New Treatments, New Hope for Patients With Lung, Breast, GI Cancers

For patients diagnosed with lung cancer or chronic lymphocytic leukemia (CLL), news that just a few years ago brought limited options means treatment choices; for some, it can mean many years of life. The same is true in breast cancer and gastrointestinal (GI) cancers, where optimizing treatment choices can make a significant difference.

New possibilities in these cancers were explored October 29, 2024, during a regional Institute for Value-Based Medicine (IVBM) event hosted by The American Journal of Managed Care in San Francisco, California.

Advances in NSCLC Offer New Options for Patients

Matthew Gubens, MD, MS, FASCO, a thoracic oncologist from the University of California San Francisco (UCSF), jokes that he’s old enough to remember when non–small cell lung cancer (NSCLC) was the “backwater” of cancer research.

Thanks to advances in immunotherapy and targeted therapy, this is no longer true, and the shift in NSCLC highlighted the first panel that Gubens moderated, featuring Aaron Lisberg, MD, a thoracic oncologist from UCLA; and Alan Chin, PharmD, BCOP, a pharmacist from UCSF. Lisberg pointed out that immunotherapies have made it possible for some patients with metastatic lung cancer to live longer, even though there’s a lot of work left to help those patients who don’t respond to immunotherapy.

“We’re not going to use the word cure yet, but I do think that at some point we are going to have to start using that term once we get 10, 15, 20 years out for some of these patients, which is really exciting,” Lisberg said.

Chin agreed that seeing immunotherapy used for treating earlier stages of NSCLC was exciting. Questions in the future, he said, will be how long a regimen of immunotherapy should last and whether adjuvant therapy should be continued. Lisberg agreed, stating that although moving immunotherapy to earlier stages of treatment represents progress, it creates new questions, such as which patients should get adjuvant therapy based on biomarkers.

Another advancement in NSCLC treatment is the use of antibody-drug conjugates (ADCs) that combine targeted therapy with chemotherapy. “A couple of years ago, people were about to sour on the idea, thinking, ‘Oh, why are we going back to chemotherapy?’” said Lisberg. However, he pointed out that the ADCs give more on-target effects, which should bring into question what populations should be targeted. Chin said that he believes that ADCs will move their way up to earlier lines of care in the next 5 years.

Lastly, genomic alterations are also a new advancement in treatment for NSCLC. “Next-generation sequencing [NGS] definitely is what we should be doing for all patients coming in,” said Chin. “The problem is there’s a huge discrepancy between what we actually see in clinic.”

Chin also pointed out that the cost of NGS could be covered by insurance, but this is not always specified in state law. As a result, some patients can’t afford NGS, primarily in rural areas. “We do see a huge discrepancy between what the real data are showing us in patients who are actually getting NGS, and it seems like almost one-third of patients aren’t getting it—whereas in clinic we’re seeing most of the patients getting it,” he said.

Advances in CLL Guided by Patient Outcomes

Advancements in CLL were also highlighted during the event, as Tim Mok, PharmD, BCPS, BCOP, a hematology oncology pharmacy research analyst at Kaiser Permanente, was joined by Sophia Humphreys, PharmD, MHA, BCBBS, from Sutter Health; and Bita Fakhri, MD, MPH, from Stanford Medicine, to discuss advancements guided by patient outcomes. Mok started with a short history of treatments, including how ibrutinib (Imbruvica, Janssen) changed the treatment of CLL when it came to market in 2014,¹ spurring the development of other Bruton tyrosine kinase (BTK) inhibitors to treat CLL.

Fakhri said that when deciding what treatment to use for her patients, she has open conversations with them about their patient-specific factors, disease-specific factors, and therapeutic-specific factors. “Fortunately, in 2024, we are talking about a menu of treatment options that are available for patients,” she said. “I always tell them the only wrong answer is not to enroll in a clinical trial that is available to you.… Outside that, it really is having that open conversation and trying to factor in all those factors.”

Humphreys noted that she was a fan of fixed-duration therapies, including biosimilars. Fakhri said that when choosing therapies for patients with disease with mutations, she presents clinical trial data to patients to determine which therapies to use. This can include using a time-limited approach for patients who have adverse prognostic features. She acknowledged that some results of remission lasting for 5 years may not be good enough for some but are good enough for others, which can help to determine how to treat them.

The panel also touched on the use of minimal residual disease (MRD) as a way of measurement of CLL, which is defined as the number of leukemic cells that are detected in peripheral blood or bone marrow following a treatment. Humphreys noted that she has seen arguments both for and against using MRD as a measurement. Fakhri recommended not using it outside of a clinical trial. “There are patients with low positive MRD who have better outcomes, much better outcomes, compared with patients who become MRD negative and then become MRD positive,” said Fakhri. “So, the kinetics matter.”

Switching BTK inhibitors is also more popular now, according to Mok. Humphreys noted that it depends on the patient when it comes to switching. “A lot of times I see physician switching really is because of tolerance; insurance has not been affecting it as much as you would expect,” said Humphreys. Fakhri said that if a treatment is working, switching is not something that she would do. Both Humphreys and Fakhri concluded that new data on chimeric antigen receptor T-cell therapy for CLL were not as effective as hoped, and they would push for other methods of treatment before using this new treatment.

Treatment Optimization in Breast, GI Cancers

The IVBM session focused not only on advances made in treatment of cancer but also on optimizing current treatments for both breast and GI cancers. Breast cancer took a highlighted role near the start of the night, with a panel moderated by Natalia Colocci, MD, PhD, from Sutter Health, and featuring experts Aditi Choudhry, MD, from John Muir Health; and Tiffany Meng, PharmD, BCOP, from UCSF as they discussed different treatment methods for breast cancer as well as new ones.

