LYMPHOMA, GLIOMA, AND RECTAL, LUNG, AND KIDNEY CANCERS

Eddy Saad, MD

Eddy Saad, MD, postdoctoral genitourinary oncology research fellow at Dana-Farber Cancer Institute; and

Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, medical director, International Strategic Initiatives, at Dana-Farber Cancer Institute; and Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School

PROSPECT: A randomized phase III trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation, followed by total mesorectal excision (TME) for treatment of locally advanced rectal cancer (LARC; Alliance N1048; Abstract LBA2)

The late-breaker abstract for PROSPECT (NCT01515787) will showcase whether or not the selective addition of neoadjuvant radiation can be spared in this patient population with rectal cancer, which can lead to further adverse events on patients.

“This phase 3 trial aims to assess whether selected patients with locally advanced rectal cancer could be spared neoadjuvant radiation therapy (in addition to chemotherapy) prior to total mesorectal excision.”

Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR‑mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC; LBA3)

Osimertinib (Tagrisso), a third-generation EGFR TKI, was previously granted accelerated approval by the FDA in this setting after demonstrating encouraging disease-free survival (DFS) outcomes, which was the primary end point, compared with placebo in this early-stage patient population with EGFR-mutant NSCLC. Overall survival (OS) is a key secondary end point of the phase 3 trial. According to a news release issued in March 2023, this is the first phase 3 study to show an OS benefit in this lung cancer setting.³

“After demonstrating a significant improvement in DFS, adjuvant osimertinib is expected to show a strong OS benefit in patients with EGFR-mutated NSCLC.”

INDIGO: a global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation (LBA1)

Vorasidenib (AG-881), defined as a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes, is being compared with placebo in INDIGO. An announcement in March 2023 from the interim analysis, which is to be presented during the meeting, stated that the agent demonstrated a significant and clinically meaningful improvement in progression-free survival vs placebo in a patient population that has seen few therapies move the needle.⁴

“This is a phase III trial assessing the efficacy of vorasidenib [IDH1/2 inhibitor] in patients with recurrent or residual IDH1-positive glioma, with an expected improvement in both progression-free survival and time to next intervention.”

SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin (BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL; LBA4)

The anticipated head-to-head comparison of the PD-1 inhibitor nivolumab (Opdivo) vs the antibody-drug conjugate brentuximab vedotin (Adcetris) will unveil the optimal of the 2 approaches for this patient population. As background, the FDA granted approval in March 2018 to brentuximab vedotin in combination with doxorubicin, vinblastine, and as a frontline treatment for adult patients with stage III/IV classical Hodgkin lymphoma.

“This phase III trial compares the combination of nivolumab plus AVD to brentuximab vedotin plus AVD in the treatment of [patients with] advanced-stage classical Hodgkin lymphoma, with a progression-free survival [PFS] primary endpoint expected to be met.”

Toni K. Choueiri, MD

Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study (Abstract LBA4500)

The addition of the PD-L1 inhibitor atezolizumab (Tecentriq) to the multikinase inhibitor cabozantinib (Cabometyx) did not meet the primary end point of PFS in this patient population of metastatic RCC who progressed during or after an immune checkpoint inhibitor, either alone or as part of a combination regimen, according to a news release issued in March 2023.⁵ The safety profile of the combination was found to be in line with the individual adverse effect profile of each agent.

“This phase 3 trial is the first to investigate the role of anti-PD1/L1 rechallenge in patients with mRCC who previously progressed on [immunotherapy]. Results are expected to be negative.”

GASTROINTESTINAL CANCER

Tanios S. Bekaii-Saab, MD

Tanios S. Bekaii-Saab, MD, leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center, medical director of the Cancer Clinical Research Office, vice chair and section chief for medical oncology in the Department of Internal Medicine, Mayo Clinic.

HER2 testing in the MOUNTAINEER trial: analysis of treatment response based on central HER2 assessment using IHC/ISH and NGS. (Abstract 3528)

The FDA approved tucatinib (Tukysa) plus trastuzumab (Herceptin) in January 2023 for the treatment of patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer (mCRC) that progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.6 The decision was based on efficacy findings from the MOUNTAINEER trial (NCT03043313), in which patients were tested for HER2 through at least immunohistochemistry (IHC), ISH (in situ hybridization), and/or next-generation sequencing (NGS) testing.

In the MOUNTAINEER analysis being presented at ASCO, investigators will showcase results of central HER2 testing across varying platforms and response to the combination regimen based on their HER2 status.

“The combination of tucatinib and trastuzumab was recently approved by the FDA for the treatment of patients with refractory HER2-positive metastatic colorectal cancer. The analysis of treatment response based on central assessment using IHC/ISH and NGS (liquid or tissue) suggest that any of these testing platforms can be used to identify patients who are eligible for and will benefit from HER2 targeted therapy.”

Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study (Abstract 3501)

The phase 2 DESTINY-CRC02 trial (NCT04744831) in HER2-positive metastatic colorectal cancer (mCRC) is testing trastuzumab deruxtecan at 2 doses: 5.4 mg/kg and 6.4 mg/kg. Previously, the agent showed activity in the HER2-positive CRC population in the DESTINY-CRC01 (NCT03384940) when given at the 6.4-mg/kg every-3-week dosing schedule.7

“T-DXd was found to be active in patients with refractory HER2-positive mCRC. At 6.4 mg/kg, T-DXd was found to exhibit promising activity at the expense of significant toxicities. DESTINY-CRC02 compared a lower dose at 5.4 mg/kg [with] the 6.4-mg/kg dose suggesting that the lower dose is at least as active with an improved toxicity profile. This study suggests that T-DXd at 5.4 mg/kg should be the new standard in this patient population. Additional findings suggest that unlike other HER2-targeted therapies, T-DXd is active regardless of RAS mutational status.T-DXd is again shown to retain activity following exposure to other HER2-targeted therapies and, therefore, would make this an option for patients who failed prior tucatinib and trastuzumab or other direct targeted strategies.”

Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): 12- and 18-month survival rates from the phase 3 NAPOLI 3 trial (4006).

The regimen of liposomal irinotecan, + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) is being compared with nab-paclitaxel and gemcitabine in the frontline setting of metastatic pancreatic ductal adenocarcinoma. During the meeting, 12- and 18-month survival rates will be unveiled, as well as safety data about both regimens.

“This is the first study to suggest that a triplet regimen with liposomal irinotecan, 5-FU and oxaliplatin (NALIRIFOX) improves overall outcomes with a longer follow-up now vs a doublet with gemcitabine and nab-paclitaxel [GP]. The toxicity profile is relatively expected and consists of additional GI toxicities and less neuropathy. This establishes NALIRIFOX as a preferred standard over GP for eligible patients. The main question that remains is whether FOLFIRINOX would exhibit similar benefits. While likely but without a direct comparison, it would be difficult to conclusively make that assumption. Thankfully, a study from Canada (PASS01; NCT04469556) will directly compare FOLFIRINOX to GP and may help answer (albeit indirectly) this question.”

Tucatinib and trastuzumab for previously treated HER2-positive metastatic biliary tract cancer (SGNTUC-019): a phase 2 basket study (Abstract 4007).

This combination of tucatinib and trastuzumab is now being tested in another gastrointestinal cancer, this time in the second-line biliary tract cancer (BTC) setting for those who progressed following at least 1 line of systemic therapy for their metastatic disease. Response and safety outcomes from this cohort of the basket study (NCT04579380) will be presented during the meeting.

“HER2 amplifications are main drivers for a subset of patients with BTC. In this study (SGNTUC-019), the combination of tucatinib and trastuzumab (TT) was found to be highly active with durable responses and was well tolerated in patients with previously treated HER2-positive metastatic BTC. This study establishes TT as a potential chemotherapy-free option for patients with HER2-positive BTC who fail prior therapy.”

Results from the pivotal phase (Ph) 2b HERIZON-BTC-01 study: zanidatamab in previously treated HER2‑amplified biliary tract cancer (BTC; Abstract 4008).

The international, phase 2b trial (NCT04466891) is testing the HER2-directed bispecific antibody zanidatamab in HER2-amplified, locally advanced unresectable or metastatic BTC. Data presented during the 2023 ASCO Annual Meeting will comprise response rates and adverse events.

“HER2 amplifications are main drivers for a subset of patients with BTC. In this study (HERIZON-BTC-01), the HER2 bispecific antibody zanidatamab was found to be highly active with durable responses and was well tolerated in patients with previously treated HER2-positive metastatic BTC. If approved, this agent should be considered as a potential chemotherapy-free option for patients with HER2-positive BTC who fail prior therapy.”

References

1. Novartis Kisqali® Phase III NATALEE trial meets primary endpoint at interim analysis demonstrating clinically meaningful benefit in broad population of patients with early breast cancer. News release. Novartis. March 27, 2023. Accessed May 31, 2023. https://www.novartis.com/news/media-releases/novartis-kisqali-phase-iii-natalee-trial-meets-primary-endpoint-interim-analysis-demonstrating-clinically-meaningful-benefit-broad-population-patients-early-breast-cancer
2. AstraZeneca and Daiichi Sankyo’s Enhertu met prespecified criteria for objective
   response rate and duration of response. News release. AstraZeneca. March 6, 2023. Accessed May 31, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/enhertu-destiny-pantumor02-shows-positive-results.html#!
3. Tagrisso demonstrated strong overall survival benefit in the ADAURA Phase III trial for adjuvant treatment of patients with early-stage EGFR-mutated lung cancer. News release. AstraZeneca. Published March 9, 2023. Accessed May 31, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-demonstrated-strong-overall-survival-benefit-in-the-adaura-phase-iii-trial.html
4. Servier's pivotal phase 3 INDIGO rial investigating vorasidenib in IDH-mutant low-grade glioma meets primary endpoint of progression-free survival (PFS) and key secondary endpoint of time to next intervention (TTNI). News release. Servier. March 14, 2023. Accessed March 14, 2023. https://www.prnewswire.com/news-releases/
5. Exelixis provides update on phase 3 CONTACT-03 trial evaluating cabozantinib in combination with atezolizumab in patients with previously treated advanced kidney cancer. News release. Exelixis. Published March 2, 2023. May 31, 2023. https://ir.exelixis.com/news-releases/news-release-details/exelixis-provides-update-phase-3-contact-03-trial-evaluating
6. Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. January 19, 2023. Accessed June 1, 2023. https://www.businesswire.com/news/home