Benjamin Herzberg, MD, is an assistant professor of medicine at Columbia University Medical Center and an oncologist at Herbert Irving Comprehensive Cancer Center in New York, New York

Dr Herzberg on Future Research Directions in KRAS-Mutant NSCLC

"Major questions are going to be: What combinations are tolerable? What can be used? What combinations are very good, synergistic, or better than just using the drugs individually? Those are somewhat separate questions that tend to get lumped together, but we have a number of trials ongoing that are trying to answer those questions. "

Benjamin Herzberg, MD, an assistant professor of medicine at Columbia University Herbert Irving Comprehensive Cancer Center, as well as an assistant professor of medicine at Columbia University Medical Center, discussed efforts to clarify the use and development of KRAS inhibitors for the treatment of patients with non–small cell lung cancer (NSCLC).

Key challenges in the evolution of KRAS-targeted therapies include identifying effective combination strategies and overcoming resistance mechanisms, particularly in 

 G12C–mutant and non-G12C–mutant tumors, Herzberg began. Although KRAS G12C inhibitors, such as adagrasib (Krazati) and sotorasib (Lumakras), have demonstrated clinical activity in patients with NSCLC, their use as monotherapy has shown limited response durability, prompting the need to explore synergistic combinations with these agents, he noted.

Combination EGFR inhibitor combination partners currently under investigation include chemotherapy agents, immune checkpoint inhibitors, and targeted agents, Herzberg stated. Of these, the most promising data to have emerged from combinations with EGFR inhibitors include those with the agents cetuximab (Erbitux) and panitumumab (Vectibix), Herzberg detailed. Notably, preclinical reports of 

 G12C inhibitors combined with immunotherapy have not demonstrated clear synergy between these classes of agents, with response rates appearing additive rather than enhanced beyond those generated by each agent as monotherapy, according to Herzberg.

Several trials are ongoing to determine which combinations are feasible and tolerable, as well as which combinations provide superior clinical benefit, Herzberg continued. Studies evaluating adagrasib in combination with checkpoint inhibitors in PD-L1–high tumors and sotorasib with chemotherapy in PD-L1–low tumors are anticipated to provide greater clarity on optimal sequencing and combination strategies in molecularly defined patient subsets, he concluded.

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Benjamin Herzberg, MD, discusses unanswered questions regarding the role of KRAS inhibitors for patients with non–small cell lung cancer.
 

Benjamin Herzberg, MD, of Herbert Irving Comprehensive Cancer Center

G12C inhibitors for NSCLC, which are sotorasib and adagrasib there is really more in common than there is different."

Benjamin Herzberg, MD, an assistant professor of medicine at Columbia University Irving Medical Center, discusses the clinical similarities and key distinctions between the two commercially available KRAS G12C inhibitors—sotorasib (Lumakras) and adagrasib (Krazati)—for the treatment of non–small cell lung cancer (NSCLC) harboring a 

According to Herzberg, sotorasib and adagrasib share many clinical attributes, including comparable toxicity and response profiles. The adverse effect spectra for both agents are consistent with on-target KRAS inhibition and typically include gastrointestinal symptoms, elevated liver enzyme levels, and fatigue. These toxicities are generally manageable and rarely treatment limiting, allowing both drugs to be administered safely in most clinical settings.

Response rates between the 2 agents are also largely similar, with both demonstrating objective response rates in the range of 35% to 45% and a median progression-free survival of approximately 6 months in previously treated patients, Herzberg said. These data support their utility in the second-line or later settings for patients with advanced 

However, Herzberg highlights 1 notable difference between the two agents: central nervous system (CNS) activity. Although sotorasib has shown potential CNS penetration based on retrospective analyses and small cohorts, the evidence supporting adagrasib’s CNS activity is more robust. Data from clinical studies with adagrasib have demonstrated intracranial responses, offering greater confidence in its ability to control brain metastases. As a result, Herzberg noted that adagrasib may be the preferred option in patients with active brain metastases or in those at higher risk for CNS progression.

The choice between sotorasib and adagrasib in clinical practice is often guided by patient-specific factors, including the presence of brain metastases and the treating physician’s experience with each agent. In the absence of head-to-head comparative data, both inhibitors remain viable and effective treatment options for 

 G12C–mutant NSCLC, Herzberg explained.

Herzbreg concluded by noting that although sotorasib and adagrasib are largely similar in their systemic activity and toxicity, the emerging intracranial data with adagrasib may offer a clinical advantage in select patient populations. Further studies will be important to clarify the comparative efficacy and CNS penetration of these agents in 

Benjamin Herzberg, MD  the clinical similarities and key distinctions between sotorasib and adagrasib for KRAS G12C+ NSCLC.

Dr Herzberg on the Distinctions Between Sotorasib and Adagrasib for KRAS G12C+ NSCLC

Dr Herzberg on Notable Ongoing Research in KRAS-Mutated NSCLC

"The key questions with KRAS-targeted agents are: [Will] the drugs be allele-specific, targeting 1 specific 

 mutation like G12C, G12D, or G12V, or are we making drugs that can target all potential 

 mutations? How are those different approaches going to play out in terms of toxicity, activity, and success?"

Benjamin Herzberg, MD, an assistant professor of medicine at Columbia University Irving Medical Center and an oncologist at Herbert Irving Comprehensive Cancer Center, discussed the 

 for patients with non–small cell lung cancer (NSCLC).

KRAS-targeted drug development remains a major focus in NSCLC, with ongoing advances in medicinal chemistry and pharmacology driving innovative strategies to inhibit 

 mutations, Herzberg began. A key question in this arena is whether KRAS inhibitors should be allele-specific—targeting G12C, G12D, or G12V—or whether pan-KRAS or pan-RAS inhibitors capable of targeting multiple mutations will offer greater therapeutic benefit, Herzberg shared. These approaches differ in terms of toxicity, efficacy, and clinical success, necessitating further investigation, he added.

Currently approved KRAS inhibitors selectively target the GDP-bound, inactive state of KRAS, but emerging strategies aim to inhibit the GTP-bound, active state as well, Herzberg explained. Novel agents include direct inhibitors and molecular glue inhibitors, which function by tethering KRAS to another molecule, thereby disrupting its activity, Herzberg detailed. Tri-complex inhibitors from Revolution Medicines exemplify this approach and include both allele-specific inhibitors and pan-RAS inhibitors that can broadly target any 

Early-phase clinical trials have reported promising responses with KRAS inhibitors in patients with 

-mutated tumors, highlighting the potential for these next-generation inhibitors, Herzberg reported. However, given the wide range of investigational compounds in development, further research is needed to determine optimal patient selection, toxicity profiles, and combination strategies, he noted. As the field continues to evolve, KRAS inhibition in NSCLC is expected to become increasingly refined, with the potential to improve outcomes for a broader patient population, Herzberg concluded.

Benjamin Herzberg, MD, discusses current and future research efforts in KRAS-mutated NSCLC.

Ramez N. Eskander, MD, is an assistant professor in the Departments of Obstetrics, Gynecology, and Reproductive Sciences at the University of California (UC) San Diego School of Medicine; as well as the director for oncology of the clinical trials office at the UC San Diego Moores Cancer Center

Rachel N. Grisham, MD, is an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York

Kelly E. McCann, MD, PhD, is an assistant professor and breast medical oncologist at UCLA.

Gregory Roloff, MD, is a hematologist/oncologist at the University of Chicago Medicine in Illinois

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, OncLive covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, we invited experts from across oncology specialties to discuss the 

long-term effects of the COVID-19 pandemic

—the onset of which occurred 5 years ago. Our guests shared how the pandemic's lingering effects continue to shape patient care. We heard from: 

Ramez N. Eskander, MD, a gynecologic oncologist and assistant professor of obstetrics, gynecology, and reproductive sciences at the University of California San Diego Health

Rachel N. Grisham, MD, an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York

Benjamin Herzberg, MD, an assistant professor of medicine at Columbia University Medical Center and an oncologist at Herbert Irving Comprehensive Cancer Center in New York, New York 

Kelly McCann, MD, PhD, an assistant professor and breast medical oncologist at UCLA Health’s David Geffen School of Medicine in Los Angeles, California

Gregory Roloff, MD, a hematologist/oncologist at the University of Chicago Medicine in Illinois

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Experts from across oncology specialties discuss the long-term effects of the COVID-19 pandemic on patient care. 

Oncology Experts Discuss the Long-Term Effects of the COVID-19 Pandemic: With Ramez N. Eskander, MD; Rachel N. Grisham, MD; Benjamin Herzberg, MD; Kelly McCann, MD, PhD; and Gregory Roloff, MD

The past 2 decades of advances in medical oncology have been fostered by a molecular revolution. Next-generation sequencing (NGS)–based mutation panels increasingly deliver information to oncologists that radically alters therapy options. This revolution has fed upstream, as new drug development is increasingly defined not by the location or type of tissue in the tumor but by molecular alterations, which instead are found across cancer types. In my Phase 1/Experimental Therapeutics Clinic, I may, in 1 clinic day, see patients with pancreatic cancer, lung cancer, colorectal cancer, melanoma, and endometrial cancer—all on the same clinical trial. Thankfully, these new drugs are 

 than our older ones. As a result, the patient-derived benefit of early-phase clinical trials is also increasing over time.

Although early-phase trials have changed dramatically, on a practical, clinical level, the way in which many patients are referred for trials has not. That is, patients—both in community practices and in academic ones—are often treated with standard-of-care therapies until no more remain, and only then are they referred for clinical trials.

Why does this occur, and why is this a problem? I have started calling our traditional way of enrolling on trials passive enrollment. All the burden falls on the treating physician, and there is no support system to actively identify, offer, prepare, and evaluate patients for clinical trials. With dozens of potentially relevant molecularly driven trials available, how is it possible to remember them all? It’s not. In addition, treatment slots are often released in cycles, filled rapidly in nationally competitive fashion, and then there are no more for months until data are generated. What if there is a patient who would willingly pause current therapy to join a study but doesn’t know about it at just the right time?

There is a better way to do this—a clinical trial 

 find and offer patients the right trials at the right time. In collaboration with the clinical informatics group at the Herbert Irving Comprehensive Cancer Center (HICCC), we have developed processes to actively screen 

reach out to their treating physician when a promising study might be available.

This involves gathering, collating, and reporting our molecular data in a fashion that can be reviewed at scale by nurses and nurse navigators; creating an “active waitlist” for a study so that, when slots are available, patients and physicians can be offered studies immediately; and real-time feedback so we can see in our data where, and when, we are opening successful trials.

-directed study we had opened released new slots, targeting a new set of mutations. We had enrolled patients in the study previously but not for these mutations. The clinical informatics group quickly expanded our mutation search, generating hundreds of potential new patients on a list. We reviewed the list for trial suitability, reached out to the treating physicians, and offered the study to a half-dozen patients who would never have otherwise had the opportunity but were more than grateful to have it. We have enrolled 

 our nationally expected number of patients in this study cohort—probably more if normalized for our institution’s size.

There is a long way to go. We are working to make all molecular tests orderable in our medical record system so that we can generate more data, more quickly, and feed it back not just for trial enrollment but also for research questions. I am excited by the potential of this system. Molecular data already drive drug design and trial design in oncology. The next step is for it to drive trial enrollment systems too. We are working to position HICCC at the forefront of this revolution.

Editor's note: Benjamin Herzberg, MD, is a medical oncologist and an associate professor of medicine at Columbia University Irving Medical Center in New York, New York.

Articles

The Herbert Irving Comprehensive Cancer Center has developed processes to actively screen any patient with a relevant mutation for an open trial.

Benjamin Herzberg, MD

Articles

Dr Herzberg on Future Research Directions in KRAS-Mutant NSCLC

Dr Herzberg on the Distinctions Between Sotorasib and Adagrasib for KRAS G12C+ NSCLC

Dr Herzberg on Notable Ongoing Research in KRAS-Mutated NSCLC

Oncology Experts Discuss the Long-Term Effects of the COVID-19 Pandemic: With Ramez N. Eskander, MD; Rachel N. Grisham, MD; Benjamin Herzberg, MD; Kelly McCann, MD, PhD; and Gregory Roloff, MD

Moving From Passive to Active Clinical Trials Enrollment