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RLY-2608 in combination with fulvestrant (Faslodex) generated clinically meaningful progression-free survival (PFS) outcomes and a favorable safety profile in heavily pretreated patients with 

-mutated, hormone receptor (HR)–positive, HER2-negative, locally advanced or metastatic breast cancer, according to findings from the first-in-human, phase 1 ReDiscover trial (NCT05216432).

At a median follow-up of 7.5 months, patients with 

-mutated, HR-positive, HER2-negative metastatic disease without 

 co-mutations who received RLY-2608 at the recommended phase 2 dose (RP2D) of 600 mg twice daily plus fulvestrant (n = 52) achieved a median PFS of 9.2 months regardless of kinase mutation status. Among those with kinase mutations, the median PFS was 10.3 months. The clinical benefit rate was 57% across all 35 patients evaluable for clinical benefit in the overall population.

Among patients with measurable disease who received RLY-2608 at the RP2D (n = 30), the overall response rate (ORR) was 33% (n = 10) in the entire population regardless of kinase mutation status. All responses were partial responses (PRs); 8 were confirmed, 1 was confirmed after the data cutoff date, and 1 was unconfirmed in an ongoing patient. In the entire population, 73% of patients experienced tumor reductions. Treatment with RLY-2608 at the RP2D produced an ORR of 53% in patients with measurable disease and a kinase mutation (n = 8). All responses were PRs; 7 were confirmed, and 1 was confirmed after the data cutoff date.

“These interim data suggest that by selectively targeting mutant 

, RLY-2608 has the potential to offer a level of benefit to patients that has not previously been possible with existing non-selective medicines, while also having significantly less toxicity,” Don Bergstrom, MD, PhD, president of Research and Development at Relay Therapeutics, stated in a news release. “We are very encouraged to see that RLY-2608 [plus] fulvestrant led to clinically meaningful progression-free survival in heavily pretreated patients with 

-mutated, HR-positive, HER2-negative metastatic breast cancer. We will move quickly to share these data with regulators and align on the design of a pivotal study, which we anticipate starting in 2025.”

The ongoing ReDiscover trial is investigating the safety, tolerability, pharmacodynamics, pharmacokinetics, and preliminary antitumor activity of RLY-2608 as monotherapy in patients with advanced solid tumors, as well as in combination with fulvestrant with or without ribociclib (Kisqali) or atirmociclib (PF-07220060) in patients with advanced breast cancer.2 At an interim data cutoff date of August 12, 2024, 118 patients were enrolled in the dose-escalation and -expansion portions of the RLY-2608 plus fulvestrant arm across all dose levels. This included 64 patients at the RP2D (dose-escalation, n = 17; dose-expansion, n = 47).1 Of those patients, 31 harbored a kinase mutation, and 33 harbored a non-kinase mutation. In total, 12 patients displayed 

 co-mutations and were excluded from the efficacy analysis to align with the currently proposed pivotal population.

All patients across dose levels had received at least 1 prior CDK4/6 inhibitor and at least 1 prior endocrine therapy. Of the patients who received the RP2D, 45% had received at least 2 prior lines of therapy, 52% had received a prior selective estrogen receptor degrader, and 25% had received prior chemotherapy or an antibody-drug conjugate. Furthermore, 59% of patients had visceral metastases and 34% of patients had a body mass index of at least 30 and/or hemoglobin A1c levels of at least 5.7%.

The news release noted that RLY-2608 plus fulvestrant was generally well tolerated across dose levels and that most adverse effects (AEs) were low grade, treatment-related, manageable, and reversible. At the RP2D, the median dose intensity was 95%; 2 patients discontinued treatment due to AEs (grade 1 pruritus, n = 1; grade 1 nausea and loss of appetite, n = 1). Most instances of hyperglycemia were grade 1; 1 patient had grade 3 hyperglycemia, and no instances of grade 4 or 5 hyperglycemia were reported. Overall, 25% of patients had a grade 3 treatment-related AE (TRAE), and no grade 4 or 5 TRAEs were observed.

The dose-escalation portion of the ReDiscover arm is currently testing biologically active doses of RLY-2608 plus fulvestrant and ribociclib and is on track to identify a dose of the agent that can be combined with a full dose of ribociclib. Initial safety data from this arm are expected to read out in the fourth quarter of 2024, and investigators plan to initiate dose-expansion cohorts in this arm in the first half of 2025. Additionally, initiation of the ReDiscover arm investigating RLY-2608 plus fulvestrant and atirmociclib is expected by the end of 2024.

An abstract with data from ReDiscover has been submitted for presentation at the 2024 San Antonio Breast Cancer Symposium.

Relay Therapeutics announces positive interim data for RLY-2608 demonstrating clinically meaningful progression free survival. News release. Relay Therapeutics, Inc. September 9, 2024. Accessed September 9, 2024. https://ir.relaytx.com/news-releases/news-release-details/relay-therapeutics-announces-positive-interim-data-rly-2608

First-in-human study of mutant-selective PI3Kα inhibitor, RLY-2608, as a single agent in advanced solid tumor patients and in combination with fulvestrant in patients with advanced breast cancer. ClinicalTrials.gov. Updated June 6, 2024. Accessed September 9, 2024. https://clinicaltrials.gov/study/NCT05216432

Articles

RLY-2608 plus fulvestrant generated clinically meaningful PFS outcomes in PI3Kα-mutated, HR-positive, HER2-negative advanced or metastatic breast cancer.



RLY-2608/Fulvestrant Yields Early Clinical Activity in PI3Kα-Mutated, HR+/HER2–Breast Cancer

Ongoing advances in immunotherapies and increasingly precise targeted therapies have shaped an optimistic and encouraging outlook for cancer care in 2024. Yet for the first time in history, the US is predicted to hit a new, sobering cancer milestone: More than 2 million people are estimated to be diagnosed with cancer in 2024 (nearly 5500 new cases per day), according to the American Cancer Society’s annual outlook report.