The phase 3 MONARCH 3 trial (NCT02246621) and the phase 3 NATALEE trial (NCT03701334) were of particular interest to the panel, especially as they revolved around cyclin-dependent kinase 4/6 inhibitors. The MONARCH 3 trial² was a randomized study testing abemaciclib (Verzenio, Eli Lilly) as an initial therapy for advanced breast cancer, and the NATALEE trial was a randomized trial that tested ribociclib (Kisqali, Novartis) with endocrine therapy in early breast cancer.³ Both of these treatments are FDA approved.

“I personally struggle to sort of balance the risk-benefit ratio because, as we all know, both of these drugs have pretty significant [adverse] effects,” said Choudhry. “So personally, for me, because both of these trials have PFS [progression-free survival] benefit but no OS [overall survival] benefit, I try to follow the trial design.… I wonder [whether] the benefit really truly exceeds the [adverse] effect profile.”

The MONARCH 3 trial had a slightly longer follow-up time, which Colocci said was important in a condition that has a long PFS. However, the MONARCH 3 trial featured a high dose of abemaciclib, and only a small number of patients were able to complete the study; Colocci suggested the dose should be lowered. PFS was noted to be the most important statistic when looking through clinical trial results, as OS often cannot be determined in the shorter follow-up times. Colocci also noted that the length of time of treatment differed between the 2 trials, which is also something to note when looking at results from clinical trials.

“From a pharmacy standpoint, I think it’s always great that patients have all these choices at different lines of therapies, but I think the question always comes down to what can they realistically tolerate, and then what is a long-term outcome that they can benefit from?” said Meng.

All panelists also noted that comprehensive panels, including NGS done early in treatment, are also valuable in treating breast cancer. This can also include doing consistent biopsies and liquid biopsies to monitor the response to treatment.

ADCs in breast cancer were also a big topic of discussion. Choudhry stated that pathology standardization is the biggest challenge in using ADCs. “I think it’s a mess,” she said. “Patients with early-stage breast cancer [that has] now metastasized, all my notes would say HER2 negative. Then I have to go back and pull the biopsy and see if they were HER2-low, and then we have to call the pathologist, and there’s really no standardization in that.” She noted that, with HER2 ultralow coming out, it could make the process more complicated, even as ADCs have had promising results.

However, both Meng and Choudhry said that they were excited about the ADC results thus far and were eager to see the long-term survival rates. “I think ADC sequencing is going to be really interesting to figure out,” said Meng. “I think if we can find a way to optimize to improve outcomes so patients can be treated for longer and tolerate their treatment longer, I think that would be really interesting to see.”

Hope S. Rugo, MD, FASCO, a professor of medicine in the Division of Hematology and Oncology at UCSF, noted that there are a lot of ways to continue research into ADCs when it comes to metastatic breast cancer, stating that it would be “interesting to understand how we analyze new ADCs in the metastatic setting.”

Treatment of GI cancers, specifically pancreatic cancer, were also touched on during the panel. Geoffrey Buckle, MD, MPH, from UCSF; Curtis Chong, MD, PhD, MPhil, FACP, from Stanford Medicine; and Andrew Ko, MD, FASCO, a colorectal and GI cancers specialist from UCSF, discussed immunotherapy in GI cancers, specifically zolbetuximab (Vyloy, Astellas), which was just recently approved for adults with locally advanced, unresectable, or metastatic gastric or gastroesophageal junction adenocarcinoma.⁴

Chong used a baseball analogy to describe the clinical efficacy of zolbetuximab in combination with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) therapy compared with FOLFOX monotherapy, describing it as in between a single and a double, which he described as extending OS by 2 to 3 months with an HR of 0.8 and an HR of 0.6 to 0.8, respectively.

Chong said that until zolbetuximab has a greater long-term survival, his preference would still be pembrolizumab (Keytruda, Merck), “but it’s not a strong preference.”

Ko agreed, saying that there are patients who were on combined chemotherapy and immunotherapy who are now on maintenance immunotherapy and doing fine. “I will probably steer more toward that, especially for your PD-L1–high patients,” said Ko. “But I can foresee a time where we’re probably going to throw the kitchen sink at them and use a combination of [chemotherapy] plus [zolbetuximab] plus your immune checkpoint inhibitor.”

They both also noted that RAS inhibitors are promising in the pancreatic world but would need more evidence to support their use. Testing for circulating tumor DNA (ctDNA) is also possible and can help monitor risk stratification and surveillance in colorectal cancer. However, Ko said that he’s not a big fan. “You got a positive ctDNA, [it] stresses the patient now, stresses you out, and you’re like, ‘Well, OK, we know you’re going to recur, but is giving you therapy now going to make a difference in that?’ I don’t know, not clearly,” said Ko.

The IVBM panel focused on several aspects of cancer care and highlighted different aspects of both management and treatment of the specific cancers. The new treatments could give a new look and prognosis to patients living with cancer in the US.

References

1. de Claro RA, McGinn KM, Verdun N, et al. FDA approval: ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3586-3590. doi:10.1158/1078-0432.CCR-14-2225
2. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5. doi:10.1038/s41523-018-0097-z
3. Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med. 2024;390(12):1080-1091. doi:10.1056/NEJMoa2305488
4. FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed November 24, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma