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Despite Progress, ADCs Still Stalled In Non-Small Cell Lung Cancer
Pictured: An antibody-drug conjugate under construction by two scientists/ Nicole Bean for BioSpace†
With antibody-drug conjugates well established in liquid tumors, companies are pivoting their focus to treating solid tumors, such as those of the breast, prostate and lung. If ADCs can be a viable treatment option for non-small cell lung cancer (NSCLC), which is particularly challenging given its resistance to chemotherapy and radiation, it could be a significant treatment advance with huge market potential.
In August 2022, AstraZeneca and Daiichi Sankyo's ADC Enhertu won FDA approval as the first antibody-drug conjugate (ADC) to treat patients with HER2-mutated metastatic NSCLC, and several more programs involving ADCs for lung cancer are moving forward.
In December 2023, the FDA accepted the Biologics License Application (BLA) for Daiichi Sankyo and Merck's patritumab deruxtecan (HER3-DXd) for the third-line treatment of NSCLC and set a PDUFA date of June 26, 2024. Then, in February, the regulator accepted the Biologics License Application for datopotamab deruxtecan (Dato-DXd), co-developed by Daiichi Sankyo and AstraZeneca, for the second-line treatment of NSCLC, setting an action date of Dec. 20.
"We're very optimistic about this, and we think that [Dato-DXd] can be an important drug for non-squamous non-small cell lung cancer patients," Mark Rutstein, SVP and head of global oncology clinical development at Daiichi Sankyo, told BioSpace.
But a major challenge in developing ADCs for NSCLC is that unlike many cancers, lung cancer isn't typically treated with antibody therapies, Christiana Bardon, co-managing partner at MPM BioImpact, told BioSpace. "The early data was not that positive."
Bardon said she believes ADCs will stall in lung cancer for the same reason: until compelling surface targets for lung cancer are developed that have good rates of internalization, there are no good markers to ensure sufficient payload delivery.
TROP2 and BeyondBut treatments like Dato-DXd could be making inroads. Results from the Phase III Tropion-Lung01 trial showed that Dato-DXd, which is directed at the TROP2 receptor, reduced the risk of disease progression or death by 25% in the overall trial population and by 37% in patients with non-squamous tumors when compared to chemotherapy. High-level overall survival results from the trial reported Monday numerically favored Dato-DXd, showing clinically meaningful improvement in a prespecified subgroup of patients. However, survival results did not reach statistical significance in the overall trial population.
Bardon said TROP2 is one of the few targets where "good progress" has been made, "but the data hasn't been that impressive" in NSCLC. Patients treated with Dato-DXd in the TROPION-Lung01 trial showed a progression-free survival (PFS) of only 4.4 median months vs. 3.7 with chemotherapy. "That's not super exciting," Bardon said, adding that Dato-DXd has not generated much excitement among lung cancer doctors.
The PFS bare minimum hurdle for something to generate excitement in the field of lung cancer would be about six months, she said. Right now, chemotherapy provides about a 20% response rate, with a PFS of six months, Bardon noted, saying this is the low bar to meet with treatments for lung cancer.
Another ADC targeting the TROP2 receptor is Gilead Sciences' Trodelvy, which is FDA-approved to treat breast cancer. However, the company announced in January that the drug did not meet the primary endpoint of overall survival in a Phase III study in NSCLC. Gilead did observe a more than three-month difference in median overall survival in a subgroup of patients, so the company plans to continue researching effectiveness in these patients.
"We will work to further identify the metastatic NSCLC patient populations that may benefit from Trodelvy," Gilead Chief Medical Officer Merdad Parsey said in a statement.
Rutstein is bullish on the potential of ADCs targeting TROP2 in NSCLC. "We haven't seen the data yet, but [Gilead] described some evidence of benefit, despite a negative trial," Rutstein said. "Overall, if you take the totality of the data with TROP2 antibody drug conjugates in NSCLC, we think there's an important potential for patients," he said.
Beyond TROP2, there are several other ADCs in development for NSCLC targeting HER2, HER3, c-MET, EGFR, NaPi2b and more.
Mythic Therapeutics is studying MYTX-011, an ADC targeting the c-MET receptor, in Phase I, and emerging ADC player Tubulis has TUB-040, which targets NaPi2b, a highly overexpressed antigen in lung and ovarian cancers, in preclinical studies.
Data showed that TUB-040 led to complete eradication of tumors with a low-dose single treatment in multiple ovarian cancer mouse models. Additionally, repeat-dose toxicology studies in nonhuman primates demonstrated that TUB-040 was well tolerated with minor and reversible adverse effects.
"The novel technology we use in TUB-040 aims to address one of the current main challenges of ADC treatments: to ensure long-term delivery of the payload to the tumor site in order to improve the durability of anti-tumor responses and ultimately clinical outcomes," Tubulis CEO and Cofounder Dominik Schumacher told BioSpace in an email. This will ultimately improve clinical outcomes, he said, adding that the asset will soon advance to Phase I clinical trials.
But some analysts are not convinced that ADCs are ready to make a substantive difference in lung cancer.
ADCs Not Ready for Prime Time in NSCLCThanks largely to the available targets of other cancers such as breast, ovarian and prostate cancers, ADCs are "much bigger" in these areas, Bardon said.
ADCs need good antibody targets so they can bind to something on the tumor to deliver the payload, Bardon explained, adding that in breast cancer, that target is HER2. Indeed, Enhertu, which targets HER2, was approved for breast cancer the week before it got the green light for HER2-low metastatic NSCLC.
"We have a good antibody that addresses that good target," Bardon said. "Therefore, it's easy to innovate on the payloads, and that's why we've gotten more sophisticated with our ability to treat breast cancer with ADCs."
But no established treatments for lung cancer are antibody dependent, and that's why there hasn't been much progress developing mature ADCs in this area, she noted.
That's not to say they're totally obsolete. Once ADCs are developed, Bardon sees the future of lung cancer treatment as a cocktail of therapies working together.
"We're just starting to get all the different ingredients of chemo, [immuno-oncology], targeted therapies, and in the future ADCs, and then we'll combine and mix and match these for the first, second and third line."
Mollie Barnes is a freelance science writer. Reach her at mollie@100yearsco.Com. Follow her on Threads and Instagram @shejustlikedtogo or LinkedIn. See more of her work at molliebarnes.Contently.Com.
Immunotherapy Before And After Surgery May Improve Lung Cancer Survival Rates
Lung cancer is the leading cause of cancer-related deaths in the world, but surgical interventions may improve survival rates, particularly when the disease is caught early.
One of the most common types of lung cancer is non-small cell carcinoma (NSCLC). A significant risk factor for this type of lung cancer is smoking. Treatment for NSCLC may involve cutting out parts of the lung to remove cancerous cells. After surgery, doctors may then have patients undergo chemotherapy or radiation to decrease the chances of lung cancer returning.
As with other forms of cancer, lung cancer treatment often involves a combined approach to help increase the chances of long-term survival.
Immunotherapy is a common treatment for lung cancer, and scientists are exploring the best ways to combine it with other therapy approaches. This form of targeted therapy uses monoclonal antibodies to help destroy cancer cells and prevent cancer growth.
A recent study published in The New England Journal of Medicineexamined the perioperative use of the immunotherapy treatment nivolumab among people who had resectable non-small-cell lung cancer. They compared the use of nivolumab pre and postsurgery with the use of only chemotherapy before surgery.
Participants who received nivolumab and chemotherapy before surgery and nivolumab postsurgery were more likely to be cancer-free 18 months later, and more participants in this group experienced a pathological complete response.
The study points to nivolumab's usefulness in improving event-free survival in people with non-small-cell lung cancer (NSCLC).
This study was the international CheckMate 77T trial, a phase three, double-blind study. It included participants with operable non-small-cell lung cancer who had not received previous systemic anticancer treatment.
Researchers randomized 461 participants to receive either nivolumab or placebo. The intervention group received nivolumab and chemotherapy before surgery, while the control group received placebo and chemotherapy every three weeks for four cycles. In total, 229 were in the nivolumab group, and 232 were in the chemotherapy group.
Participants then underwent surgery within six weeks of this pre-surgical intervention. Within three months of surgery, the intervention group received nivolumab every four weeks for a year, while the other group received a placebo.
Researchers looked at event-free survival as a primary outcome. Secondary outcomes included:
The average follow-up time with participants was 25.4 months.
Overall, the group that received nivolumab experienced superior outcomes to the chemotherapy group. Event-free survival at 18 months was 70.2% for the intervention group and 50% for the chemotherapy group.
"For patients with resectable stage IIA to IIIB non-small cell lung cancer (NSCLC), neoadjuvant nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab had a significantly extended event-free survival compared with neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant placebo," non-study author Mahran Shoukier, MD, an oncologist affiliated with Memorial Hermann, explained to Medical News Today.
Additionally, about a quarter of the intervention group also experienced a pathological complete response, while less than 5% of the chemotherapy group did.
About 35% of the intervention group experienced major pathological responses compared to about 12% of the chemotherapy group.
The groups experienced a similar number of adverse events, but the number of adverse events that resulted in treatment discontinuation was higher in the intervention group. Still, researchers noted that the intervention had no unexpected safety signals.
"The study showed the importance of using nivolumab in addition to the chemotherapy in the neoadjuvant regime for resectable NSCLC (stage IIA to stage IIIB) and then using nivolumab in the adjuvant setting after surgery. This will extend the event-free survival and increase the pathological response without unexpected safety signals."
— Mahran Shoukier, MD, oncologist
The findings offer hope for improving survival rates for this deadly form of cancer.
"The burden imposed by lung cancer in the U.S. And the world at large is enormous," Jack Jacoub, MD, board certified medical oncologist and medical director of MemorialCare Cancer Institute at Orange Coast Medical Center in Fountain Valley, CA, told MNT. Jacoub was not involved in the study.
"Just a few years ago, the average survival for stage III lung cancer — [two-thirds] of the study population — was 1.5 years. Now, in the era of immunotherapy, this number has been dramatically improved," Jacoub noted.
The study reported [that] 70% of patients are now alive and without any evidence of disease at that same time interval using perioperative therapy and 50% using preoperative therapy alone, which is tremendous progress. Moreover, the benefit from both approaches adds very little to the side effects already known with chemotherapy alone," he continued.
Despite the promising implications, the study does have certain limitations.
First, it focused on a specific cancer type, meaning the results cannot necessarily be generalized to other cancer types. Less than 40% of participants completed one full year of nivolumab treatment post-surgery, which could have also impacted the results.
Researchers also acknowledge that Black participants were underrepresented, which suggests the need for more diverse follow-up. About 70% of the participants were male, so future research could include more female participants.
"Although we do not know overall survival — follow-up beyond the 2 years reported — it obviously will blow away the recent historical numbers with chemotherapy alone. Hence, this is a very significant trial and will likely change practice. This treatment will likely be available for stage II and III resectable lung cancer patients very soon in the U.S., and uptake by cancer treatment providers will likely be rapid thereafter."
— Jack Jacoub, MD, board certified medical oncologist
Nivolumab Betters Event-Free Survival Vs Chemo In Non-Small Cell Lung Cancer
An interim analysis of the CheckMate 77T trial shows that nivolumab plus chemotherapy improves event-free survival in resectable non-small cell lung cancer vs chemotherapy alone.
3D rendered medical illustration of male anatomy with lung cancer: © Sebastian Kaulitzki- stock.Adobe.Com
The inclusion of perioperative nivolumab (Opdivo) to neoadjuvant chemotherapy delivered improvements in event-free survival (EFS) compared with chemotherapy alone in patients with resectable non-small cell lung cancer (NSCLC), according to findings from the phase 3 CheckMate 77T trial (NCT04025879).1,2
The findings, published in The New England Journal of Medicine, showed that at a median follow-up of 25.4 months, 70.2% of patients in the nivolumab arm reached 18-month EFS vs 50.0% in the chemotherapy arm (HR, 0.58; 97.36% CI, 0.42-0.58; P <.001). Further, a pathological complete response (pCR) was observed in 25.3% and 4.7% of patients in the nivolumab and chemotherapy arms, respectively (OR, 6.64; 95% CI, 3.40-12.97), while a major pCR occurred in 35.4% and 12.1% of patients, respectively (OR, 4.01; 95% CI, 2.48-6.49).
Regarding safety, grade 3 and 4 treatment-related adverse events (AEs) were observed in 32.5% of patients in the nivolumab arm and 25.2% in the chemotherapy arm. Among patients who underwent surgery, surgery-related AEs were reported in 41.0% of patients in the nivolumab group vs 38.8% in the chemotherapy group. A total of 11.8% of patients in each group experienced grade 3 or 4 AEs.
"The rationale for the study stems from the evidence that nivolumab plus chemo is the standard of care neoadjuvant treatment for eligible patients with resectable non-small cell lung cancer, having demonstrated improvements in [event-free survival] and the pCR as compared with chemo in the CheckMate-816 study. [NCT02998528]. So, a perioperative treatment approach including adjuvant nivolumab could potentially further reduce the risk of disease relapse and improve clinical benefit in our patients with resectable non-small cell lung cancer," Tina Cascone, MD, PhD, assistant professor, in the Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, said in an interview with Targeted OncologyTM.
CheckMate 77T follows the landmark CheckMate 816 study, which showed an overall survival (OS) benefit with neoadjuvant nivolumab plus chemotherapy over chemotherapy alone at an interim analysis.2
CheckMate 77T randomized patients with stage IIA to IIIB NSCLC to receive neoadjuvant chemotherapy with or without nivolumab every 3 weeks for 4 cycles.1,2 Surgery was then followed by neoadjuvant nivolumab or placebo every 4 weeks for 1 year. The study's primary end point is EFS per blinded independent review, and secondary end points include pCR, major pathologic response, OS, and safety.
"As far as baseline patient characteristics, these were generally balanced between treatment arms. More than 50% of patients were from Europe, more than 20% were from Asia, approximately two-thirds of patients have stage III disease, and about 90% of patients currently smoke or have smoked in the past. More than 50% of patients had tumor PD-L1 expression of 1% or more, and about 40% of patients at tumor PD-L1 expression of less than 1% and most patients received carboplatin-based chemotherapy in both arms," added Cascone.
REFERENCES: 1. Cascone T, Awad M, Spicer J, et al. Perioperative nivolumab in resectable lung cancer. N Engl J Med. 2024;390(19):1756-1769. Doi:10.1056/NEJMoa2311926 2. Perioperative treatment with nivolumab results in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. News release. ESMO. May 22, 2024. Accessed May 23, 2024. Https://tinyurl.Com/26d5d5de
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