The number gives rise to concern because, despite innovations in care, significant challenges remain, partic- ularly in overcoming long-established health disparities that prevent equal access to diagnostic care, standard-of- care therapies, and novel treatments. For example, more than 90% of drug trial participants identify as White. It is a statistic that is of deep concern to clinicians every- where, but it is especially concerning to those in South Florida, where most of the population has origins in Latin America and the Caribbean. 

The problem has garnered widespread attention, and the FDA’s latest guidance documents recommend that study designers and investigators discuss plans for increasing diversity early in the process.

 Without adequate representation of underrepresented populations in a clinical trial, the postapproval requirements of a drug may be affected, the FDA reports.

Baptist Health Miami Cancer Institute launched the Center for Equity in Cancer Care & Research to address this issue. Its mission is to identify and decrease disparities in cancer care and improve participation of underrepresented populations in clinical trials. With approximately 200 trials open at the institute, part of the center’s goal is to ensure that the latest advances are reaching all patients with cancer.

However, we know cancer incidence is not the same across all ethnicities; consider the following: 

The incidence of major cancers (eg, lung, colorectal, kidney) among Black men is higher than for White men.

Black women have a higher incidence of cancers with low survival, such as stomach and pancreatic cancer. 

Black women are nearly twice as likely to die of uterine cancer as White women.

The incidence of prostate cancer is 70% higher in Black men than in White men, and mortality rates in Black individuals are twice as high compared with those of White individuals. 

In general, Hispanic individuals are less likely to be diagnosed with cancer than White individuals but have a higher incidence of specific types of cancer. For example, Hispanic men and women have nearly double the incidence and mortality rates of liver and stomach cancers compared with White individuals.

In terms of clinical trial participation, Miami Cancer Institute is working closely with patient navigators, community health workers, and local faith-based organi- zations to educate people and reduce some of the cultural mistrust that exists among underrepresented populations.

In addition to boosting diverse participation in clinical trials by 50% over the next 2 to 3 years and increasing numbers in cancer screenings, the Center for Equity in Cancer Care & Research is taking a close look at the many social determinants of health that can negatively affect outcomes. One area we are continuing to develop is our Spanish-language materials because approximately 20% of the institute’s patients indicate that they do not read English well enough to understand consent forms. 

The institute is also working on increasing screening numbers of cancer detection in alignment with President Joe Biden’s Cancer Moonshot program, which aims to decrease the age-adjusted cancer death rate by 50% in the next 25 years.

 The American Lung Association’s State of Lung Cancer 2023 report stated that Florida’s lung cancer screening rate of 2.4% was far below the national average of 4.5%.

To build awareness and encourage those at highest risk to undergo lung cancer screenings, Baptist Health and the American Lung Association joined forces in 2021 as part of the Saved by the Scan campaign.

 The partnership was the first between a large health care organization and the American Lung Association, and it produced encouraging results. The campaign resulted in a 55% increase in lung cancer screenings, using low-dose CT scans. Additionally, Baptist Health has partnered with the LUNGevity Foundation, the nation’s leading lung cancer–focused nonprofit organization, to set up a screening program centered on the Hispanic/Latino community.

As we work together to focus our efforts to provide equal access to high-quality care for all, the cancer community pushes forward on cutting-edge trials and advances that are leading to longer survival, improved quality of life, and cures. There is every reason to have an optimistic outlook for cancer care in 2024.

Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820

Diversity plans to improve enrollment of participants from underrepresented racial and ethnic populations in clinical trials; draft guidance for industry; availability. FDA. April 13, 2022. Accessed March 5, 2024. bit.ly/3LznYiE 

Fernandez J. Cancer care outlook 2024: more treatment advances and more minority involvement in clinical trials. Baptist Health South Florida blog. February 5, 2024. Accessed March 5, 2024. bit.ly/4cK4Vy

NIH study outlines opportunities to achieve President Biden’s Cancer Moonshot goal of reducing cancer death rates in the United States. News release. National Institutes of Health. April 17, 2023. Accessed March 5, 2024. bit.ly/4cCyrG9

American Lung Association. State of Lung Cancer 2023. Accessed March 5, 2024. bit.ly/4cLDZhE

Manmeet S. Ahluwalia, MD, MBA, FASCO, discusses ongoing efforts to overcome challenges in cancer care in 2024. 

Cancer Care in 2024: Striving to Overcome the Challenges

As an emerging and growing specialty, oral medicine is still largely inaccessible to many patients with cancer, as well as patients with autoimmune or inflammatory conditions. Commonly, patients with these health concerns experience poor quality of life due to mouth sores, pain, burning, mouth dryness, or other oral conditions. However, we know from experience that with appropriate and timely identification of potential problems, we can help eliminate or reduce the incidence and severity of complications attributed to cancer therapy and illness.

Over 2 million new cancer cases are expected to be diagnosed in the US in 2024.

 Among all patients with cancer, approximately 40% who receive chemotherapy, 80% who undergo a stem cell transplant, and 90% of those who received radiation for head and neck malignancies experience oral complications.

When you consider the number of patients with cancer—along with the conservatively estimated 23.5 million Americans at increased risk for oral health problems due to autoimmune diseases such as lupus, rheumatoid arthritis, Type 1 diabetes, celiac disease, and psoriasis— the need to improve access to oral medicine specialists is clear. It’s also necessary to broaden the understanding of how we can be of benefit to patients.

As the only board-certified cancer center–based oral medicine specialist in South Florida, I care for patients with problems of the lips, roof of the mouth, tongue, salivary glands, and the inner lining of the cheeks. At Miami Cancer Institute, we treat oral lichen planus, aphthous ulcers, dry mouth, jaw osteonecrosis, burning mouth syndrome, temporomandibular disorders, and oral infections (herpes simplex virus and candidiasis), as well as oral precancers, such as leukoplakia, and oral toxicities of targeted therapies and immunotherapies.

Procedures performed include biopsy of oral lesions, intralesional steroid injections, nonsurgical sequestrectomy (of the jawbone), topical and systemic medical treatments, and trigger point injections.

Dental evaluations are particularly important for patients with cancer who are scheduled for bone marrow transplants or head and neck radiation, as an issue in this area during or after treatment can lead to severe complications or death. We are working to build our relationships with the local dental community and have developed a dental education packet for patients to bring to their dentists to obtain x-rays or clearance prior to starting treatment for head and neck cancers.

We urge anyone who has a sore, bump, or colored lesion in the mouth that doesn’t go away, or a dry or painful mouth or canker sore that doesn’t heal, to seek the care of an oral medicine specialist. It’s also our responsibility to continue to educate the public about the importance of receiving the human papillomavirus vaccine because the virus is responsible for the majority of cases of oropharyngeal cancer.

Working together, dentists, primary care providers, and specialists can deliver the best quality care to our medically complex patients, improving quality of life and preventing life-threatening complications.

Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/ caac.21820

Leukemia & Lymphoma Society. Dental and Oral Complications of Cancer Treatment Facts. September 2016. Accessed July 18, 2024.xw bit.ly/3Y9wuMV

Alessandro Villa, DDS, PhD, MPH, discusses the importance of oral medicine in cancer treatment.

The Importance of Oral Medicine in Cancer: Evaluation and Treatment

The issue of financial toxicity in cancer care is widespread, with approximately 50% of patients with cancer facing economic hardship related to their disease and/or treatment.

 In response, investigators are developing preventive interventions that can be implemented at scale to identify patients most at risk for financial toxicity and offer them assistance.

“The National Cancer Institute defines financial toxicity as the problems that a patient has related to the cost of their care, and they highlight that patients with cancer are more likely to have problems with financial toxicity [compared] with [those with] other chronic diseases,” Fumiko Chino, MD, an assistant attending radiation oncologist at Memorial Sloan Kettering Cancer Center in Middletown, New Jersey, said in an interview with 

. “Financial toxicity is best studied and best categorized within cancer. Our treatments are intense and expensive. Even into survivorship, [patients] can still have chronic adverse effects, [such as] peripheral neuropathy, durable costs, or career effects related to treatment.”

Feasibility of Financial Toxicity Screening

During the 2024 American Society of Clinical Oncology Annual Meeting, Chino and coauthors presented findings from a financial toxicity and health-related social risks screening program that was implemented at an urban comprehensive cancer center from September 2022 to August 2023. The study included patients who received treatment for breast, gynecologic, gastrointestinal, or thoracic cancer.

The authors employed a validated screening tool, the 11-item Comprehensive Score for Financial Toxicity (COST) tool, which assessed financial toxicity risk on a scale of 0 to 44. Lower scores indicated a patient was at a higher risk for financial toxicity. Additionally, patients responded to a health-related social risks checklist that aimed to identify food, housing, medicine, and transportation insecurity. Patients could respond to the survey via an online portal every 4 months and a COST score of 20 or less or any endorsement of a health-related social risks checklist item was considered a positive screen; these patients were offered a referral for financial assistance counseling.

“We wanted to capture what’s happening with our patients in terms of financial toxicity and intervene early in order to stop the downstream effects that we know financial toxicity can drive,” Chino explained. “Financial toxicity can compromise cancer outcomes. Patients may skip scans or may just skip treatment altogether.”

Study results demonstrated that patients who completed screening (n = 28,606) screened positive at a rate of 32%. Patients indicated they were experiencing housing, transportation, food, and medicine insecurity at rates of 25%, 24%, 23%, and 21%, respectively. Most patients who screened positive (60%) also had a COST score of 20 or less.

However, just 51% of patients who screened positive and were offered referral for counseling accepted it. Patients who accepted help cited out-of-pocket costs (68%), nonmedical expenses (39%), concerns about insurance (23%), and medication costs (18%) as financial concerns related to their cancer treatment. Patients with worse financial toxicity (β = 1.15; 95% CI, 1.13-1.16), more self-identified health-related social risks (β = 1.19; 95% CI, 1.13-1.25), or younger age (β = 1.01; 95% CI, 1.008-1.02), and those who were not White (β = 1.70; 95% CI, 1.49-1.93) were more likely to accept referral to the financial assistance team.

Chino and her coauthors concluded that screening for financial toxicity and health-related social risks was feasible. However, they noted that additional work is needed to better integrate the patient voice in how to offer and provide financial toxicity assistance. In addition, including financial navigators in real-world workflows would be helpful, they said.

“[Our findings] indicate that screening is not enough; we need to make sure that we’re meeting people where they are and finding the best way of providing help,” Chino said. “One of the benefits of doing this type of research at scale—almost 30,000 patients had completed the screening—is to tease out some of that important information.”

Taking a Step Beyond Screening to Tackle Financial Toxicity

There are several randomized studies and pilot programs examining other interventions to address and mitigate the impact of financial challenges that patients with cancer can experience. “There’s a lot of work to be done. For example, there are education initiatives [concerned with] improving financial and health insurance literacy for patients. How do we educate [patients] to better advocate for themselves? How can we deliver care more efficiently?” Chino said.

In a randomized study (NCT03572374) being conducted at multiple Memorial Sloan Kettering Cancer Center sites in the United States, investigators are evaluating the impact of breast cancer treatment on patients’ employment status. The investigators are evaluating an early version of a mobile app that is designed to aid patients in maintaining their jobs during and following treatment.

The app, known as TEAMWork, uses a 2-pronged approach that focuses on interactions with the patient’s employer and the clinical team. The app’s menu includes videos featuring actors demonstrating how to request accommodations from an employer, templates for letters to request accommodations, links to relevant websites, legal information, and contact information of law firms willing to provide pro bono assistance. The study is comparing TEAMWork with an informational booklet containing similar information to the app but without the multimedia components. The primary objective of the study is to evaluate how many patients are still employed after 2 years.

In another randomized clinical trial, CAFÉ (NCT05018000), investigators are examining the impact of a novel financial navigation intervention on the financial hardship and health-related quality of life of patients who have received a cancer diagnosis within 120 days of enrollment. The CAFÉ intervention consists of patients meeting with a financial navigator who provides them with a comprehensive assessment of their financial needs and questions, as well as helping them plan for paying household expenses in addition to out-of-pocket treatment costs. The financial navigator also will offer proactive personalized referrals to community organizations and resources to further aid patients.

The CREDIT study (NCT04960787) is building upon the use of financial navigators by adding an online training component. In the study, patients will meet with a Consumer Education and Training Services counselor and a Patient Advocate Foundation case manager for approximately 1 hour every month for 6 months. Additionally, patients will complete questionnaires covering education, employment, finances, insurance, and quality of life, as well as have their credit reports assessed at baseline, 3 months, 6 months, and 1 year. Patients will receive financial literacy training via online videos and will have the option to have their spouse or caregiver participate.

“Opening the conversation with patients is an important step to understand how their treatment burden is affecting their lives,” Chino said in conclusion. “Knowing details [such as] if a patient works full time vs part time, or if they have paid time off, makes a huge difference in the treatment recommendations because I’ll use that as an opportunity to have a discussion based on their specific needs. For some patients, it’s not a big deal to take off 2 months for treatment. Other patients don’t have that capacity. Even a simple thing such as streamlining treatments can have a large impact on combating financial toxicity.”

Smith GL, Banegas MP, Acquati C, et al. Navigating financial toxicity in patients with cancer: a multidisciplinary management approach. 

. 2022;72(5):437-453. doi:10.3322/caac.21730

Thom B, Aviki EM, Chino F. Implementing financial toxicity and health-related social risks screening and referral. 

. 2024;42(suppl 16):11006. doi:10.1200/JCO.2024.42.16_suppl.11006

Talking to employers and medical staff about breast cancer treatment and your job. ClinicalTrials.gov. Updated March 25, 2024. Accessed July 10, 2024. https://clinicaltrials.gov/study/NCT03572374

Cancer Financial Experience (CAFE). ClinicalTrials.gov. Updated April 19, 2024. Accessed July 10, 2024. https://clinicaltrials.gov/study/NCT05018000

Financial navigation program to improve understanding and management of financial aspects of cancer care for patients and their spouses (CREDIT). ClinicalTrials.gov. Updated May 6, 2024. Accessed July 10, 2024. https://clinicaltrials.gov/study/NCT04960787

Investigators are developing preventive interventions to identify patients most at risk for financial toxicity and offer them assistance.

Optimize Interventions to Get a Step Ahead of Financial Toxicity in Cancer Care

The transmembrane glycoprotein KIM-1, expressed by injured renal proximal tubular cells and renal cell carcinoma (RCC) cells, has emerged as a potential biomarker and all eyes are on next steps for the marker following encouraging exploratory analysis data presented at the 2024 American Society of Clinical Oncology Annual Meeting.

Exploratory findings came from the phase 3 IMmotion010 trial (NCT03024996), which in its primary analysis failed to show prolonged disease-free survival (DFS) with adjuvant atezolizumab (Tecentriq) vs placebo in patients with RCC who had an increased risk of disease recurrence.

Data from the retrospective, exploratory analysis of the trial demonstrated that high postnephrectomy KIM-1 serum levels were associated with worse DFS overall. The findings, although exploratory, provided a welcome signal in a disease in which response biomarkers have been lacking. Results showed that patients with KIM-1–high status at baseline (n = 300) experienced a median DFS of 35.88 months compared with 57.23 months among those with KIM-1–low status at baseline (n = 452; HR, 1.75; 95% CI, 1.40-2.17).

 A baseline KIM-1 level of 86 pg/mL was identified by investigators as the optimized threshold for determining KIM-1–high vs KIM-1–low subgroups.

“Now that there are approved adjuvant therapies [in high-risk RCC]—pembrolizumab [Keytruda] is approved—the question is, ‘Can [KIM-1] be added to current risk stratification tools and nomograms to improve or enrich the group of patients who are at highest risk of recurrence?’” Robert Uzzo, MD, MBA, FACS, said in an interview with 

. “Right now, we offer adjuvant pembrolizumab to patients with a clinical high risk of recurrence, but we realize that not all patients are going to benefit from it. If we could take our current risk stratification models and nomograms and add KIM-1 to [them to determine] the group of patients who would benefit the most, that would be a big win.”

In IMmotion010, patients with high baseline KIM-1 serum levels experienced an improvement in DFS when treated with atezolizumab (n = 151) vs placebo (n = 149). The median DFS was not estimable (NE) for patients with high baseline KIM-1 serum levels treated with atezolizumab compared with 21.16 months for those given placebo (HR, 0.72; 95% CI, 0.52-0.99). In the KIM-1–low subgroup, the median DFS was 57.23 months for those treated with atezolizumab (n = 229) and was NE for those given placebo (n = 223; HR, 1.12; 95% CI, 0.88-1.63) (

“There’s [also] still not uniform consensus on who the patients are [with RCC who are] most suitable for adjuvant therapy. Despite the DFS and overall survival [OS] benefit with pembrolizumab, there’s still some debate in the field, and different doctors who know a lot about this, do things differently, which tells you it’s not uniform,” Brian Rini, MD, said in an interview with 

. “What if you have a patient who’s technically high risk, but only has a 30% risk of recurrence, [and] you’re exposing them to potential lifelong or life-threatening toxicities [with adjuvant therapy]?”

Rini added that he tends “to give adjuvant pembrolizumab [to patients at] the higher end of the phase 3 KEYNOTE-564 [NCT03142334] risk [criteria], but other doctors give it to everybody, and other doctors don’t give it to anybody. If this could at least help refine that, remove some of those lower-risk patients or include them appropriately, much like [with] circulating tumor DNA, the treating physician would feel a lot better about exposing that patient to the risk [of adverse effects].”

Patients in the KIM-1–high subgroup were less likely to experience an on-treatment increase in KIM-1 levels with atezolizumab (9%) vs placebo (15%; 

 < .0001), according to findings from IMmotion010. In the KIM-1–low subgroup, rates of increased KIM-1 levels were 16% vs 14%, respectively (

 = .57). Investigators noted that an on-treatment increase in KIM-1 level was associated with worse median DFS in patients in both the KIM-1–high and KIM-1–low subgroups.

“It would be great to see data in that [adjuvant] setting [and] to understand whether it can be complementary to our risk stratification models. To estimate risk of recurrence for an individual patient, you look at T stage and N stage, grade, and perhaps necrosis,” Rini said. “But those models are 2 to 3 decades old, and they’re not very good. You can put the same patient data into 3 different models and get 3 very different estimates of recurrence, which tells you none of them are very good [or] accurate.”

Additionally, patients with KIM-1–high disease who had an increase in KIM-1 level on-treatment with atezolizumab (n = 12) experienced a median DFS of 14.8 months, whereas median DFS was NE for those with no increase on atezolizumab (n = 126; HR, 1.68; 95% CI, 0.77-3.69). In the placebo arm, these figures were 4.8 months (n = 36) vs 45.4 months (n = 105) in patients with and without on-treatment increases in KIM-1 (HR, 3.53; 95% CI, 2.24-5.58), respectively. Patients treated with atezolizumab with KIM-1–low disease who experienced an increase in KIM-1 level on-treatment (n = 34) experienced a median DFS of 11.5 months vs survival length that was NE among those with no increase (n = 179; HR, 3.56; 95% CI, 2.21-5.75). These figures were 29.0 months in 28 patients and NE in 179 patients who received placebo (HR, 2.51; 95% CI, 1.42-4.44), respectively.

Comparison of serum levels from the trial also showed that KIM-1 was the most significantly enriched circulating protein in recurrence vs baseline serum samples.

Could KIM-1 Distinguish Benign From Malignant Tumors?

“KIM-1 levels are currently being explored as a biomarker to identify kidney tumors and distinguish cancerous lesions from benign ones. That’s something you can’t currently do with a plasma test, urine test, or any imaging including PET scans. It’s only done on biopsy. If these findings hold up to be true, then this biomarker may very well change the way we make diagnoses of kidney cancer,” Uzzo said. “As a derivative to that, this could this be used for preoperative diagnosis of any large kidney mass prior to making treatment decisions, and if the test is robust enough it could even be used for smaller renal masses to help clarify current treatment dilemmas.”

Prenephrectomy plasma KIM-1 was associated with malignant pathology, worse metastasis-free survival, and risk of death in patients with renal masses, according to data from the prospective K2 trial and an academic biorepository published in a 

 study. Data from K2 making up cohort 1 of the study showed that plasma KIM-1 distinguished RCC vs benign masses with area under the receiver operating curve (AUC-ROC, 0.81; 95% CI, 0.76-0.86). Findings from cohort 2 including data from the academic biorepository revealed that plasma KIM-1 distinguished RCC vs benign masses in patients with clinical T1a RCC (AUC-ROC, 0.74; 95% CI, 0.67-0.80).

Further, a plasma KIM-1 cut point identified using data from cohort 2 showed a sensitivity of 92.5% and specificity of 60% for identifying RCC in cohort 1. Long-term follow-up data from cohort 1 revealed that higher prenephrectomy plasma KIM-1 was also associated with worse OS (multivariable HR, 1.31 per unit increase in log plasma KIM-1; 95% CI, 1.10-1.54).

“The most relevant and recent [data on KIM-1] are from 3 prospective studies—the adjuvant phase 3 ASSURE [NCT00326898] study with sorafenib [Nexavar] and sunitinib [Sutent] vs placebo, the phase 3 CheckMate 914 [NCT03138512] trial with ipilimumab [Yervoy]/nivolumab [Opdivo] or nivolumab vs placebo, and more recently IMmotion010 with atezolizumab vs placebo,” Rini said. “Each of those looked at KIM-1, which is a soluble protein at baseline, a couple of postnephrectomy time points, and recurrence roughly—not all the studies did it exactly the same way.”

In ASSURE, findings demonstrated that elevated plasma KIM-1 levels postnephrectomy were associated with worse DFS and OS in patients with resected high-risk RCC. Investigators noted that a Kaplan-Meier analysis revealed a trend toward worse OS for patients who had higher baseline KIM-1 levels (log-rank 

Findings from an exploratory post hoc analysis of CheckMate 914 published in 

 in March 2024 were in line with those of IMmotion010: When examining patients in the highest quartile of pretreatment KIM-1 level, DFS was improved with the combination vs placebo (HR, 0.60). However, unlike in IMmotion010 where an increase in KIM-1 levels on treatment was positively associated with higher DFS only in the investigational arm, an increase in KIM-1 levels in CheckMate 914 was associated with higher DFS rates in both the nivolumab plus ipilimumab and placebo arms.

However, IMmotion010 investigators noted that additional validation studies of the minimally invasive circulating biomarker are needed to confirm its utility for identifying minimal residual disease, predicting outcomes to checkpoint inhibitor therapy, and longitudinal monitoring of disease recurrence.

“There is currently no biomarker that helps us predict recurrence risks in kidney cancer, and there is no biomarker that can currently help us diagnose kidney cancer in a noninvasive way. The only way to do that is with biopsy or resection with their attendant risks. If we had that biomarker, it would fundamentally change the landscape of diagnosis, prognosis, and risk management,” Uzzo said. “KIM-1, where there have been very early studies in the past several years, is now coming to the fore as potentially the most promising biomarker in kidney cancer.”

Xu W, Puligandla M, Halbert B, et al. Plasma KIM-1 is associated with recurrence risk after nephrectomy for localized renal cell carcinoma: a trial of the ECOG-ACRIN Research Group (E2805). 

. 2021;27(12):3397-3403. doi:10.1158/1078-0432.CCR-21-0025

Albiges L, Bex A, Suárez C, et al. Circulating kidney injury molecule-1 (KIM-1) biomarker analysis in IMmotion010: a randomized phase 3 study of adjuvant (adj) atezolizumab (atezo) vs placebo (pbo) in patients (pts) with renal cell carcinoma (RCC) at increased risk of recurrence after resection.

. 2024;42(suppl 16):4506. doi:10.1200/JCO.2024.42.16_suppl.4506

Xu W, Gaborieau V, Niman SM, et al. Plasma kidney injury molecule-1 for preoperative prediction of renal cell carcinoma versus benign renal masses, and association with clinical outcomes. 

. Published online May 3, 2024. doi:10.1200/JCO.23.00699

Vemula SV, Xu W, Wang Y, et al. High serum kidney injury marker-1 and high baseline tumor PD-L1 protein expression levels are independently associated with treatment effect in adjuvant nivolumab plus ipilimumab vs placebo in localized clear cell renal cell carcinoma. 

. 2024;84(suppl 6):5151. doi:10.1158/1538-7445.AM2024-5151

Brian Rini, MD, and Robert Uzzo, MD, MBA, FACS, highlight the utility of the potential biomarker KIM-1 in renal cell carcinoma. 

The Noninvasive Biomarker KIM-1 Is Front and Center in RCC Investigations 

The acceleration of targeted therapy drug development has led investigators to home in on 

 G12C, as agents, such as sotorasib (Lumakras) and adagrasib (Krazati), are approved in colorectal cancer (CRC) for patients with the specific mutation. Tanios Bekaii-Saab, MD, noted that the “

 G12R, has been an area of recent investigation generating excitement. 

 mutations are present in approximately 40% of advanced CRCs, the 

 G12C mutation only occurs in approximately 3% of patients, whereas 

 Data from the National Cancer Institute indicated that the 

 G12D mutation is present in approximately 1 in 10 CRC cases and in more than 1 in 3 pancreatic cancers.

 Clinical trials are examining EGFR plus KRAS inhibition to target 

 G12C mutations in gastrointestinal (GI) cancers, and newer trials with RAS(ON) multiselective inhibitors are breaking ground as well.

“There is a lot more to come,” Bekaii-Saab noted on key clinical trials in GI cancer. “There are a number of these studies that are challenging us, clarifying, and complicating our landscape. A conference like the International Symposium of Gastrointestinal Oncology [ISGIO] in October summarizes the findings of the year, digests them, and gives the GI community oncologist a good [idea] of how to best practice in GI oncology.” 

The 2024 ISGIO conference occurring October 11-12 in Hollywood, Florida, will present the latest updates in GI cancer from a multidisci- plinary angle via case-based learning, debates, panel discussions, and didactic segments.

Bekaii-Saab, who is cochair of the event with Eileen M. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center, is the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research I, a chair and consultant in the Division of Hematology and Medical Oncology, and a professor at the Mayo Clinic College of Medicine and Science at Mayo Clinic in Phoenix, Arizona.

 Revolution,” and “Hitting the Target: Molecular Tumor Board With the Experts” will be of interest, and in anticipa- tion of the live meeting, Bekaii-Saab previewed some of the ongoing research evaluating KRAS- directed therapies and more in an interview with 

EGFR Plus KRAS Inhibition as Part of the “

EGFR is recognized as a major upstream activa- tor of RAS-MAPK signaling, a proposed crucial mechanism of resistance to KRAS G12C inhibition in CRC.

 Data from the phase 1/2 KRYSTAL-1 trial (NCT03785249) revealed that dual KRAS/EGFR inhibition with the irreversible, selective KRAS G12C inhibitor adagrasib plus the EGFR monoclonal antibody cetuximab (Erbitux) resulted in encouraging clinical activity for patients with unresectable or metastatic 

 G12C–mutated CRC who received a median of 3 prior lines of therapy. The overall response rate (ORR) in patients who received the doublet (n=94) was 34.0% (95% CI, 24.6%-44.5%) per blinded independent central review and 42.6% (95% CI, 32.4%-53.2%) as assessed by investigator; all responses were partial.

The combination received accelerated approval from the FDA in June 2024 for the treatment of patients with 

 G12C–mutated locally advanced or metastatic CRC who received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

“Next-generation sequencing testing is a human right, now; everyone should get it because not only do we have agents available that [target] the alterations, but also a lot of stud- ies require [it]. Looking at [mutations such as] 

, the one that is very interesting and emerging is 

 has been a target of interest for decades, and we never thought we would get to the point where we can target it. First, we have the 

 G12C mutation. I’ve done a lot of work [targeting it] with adagrasib and there’s a lot of work done with sotorasib and other [agents targeting 

Adagrasib plus cetuximab is under evaluation vs standard-of-care chemotherapy for the treatment of patients with advanced 

 G12C–mutated CRC in the second-line setting in the phase 3 KRYSTAL-10 trial (NCT04793958). Additionally, in a phase 1b trial (NCT04449874), patients with 

 G12C–mutated CRC who were naive to KRAS G12C inhibition achieved an ORR of 62.5% (95% CI, 40.6%-81.2%) when treated with divarasib (GDC-6036) plus cetuximab (n=24). The median duration of response was 6.9 months.

“Though the [data] look consistent with CRC, meaningful outcomes can occur [when] adding an EGFR inhibitor [to treatment as shown in] data published in pancreas and biliary cancers that look very promising,” Bekaii-Saab noted.

Patients with pancreatic ductal adenocarcinoma (PDAC) treated with adagrasib in the KRYSTAL-1 study (n=21) experienced a confirmed ORR of 33.3% with a disease control rate (DCR) of 81.0% observed. Further, the median progression-free survival (PFS) was 5.4 months (95% CI, 3.9-8.2) and the median overall survival (OS) was 8.0 months (95% CI, 5.2-11.8). Those with biliary tract cancer (n=12) experienced a confirmed ORR of 41.7% and a DCR of 91.7%; the median PFS was 8.6 months (95% CI, 2.7-11.3), and the median OS in this patient population was 15.1 months (95% CI, 8.6-not estimable [NE]).

“Adagrasib looks very promising [because] it’s on the National Comprehensive Cancer Network guidelines now for patients with KRAS G12C [mutations], but that’s only a small piece of the 

Examining Additional Mutations Making Up the “

 G12C is the least common but was the easiest alteration to go after. [However,] now we’re seeing an explosion [in exploration]—we’re going after 

 G12V. There are studies looking at RAS(ON) [and] RAS

 mutation]. These [inhibitors] are going to be a bit more challenging in the sense that if you have a target-specific agent, those will most likely get priority over all 

 [mutation–targeted agents] for many reasons. Perhaps that’s a discussion to be had at ISGIO,” Bekaii-Saab said.

Data from the phase 1 AMPLIFY-201 trial (NCT04853017) showed that treatment with the ELI-002 2P vaccine, which enhances lymph node delivery and immune response using amphiphile modification of G12D- and G12R-mutated 

 peptides together with CpG oligonucleotide adjuvant,

 resulted in a tumor biomarker response rate of 84% among 25 patients; 20 patients had pancreatic cancer and 5 had CRC. Investigators noted that the vaccine induced considerable T-cell responses in patients with immunotherapy-recalcitrant 

-mutated tumors. AMPLIFY-201 also plans to transition to treatment with the ELI-002 7P vaccine which contains all 7 Amph-peptides of G12D, G12R, G12V, G12A, G12C, G12S, and G13D.

The RAS(ON) multiselective inhibitor RMC-6236 was evaluated in the first-in-human phase 1 RMC-6236-001 trial (NCT05379985) as second-line therapy in patients with PDAC and 

 mutations including G12X, G13X or Q61X, and KRAS G12X mutations. At doses ranging from 160 mg to 300 mg orally daily, the median PFS in patients with RAS-mutated disease (n = 56) was 7.6 months (95% CI, 5.3-NE) and 8.1 months (95% CI, 5.9-NE) among those with KRAS G12X–mutated disease (n = 42). Patients who received a first dose of RMC-6236 at least 20 weeks prior to the data cutoff date to allow for 3 potential scans experienced an ORR of 27% in the 

 G12X–mutated group (n=48) and 26% in the 

Safety data revealed that the most common any-grade treatment-related adverse effects (TRAEs) were rash (87%), diarrhea (46%), and nausea (43%). Grade 3 or greater TRAEs occurred in 22% of patients, and 28% of patients expe- rienced a TRAE leading to dose modification. Notably, no TRAEs led to dose discontinuation.

Following the encouraging data, Revolution Medicines, the manufacturer of RMC-6236, announced that a phase 3 study called RASolute 302 is expected to be initiated in the second half of 2024. The trial will examine RMC-6236 vs chemotherapy in the second-line setting for the treatment of patients with metastatic PDAC.

“The RAS pathway is an example of how we continue to move the needle very aggressively in a positive way to continue to go after targets leading to a significant enhancement of patient outcomes,” Bekaii-Saab said. “Are we there yet? We’re getting closer, but we still have a long way to go. There are mechanisms of resistance we need to understand. We need to understand how to go after these mechanisms of resistance and continue to understand how to best optimize outcomes in a way that will prolong survival for patients with advanced disease.”

Pellatt AJ, Bhamidipati D, Subbiah V. Ready, set, go: setting off on the mission to target 

. Published online May 13, 2024. doi:10.1200/OP.24.00295

Ben-Ari E. In mouse study, KRAS-targeted drug shows potential against pancreatic cancer. National Cancer Institute. January 12, 2023. Accessed July 18, 2024. bit.ly/4bIQvNx

2024 International Symposium of Gastrointestinal Oncology (ISGIO). Physicians’ Education Resource. Accessed July 15, 2024. bit.ly/4d1zCyu

Desai J, Alonso G, Kim SH, et al; GO42144 Investigator and Study Group. Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. 

. 2024;30(1):271-278. doi:10.1038/s41591-023-02696-8

Yaeger R, Uboha NV, Pelster MS, et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. 

. 2024;14(6):982-993. doi:10.1158/2159-8290.CD-24-0217

FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. FDA. June 21, 2024. Accessed July 16, 2024. bit.ly/4f31swm

Pant S, Yaeger R, Spira AI, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. 

. 2023;41(suppl 36):425082. doi:10.1200/JCO.2023.41.36_suppl.425082

Pant S, Wainberg ZA, Weekes CD, et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. 

. 2024;30(2):531-542. doi:10.1038/s41591-023-02760-3

A study of ELI-002 in subjects with KRAS mutated pancreatic ductal adenocarcinoma (PDAC) and other solid tumors (AMPLIFY-201). ClinicalTrials.gov. Updated June 20, 2024. Accessed July 16, 2024. https://clinicaltrials.gov/study/NCT04853017

RMC-6236: pancreatic cancer update to support pivotal phase 3 trial. Revolution Medicines. July 15, 2024. Accessed July 16, 2024. bit.ly/3WlVgZ1

The acceleration of targeted therapy drug development has led investigators to home in on RAS mutations as agents are approved in colorectal cancer.

Analyzing the “RAS Pie” for Methods to Target Mutations in GI Cancers

The treatment of patients with stage III non–small cell lung cancer (NSCLC) requires a multidisciplinary approach that often hinges on the resectability of the disease. Thus, investigators are working to develop targeted therapies that can be used in conjunction with surgery and chemoradiotherapy in patients with unresectable disease and also tease out the added benefit of a perioperative approach, demonstrating beyond doubt that targeted therapy is equally effective in earlier stages of disease.

“We know that the question about resectability is a very complicated one,” Aditya Juloori, MD, said. “It’s very dependent on multiple factors, [including] patien-related factors and disease-extent factors. This is a moving target. There are guidelines that exist, but the guidelines might be different in the future [compared with] where we are now. Each…patient deserves a full discussion.”

, a panel of clinicians specializing in caring for patients with lung cancer discussed clinical trial updates on agents in stage III NSCLC, many of which had been presented during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. The panelists talked through pertinent data and therapy selection considerations regarding the treatment of patients with resectable or unresectable stage III disease.

Neoadjuvant and Perioperative Options in Resectable Stage III NSCLC

At the ASCO meeting, investigators presented updated findings from clinical trials that examined neoadjuvant and perioperative treatment approaches for patients with resectable stage III NSCLC. During their discussion, the panelists sought to further elucidate disease factors and treatment considerations that would lead to them choosing one approach over another in a given patient. 

“It’s very important [to note] that we have several neoadjuvant/perioperative regimens,” Sandip P. Patel, MD, said. “One important point is that these are for patients who are, at the time…you meet them, resectable. At that point in time, we don’t yet have data around conversion therapy. This is an area of active interest, but discussions around this take place in multidisciplinary tumor boards.”

The phase 3 AEGEAN study (NCT03800134), findings from which informed the July 2024 decision by the FDA’s Oncologic Drugs Advisory Committee to require adequate within trial assessment of contribution of treatment phase in new trial design proposals for perioperative regimens for resectable NSCLC, enrolled patients with treatment-naive stage IIA-IIIB resectable NSCLC.

 Patients were randomly assigned 1:1 to receive the anti–PD-L1 antibody durvalumab (Imfinzi) perioperatively with neoadjuvant chemotherapy, or neoadjuvant chemotherapy alone. The coprimary end points were event-free survival (EFS) and pathological complete response (pCR) via blinded independent central review (BICR).

Primary analysis findings from AEGEAN demonstrated that adding perioperative durvalumab to neoadjuvant chemotherapy significantly improved EFS compared with neoadjuvant chemotherapy alone (HR, 0.68; 95% CI, 0.53-0.88; 

 = .004); the difference in pCR rate between the 2 arms was 13.0% (95% CI, 8.7%-17.6%) in favor of the durvalumab arm (

 < .001). Additionally, results from an exploratory analysis presented during ASCO 2024 showed that patients with baseline N2 nodal status (n = 181) achieved a similar benefit to the overall population with the addition of durvalumab; the difference in pCR rate between the durvalumab and placebo arms was 11.7% (95% CI, 5.6%-18.4%) in favor of durvalumab. EFS benefit in favor of durvalumab was also consistent between the baseline N2 population and the overall population and was seen in patients with single- (n = 273; HR, 0.61; 95% CI, 0.39-0.94) and multistation (n = 74; HR, 0.69; 95% CI, 0.33-1.38) N2 disease.

In another phase 3 study, CheckMate 816 (NCT02998528), investigators examined neoadjuvant treatment with nivolumab (Opdivo) plus chemotherapy in patients with stage IB to IIIA resectable NSCLC with no known 

 alterations. Patients were randomly assigned 1:1 to receive nivolumab plus chemotherapy or chemotherapy alone, followed by surgery. EFS and pCR, both per BICR, represented the primary end points; overall survival (OS) was a key secondary end point.

Data from the 4-year update of CheckMate 816 demonstrated that patients who received nivolumab (n = 179) achieved a median EFS of 43.8 months vs 18.4 months among patients who received chemotherapy alone (n = 179; HR, 0.66; 95% CI, 0.49-0.90); the 48-month EFS rates were 49% vs 38%, respectively. The median OS (HR, 0.71; 98.36% CI, 0.47-1.07; 

 = .0451; unstratified HR, 0.69; 95% CI, 0.49-0.97) and lung cancer–specific survival (unstratified HR, 0.62; 95% CI, 0.41-0.93) significantly favored the nivolumab arm. Notably, the survival benefit with nivolumab vs chemotherapy alone was observed in patients whether they received cisplatin (HR, 0.79; 95% CI, 0.53-1.17) or carboplatin (HR, 0.36; 95% CI, 0.16-0.81), and whether they had undergone lobectomy (HR, 0.71; 95% CI, 0.41-1.21) or pneumonectomy (HR, not calculable). Moreover, pCR appeared to correlate with improved OS in patients in the investigational arm (HR, 0.08; 95% CI, 0.02-0.34).

Findings from CheckMate 816 supported the March 2022 FDA approval of nivolumab plus platinum-doublet chemotherapy for adult patients with resectable NSCLC in the neoadjuvant setting. The decision made the combination the first FDA-approved neoadjuvant therapy for early-stage NSCLC.

Clinicians specializing in caring for patients with lung cancer discussed clinical trial updates on agents in stage III NSCLC.

Vol. 25/No. 10 | Oncology Live®