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During the 2024 ASCO Annual Meeting, investigators shared preliminary and updated findings from 2 phase 3 studies evaluating the HER2-directed antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) against different comparators in patients with metastatic breast cancer with differing HER2 status with the potential to expand the use of the agent: DESTINY-Breast06 (NCT04494425) and DESTINY-Breast03 (NCT03529110).

In August 2022, the FDA approved T-DXd for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer following prior treatment with an anti–HER2-based regimen in either the metastatic setting or the neoadjuvant or adjuvant setting who have experienced disease recurrence during or within 6 months of completing treatment. The approval was supported by previous findings from DESTINY-Breast03.

“I expect that the use of the [T-DXd] will expand across categories of HER2 expression; it will expand and will be used in earlier settings when it’s needed and required,” Paolo Tarantino, MD, a researcher at the European Institute of Oncology in Milan, Italy, and a clinical research fellow at Dana-Farber Cancer Institute in Boston, Massachusetts, said in an interview with 

. “I was impressed when I saw the first phase 1 trial of T-DXd when it was still called DS-8201, and I’m still impressed every time I see a new clinical trial with this drug. It’s extremely effective, both for HER2-positive metastatic breast cancer [and] HER2-low and even ultralow [disease].”

Updated Findings From DESTINY- Breast03 Further Solidify T-DXd in HER2+ Disease

The open-label, multicenter DESTINY-Breast03 trial enrolled patients with unresectable or metastatic HER2-positive breast cancer who had previously received trastuzumab (Herceptin) and a taxane. Eligible patients needed to have documented radiographic disease progression and adequate renal and hepatic function. Those who had previously received a HER2-directed ADC in the metastatic setting, had uncontrolled or significant cardiovascular disease, or had a history of or current interstitial lung disease were excluded. Prior therapy with ado-trastuzumab emtansine (T-DM1; Kadcyla) was not permitted (Figure 1).

After enrollment, patients were randomly assigned 1:1 to receive T-DXd 5.4 mg/kg every 3 weeks or 3.6 mg/kg T-DM1 every 3 weeks. Patients were stratified by hormone receptor status, prior treatment with pertuzumab (Perjeta), and history of visceral disease.

At the November 20, 2023, data cutoff, updated survival findings from DESTINY- Breast03 presented during ASCO 2024 showed that patients who received T-DXd (n=261) achieved a median investigator-assessed PFS of 29.0 months (95% CI, 23.7-40.0) compared with 7.2 months (95% CI, 6.8-8.3) in the T-DM1 arm (n=263; HR, 0.30; 95% CI, 0.24- 0.38). The 36-month PFS rates were 45.7% (95% CI, 38.9%-52.2%) and 12.4% (95% CI, 8.1%- 17.7%), respectively.

The median investigator-assessed OS in the T-DXd arm was 52.6 months (95% CI, 48.7-not evaluable [NE]) compared with 42.7 months (95% CI, 35.4-NE) in the T-DM1 arm (HR, 0.73; 95% CI, 0.56-0.94). The 36-month OS rates were 67.6% (95% CI, 61.3%-73.0%) and 55.7% (95% CI, 49.2%-61.7%), respectively. The respective 42-month OS rates were 62.5% (95% CI, 56.2%- 68.3%) and 50.1% (95% CI, 43.6%-56.2%).

“What we knew already was that T-DXd improved both PFS and OS compared with T-DM1, but at the prior presentations of this study, we never had an actual amount of improvement in OS because it was not reached in the treatment arms,” Tarantino explained. “Now, at this ASCO, we had the final presentation of the OS that was published concurrently in Nature Medicine. It showed that the use of T-DXd in the second line compared with T-DM1 prolonged OS by 10 months. This is highly relevant and highly clinically impactful to see almost a 1-year improvement in OS, the most meaningful end point.”

The median follow-up was 43.0 months (range, 0.0-62.9) in the T-DXd arm vs 35.4 months (range, 0.0-60.9) in the T-DM1 arm. The median treatment duration was 18.2 months (range, 0.7-56.6) vs 6.9 months (range, 0.7-55.2), respectively.

Additional results demonstrated that the confirmed investigator-assessed ORR was more than doubled with T-DXd vs T-DM1, at 78.9% (95% CI, 73.5%-83.7%) vs 36.9% (95% CI, 31.0%- 43.0%), respectively. The complete response (CR) rates were 12.6% and 4.2%, respectively. The respective median DOR rates were 30.5 months (95% CI, 23.0-NE) and 17.0 months (95% CI, 14.1-23.7); the 36-month DOR rates were 48.9% (95% CI, 41.3%-56.1%) and 28.7% (95% CI, 18.9%-39.2%), respectively.

In terms of safety, patients in the T-DXd and T-DM1 arms experienced any-grade drug-related treatment-emergent adverse effects (TEAEs) at rates of 98.1% and 87.4%, respectively. Patients in both arms experienced drug-related TEAEs of at least grade 3 severity (48.6% vs 42.5%), serious drug-related TEAEs (13.6% vs 7.7%), drug-related TEAEs associated with dose interruption (44.0% vs 18.4%), drug-related TEAEs associated with dose reduction (28.0% vs 15.3%), and drug-related TEAEs associated with treatment discontinuation (22.6% vs 7.3%). No patients in either arm experienced drug-related TEAEs leading to death.

“These data reinforced what we already knew and reinforced the position of T-DXd in patients whose disease progressed after chemotherapy and trastuzumab in earlier lines for HER2-positive metastatic breast cancer,” Tarantino said. “We await [results from] the first-line trial, [the phase 3] DESTINY-Breast09 study [NCT04784715], which is ongoing, [results of which] we may hear about within the next year.”

Data From DESTINY-Breast06 to  Establish T-DXd in Earlier-Line HER2-Low Disease

The open-label, multicenter DESTINY-Breast06 study enrolled patients with hormone receptor–positive, HER2-low metastatic breast cancer, with HER2-low status being defined as an immunohistochemistry (IHC) of 1+ or 2+/in situ hybridization negative and HER2- ultralow status being an IHC of 0. Patients needed to have received at least 2 prior lines of endocrine therapy with or without targeted therapy for metastatic breast cancer or 1 prior line for metastatic breast cancer with progression at or before 6 months of initiating frontline endocrine therapy plus a CDK4/6 inhibitor or disease recurrence at or before 24 months of initiating adjuvant endocrine therapy. Other inclusion criteria included being at least 18 years old and not having received prior chemotherapy for advanced or metastatic breast cancer (Figure 2).

After enrollment, patients were randomly assigned 1:1 to receive 5.4 mg/kg T-DXd every 3 weeks or physician’s choice of capecitabine (Xeloda), nab-paclitaxel (Abraxane), or paclitaxel. Patients were stratified by prior CDK4/6 inhibitor use, HER2 expression, and prior treatment with a taxane in the nonmetastatic setting.

The primary end point was PFS in the population with hormone receptor–positive, HER2-low disease. Secondary end points included OS, ORR, DOR, and PFS in the intention-to-treat (ITT) population, which comprised the HER2-low and HER2-ultralow populations, as well as safety. Figure 2.

“DESTINY-Breast06 was a trial that [intended to] extend the footprint of T-DXd. This is a drug that’s now been FDA approved for a few years; it was initially [approved for] patients who have HER2- positive disease that is relatively late line, so these are patients whose cancers are actually driven by the HER2 oncogene,” V. K. Gadi, MD, PhD, a professor in the Department of Medicine, Division of Hematology/Oncology, at the University of Illinois College of Medicine and the deputy director of the University of Illinois Cancer Center in Chicago, said in an interview with OncologyLive. “However, [with T-DXd] being an ADC, the question was, Could we get the active molecule—the chemotherapy portion of it—into cells that have lower levels of HER2 and see efficacy there?”

At the March 18, 2024, data cutoff, primary findings from DESTINY-Breast06 presented during ASCO 2024 demonstrated that patients with HER2-low disease who received T-DXd (n=359) achieved a median PFS by blinded independent central review of 13.2 months compared with 8.1 months in the physician’s choice arm (n=354; HR, 0.62; 95% CI, 0.51-0.74; P<.0001). Similarly, the median PFS in the ITT population was 13.2 months vs 8.1 months in the T-DXd (n = 436) and the physician’s choice (n=430) arms (HR, 0.63; 95% CI, 0.53-0.75; 

“When you look at the PFS curves, they separate early, they stay separated, and that translated into a median difference of 5.1 months. At different time points [on the PFS curves], T-DXd is comfortably above standard-of-care chemotherapy,” Gadi noted.

Moreover, the 12-month OS rates among patients with HER2-low disease who received T-DXd and physician’s choice of treatment were 87.6% and 81.7%, respectively (HR, 0.83; 95% CI, 0.66-1.05; 

 =.118). In the ITT population, the 12-month OS rates were 87.0% and 81.1%, respectively (HR, 0.81; 95% CI, 0.65-1.00).

Notably, the median PFS improvement observed with T-DXd (n=76) vs physician’s choice of therapy (n=76) in the population with HER2-ultralow disease was consistent with the overall findings, at 13.2 months vs 8.3 months, respectively (HR, 0.78; 95% CI, 0.50-1.21). The 12-month OS rates among these patients were 84.0% and 78.7%, respectively (HR, 0.75; 95% CI, 0.43-1.29).

In the safety population in the T-DXd (n=434) and physician’s choice (n=417) arms, patients experienced any-grade TEAEs at respective rates of 98.8% and 95.2%. Patients in both arms experienced treatment-related TEAEs (96.1%vs 89.4%), serious TEAEs (20.3% vs 16.1%), TEAEs associated with treatment discontinuation (14.3% vs 9.4%), TEAEs associated with dose interruptions (48.4% vs 38.4%), TEAEs associated with dose reductions (24.7% vs 38.6%), and TEAEs leading to death (2.5% vs 1.4%).
“There’s a chance that [T-DXd] gets regulatory approval to move up into this line [of therapy],” Gadi said.

“Then the other question [comes down to safety because] T-DXd is, in some ways, more toxic than what we use otherwise [in this setting]. 

Capecitabine is an exceptionally well-tolerated drug for most patients; T-DXd is less so. However, the efficacy margin is big enough that it’s tempting to look at this [as a treatment option]. It will be an individualized patient decision.”

“This was a positive trial, and we’re all excited about it. Now, how do we put this into play? How are we going to individualize [treatment] decisions? There are a lot of thoughtful things that we must move through as the next phase of things,” Gadi added in conclusion.

FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Updated May 11, 2022. Accessed June 19, 2024. bit.ly/3ybhZLL

DS-8201a versus T-DM1 for human epidermal growth factor receptor 2 (HER2)-positive, unresectable and/or metastatic breast cancer previously treated with trastuzumab and taxane [DESTINY-Breast03]. ClinicalTrials.gov. Updated June 12, 2024. Accessed June 19, 2024. https://classic.clinicaltrials.gov/ct2/ show/NCT03529110

Hamilton EP, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated survival results of DESTINY- Breast03. 

. 2024;42(suppl 16):1025. doi:10.1200/ JCO.2024.42.16_suppl.1025

Study of trastuzumab deruxtecan (T-DXd) vs investigator’s choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer (DB-06). ClinicalTrials.gov. Updated April 12, 2024. Accessed June 19, 2024. https://classic. clinicaltrials.gov/ct2/show/NCT04494425

Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). 

. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_ suppl.LBA1000

Articles

Paolo Tarantino MD, and V. K. Gadi, MD, PhD discuss data from DESTINY-Breast03 and DESTINY-Breast06.

DESTINY-Breast03 and DESTINY-Breast06 Data Shape Metastatic Breast Cancer Treatment

Since its inception, the 340B Drug Pricing Program has aimed to improve access to affordable medications for patients with cancer and other diseases. Although the program has been largely successful in some areas, there are other aspects of its current iteration that have led to it falling short or causing unintended consequences for patients and health care systems who participate in the program.

“The 340B Drug Pricing Program is a federal program implemented in 1992 that allows participating hospitals to purchase eligible outpatient medications at discounts from manufacturers,” Kassem Faraj, MD, urologic oncology fellow at Michigan Medicine in Ann Arbor, explained in a statement to 

. “Eligible hospitals serve a disproportionate share of Medicaid and low-income Medicare patients. Participating hospitals can generate significant savings from the program in the setting [where] they are reimbursed positively for these therapies. The goal of the program is for hospitals to use these savings to stretch federal resources and programs as far as possible for patients and their communities.”

, Faraj and coauthors sought to characterize the impact of the 340B program on the treatment of patients with advanced prostate cancer. They assessed the use of oral specialty drugs for the treatment of patients with prostate cancer as the primary outcome; secondary outcomes included patient monthly out-of-pocket costs and treatment adherence. Investigators used a 20% national sample of patients with Medicare diagnosed with advanced prostate cancer between 2012 and 2019.

Findings from the retrospective study demonstrated that patients who were treated at 340B-participating centers (n = 2237) were not significantly more likely to receive an oral specialty drug for prostate cancer compared with those treated at a center that did not participate in the 340B program (n = 1100; OR, 0.94; 95% CI, 0.76-1.16; 

 = .58). Notably, patients with a higher social vulnerability index (SVI) received oral specialty drugs at a lesser rate; the use of these agents decreased with each 0.1-point increase in SVI (OR, 0.95; 95% CI, 0.93-0.97; 

Regarding out-of-pocket costs, monthly costs for patients with low-income subsidies were not associated with 340B participation (coefficient, –0.10; 95% CI, –0.22 to 0.07; 

 = .26). Participation in the 340B program (OR, 1.26; 95% CI, 0.89-1.8; 

 = .2) and patient SVI (OR, 0.97; 95% CI, 0.89-1.1; 

 = .46) were both not significantly associated with treatment adherence. However, the interaction between hospital 340B participation and social vulnerability on treatment adherence was statistically significant (

“The key findings [from our study] were that the 340B program was not associated with differences in initiating therapy for advanced prostate cancer. However, among those who were started on therapy, 340B was associated with increased treatment adherence in [men with high SVI],” Faraj noted. “The evidence in the literature has mainly assessed the program’s effect on safety net programs. These include the propensity to provide discounted or free medications, care to the uninsured, uncompensated care, and [expansion of] the availability of low-profit services. There are conflicting data on whether the program positively or negatively influences a hospital’s likelihood of investing in these programs.”

Although participation in the 340B program has been shown to increase safety net spending, defined as spending by clinics and hospitals that serve patients who are uninsured, the overall impact of this spending on improving care for patients with cancer is debatable. Nikpay et al conducted an analysis using data from nonprofit and public hospitals that participated in the 340B program in the United States from 2011 to 2015 with the aim of describing the relationship between participation in the programs and hospital safety net spending.

The study compared new participant hospitals in the program with 3 control groups: all other hospitals, nonparticipants, and not-yet participants. Outcomes included spending on a variety of safety net measures, including charity care, community benefit spending, charity care policies, and low-profit service-line provisions.

Results from the analysis showed that compared with all other hospitals, hospitals that were new participants in the 340B program increased charity care spending by 21.8% (SE, 9.8); this spending increase was 28.9% (SE, 8.8) and 21.3% (SE, 9.8) compared with nonparticipating hospitals and hospitals that had not yet participated, respectively. However, compared with hospitals that had not yet participated, 340B participants displayed decreased spending on cash donations and research by 42.8% (SE, 19.5) and 67.3% (SE, 29.8), respectively. The study authors concluded that although the program potentially offers more patients discounted care via charity care, these gains for patients are fully offset by cutbacks in other key programs that benefit the community.

“There are [also] concerns that participating hospitals may be incentivized to utilize expensive therapies, given that the savings they generate after entering the program can be substantial,” Faraj added. “Some [research] has demonstrated that the program has been associated with increased spending on oncologic drugs, although the implications of these findings on quality are not clear.”

, investigators examined data from 95,127 outpatient biologic oncology drug spending instances in 478 hospitals in the US between 2007 and 2019. The study compared spending for commercially insured patients treated at hospitals that were new 340B participants vs those treated at nonparticipating hospitals. Data were included from patients who received any of the 5 drugs of interest: filgrastim (Neupogen), pegfilgrastim (Neulasta), trastuzumab (Herceptin), bevacizumab (Avastin), and rituximab (Rituxan).

Commercially insured patients treated at 340B-participating hospitals experienced increased amounts paid for oncologic treatment episodes vs those treated at nonparticipating hospitals. Costs for these patients rose by $5132.37 (95% CI, $1656.82-$8607.92; 

 = .004), $4625.08 (95% CI, $1239.56-$8010.60; 

 = .007), and $6504.18 (95% CI, $2829.79-$10,178.56; 

 = .001) in years 1, 2, and 3 of participation. Notably, there was no significant differential trend in episode spending when 340B-participating and nonparticipating hospitals treated patients with Medicare Advantage.

Further research conducted by the North Carolina State Health Plan for Teachers and State Employees revealed that many hospitals in the state used the 340B program to overcharge patients with cancer for oncologic drugs. Some hospitals that participated in the program chased higher profits by expanding into more affluent neighborhoods with higher rates of insurance and greatly increasing the number of contracts with external pharmacies, they said. The study authors noted that although the program theoretically allows for participating hospitals to share the savings they experience with patients or reinvest these savings in other areas to benefit the community, there is no legal requirement that they do so.

Findings from an analysis of medical claims by the North Carolina State Health Plan for Teachers and State Employees showed that 340B hospitals in the state charged an average price markup of 5.4 times the discounted acquisition costs for outpatient oncologic infusion drugs compared with 2.9 times the US commercial price at non-340B hospitals. Additionally, 340B hospitals billed the North Carolina State Health Plan at a higher price markup of 84.8% vs nonparticipating hospitals from 2020 to 2022. Some 340B hospitals averaged up to $6026 in profit per claim and charged as much as 12.7 times the acquisition cost for oncology drugs; 15 of the 21 hospitals that filed over 300 claims related to treating state employees with cancer charged at least triple the acquisition cost.

“Future research should assess the implications of the program on the quality of care being delivered to patients. Many hospital advocates and hospitals themselves report that 340B savings are being used to improve various aspects of patient care,” Faraj said. “The goals of the program are vague and open to interpretation, which in turn has made it challenging to assess the program’s effectiveness. As an initial step to improve the program, reform could focus on providing guidance on how hospitals can use savings from discounted medications. This would allow governing bodies to establish objective measures to assess the program’s effectiveness.”

Faraj KS, Kaufman SR, Oerline M, et al. The 340B program and oral specialty drugs for advanced prostate cancer. 

. 2024;130(12):2160-2168. doi:10.1002/cncr.35262

Nikpay SS, Buntin MB, Conti RM. Relationship between initiation of 340B participation and hospital safety-net engagement. 

. 2020;55(2):157-169. doi:10.1111/1475-6773.13278

Chang J, Karaca-Mandic P, Nikpay S, Jeffery MM. Association between new 340B program participation and commercial insurance spending on outpatient biologic oncology drugs. 

. 2023;4(6):e231485. doi:10.1001/jamahealthforum.2023.1485

Overcharged: State Employees, Cancer Drugs, and the 340B Drug Pricing Program

. North Carolina State Health Plan. Accessed May 31, 2024. https://www.shpnc.org/documents/overcharged-state-employees-cancer-drugs-and-340b-drug-price-program/download?attachment

Kassem Faraj, MD, details the 340B Drug Pricing program and data from a study examining participation in the program for patients with advanced prostate cancer. 

340B Drug Pricing Program Ostensibly Improves Cancer Care but Carries Unforeseen Consequences

As the 2024 edition of the American Society of Clinical Oncology (ASCO) Annual Meeting drew to a close, clinicians were left to digest practice-changing presentations, sparking excitement among those who attended the meeting in Chicago, Illinois.

“In the field of renal cell carcinoma [RCC], this ASCO has been important because we’re seeing more biomarker sessions,” Laurence Albiges, MD, PhD, of Gustave Roussy in Villejuif, France, said in an interview with 

. Bradley McGregor, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, added, “We’re seeing incremental steps trying to take the data we have and find signals. The story of KIM-1 in the adjuvant space for RCC is intriguing—might that be a biomarker we can [use to] help identify which patients need to undergo adjuvant therapy for RCC?”

ASCO 2023-2024 president, Lynn M. Schuchter, MD, also emphasized the importance of building a bridge between the academic and community setting, tying into her theme of the meeting: “The Art and Science of Cancer Care: From Comfort to Cure.”

“Across the US and globally, the lines are [becoming] much more blurred between academic medical oncologists and the community setting. Our patients are in the community, want access to clinical trials, [and] more community oncologists recognize the need for specialization,” Schuchter said.

Through our live coverage, we conducted more than 100 exclusive interviews with key opinion leaders, and our 

: On Location interviews hosted by Chandler Park, MD, FACP, of Norton Cancer Institute, and Yan Leyfman, MD, of Memorial Sloan Kettering Cancer Center, captured all aspects of this year’s ASCO meeting. See top-line coverage below of nearly 20 exciting abstracts and visit 

 for full, comprehensive coverage of the data.

University of Illinois Cancer Center, UI Health

"Of the] top 3 [abstracts presented at ASCO], DESTINY-Breast06 is up there. It’s practice changing, and anything that changes practice in hormone receptor–positive breast cancer—the most common breast cancer—is probably first place.”

Findings from the phase 3 DESTINY-Breast06 trial (NCT04494425) revealed that treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs investigator’s choice of chemotherapy in pretreated patients with hormone receptor–positive, HER2-low metastatic breast cancer.

The median PFS among patients with HER2-low disease who received T-DXd (n = 359) was 13.2 months vs 8.1 months for those given chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; 

 < .0001) per blinded independent central review (BICR). In the intention-to-treat (ITT) population comprised of patients with HER2-low and -ultralow disease, the median PFS was 13.2 months with T-DXd (n = 436) vs 8.1 months with chemotherapy (n = 430; HR, 0.63; 95% CI, 0.53-0.75; 

 < .0001). At approximately 40% maturity, the 12-month overall survival (OS) data showed an OS rate of 87.6% in the T-DXd arm vs 81.7% in the chemotherapy arm among patients with HER2-low disease and 87.0% vs 81.1%, respectively, in the ITT population.

Winship Cancer Institute of Emory University

"This study’s data demonstrated that this combination is a strategy for patients where [appropriate]; abemaciclib is widely available with a toxicity profile that we know and understand. Also, 30% of patients in this study were biomarker negative—they didn’t have an 

 mutation or a PI3K pathway alteration—and for those patients this offers a targeted therapy option post CDK4/6 inhibition. Regardless of the presence or absence of an 

 mutation or PI3K pathway alteration, [patients experienced] benefit with fulvestrant and abemaciclib.”

The phase 3 postMONARCH trial (NCT05169567) was the first phase 3, randomized, placebo-controlled study to demonstrate the benefit of continued CDK4/6 inhibition beyond progression on a CDK4/6 inhibitor. Study findings showed that the addition of abemaciclib (Verzenio) to fulvestrant (Faslodex) led to a significant improvement in PFS vs fulvestrant alone in patients with hormone receptor–positive, HER2-negative advanced breast cancer who had disease progression on a CDK4/6 inhibitor and endocrine therapy.

Data from the primary analysis indicated that treatment with the doublet (n = 182) led to a median investigator-assessed PFS of 6.0 months (95% CI, 5.6-8.6) vs 5.3 months (95% CI, 3.7-5.6) with fulvestrant alone (n = 186), translating to a 27% reduction in the risk of disease progression or death (HR, 0.73; 95% CI, 0.57-0.95; nominal 

 = .02). The 6-month PFS rates in the respective arms were 50% and 37%.

"[For] PFS2, time from randomization to experimental vs placebo therapy and then progression on the second therapy, it was interesting to see [that] the difference between the 2 arms widens—it was 24.0 months vs 15.1 months, respectively. Now the Δ is 8.9 months, meaning if you’re treating patients with a potentially better therapy in the first line that keeps giving [benefit, then] the second line [will] look better as well in patients who receive triplet vs fulvestrant plus palbociclib plus placebo. That was an important piece of information [from INAVO120].”

Based on data from the phase 3 INAVO120 trial (NCT04191499), on May 28, 2024, the FDA granted priority review to the new dr

ug application seeking the approval of inavolisib (GDC-0077) in combination with palbociclib (Ibrance) and fulvestrant for the treatment of adult patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer harboring 

 mutations, following recurrence on or within 12 months of completing adjuvant endocrine therapy. The target action data for the FDA decision is November 27, 2024.

INAVO120 met its primary end point as patients treated with inavolisib plus palbociclib and fulvestrant (n = 161) experienced a statistically significant and clinically meaningful improvement in PFS compared with placebo plus palbociclib and fulvestrant (n = 164; HR, 0.43; 95% CI, 0.32-0.59; 

 < .0001). Additional efficacy data presented at the 2024 ASCO Annual Meeting revealed that at a median follow-up of 21.3 months, the median time from random assignment to end or discontinuation of next-line treatment or death from any cause was 24.0 months (95% CI, 18.6-not evaluable [NE]) vs 15.1 months (95% CI, 13.5-22.3), respectively (stratified HR, 0.54; 95% CI, 0.38-0.77).

"The interesting finding is that [treatment with] the combination of nivolumab and ipilimumab [elicited] a higher response rate of 33%, including 5 patients who had a CR, which is unheard of in [those with] clear cell carcinoma who have received prior chemotherapy and have advanced or metastatic disease. Importantly, patients who responded to the combination had a durable response; we had patients staying on study as they approached the 2-year mark, and even today patients are continuing treatment.”

Combination treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) bested nivolumab monotherapy, according to data from the final analysis of the phase 2 BrUOG 354 trial (NCT03355976), which demonstrated that patients with recurrent, advanced, or metastatic ovarian or other extra-RCC carcinomas experienced improved outcomes with the combination vs monotherapy.

Findings showed that 16.7% of patients treated with nivolumab plus ipilimumab (n = 30) achieved a complete response (CR), whereas no patients treated with nivolumab alone (n = 14) experienced a CR; partial response rates were 16.7% vs 14.3%, respectively. Additionally, the median PFS was 5.6 months (95% CI, 1.6-29.2) in the doublet arm compared with 2.2 months (95% CI, 1.2-3.4) in the monotherapy arm, and the median OS was 24.7 months (95% CI, 5.9-not reached [NR]) vs 17.3 months (95% CI, 2.1-42.7), respectively.

"[This] very interesting phase 3 trial [was examining] lymph node assessment in patients undergoing interval cytoreduction. That is practice-changing [data], because we don’t need to incorporate lymph node dissection in normally appearing lymph nodes when patients undergo interval cytoreduction [therapy] after neoadjuvant chemotherapy in ovarian cancer.”

Data from the phase 3 CARACO trial (NCT01218490) revealed that adding retroperitoneal lymphadenectomy to cytoreductive surgery in primary surgery or interval surgery following neoadjuvant chemotherapy does not improve PFS or OS in patients with advanced ovarian cancer and no suspicious nodes.

Regarding the primary end point of PFS, patients who did not receive retroperitoneal lymphadenectomy (n = 193) experienced a median PFS of 14.8 months compared with 18.6 months for those who did (HR, 0.96; 95% CI, 0.77-1.20; 

 = .712). The median OS was 48.9 months compared with 58.8 months, respectively (HR, 0.92; 95% CI, 0.72-1.17; 

"[This phase 2] study with dostarlimab checkpoint therapy was originally presented at ASCO and published in 

 [in 2022] and showed 14 of 14 patients achieved CRs in the early-line setting. [This] data set of a larger number of patients demonstrates and validates that in a biomarker-driven population of patients with rectal cancer in an early setting, a lot of patients can achieve CRs. In oncology, studies [such as this] show that [if] we treat patients with potent drugs earlier, we can improve outcomes.”

All 42 patients with locally advanced mismatch repair–deficient (dMMR) rectal cancer who completed treatment with dostarlimab-gxly (Jemperli) in a phase 2 study (NCT04165772) achieved a clinical CR, and responses were durable at a median follow-up of 17.9 months (range, 0.3-50.5). Following treatment with the PD-1 inhibitor, 24 patients experienced a sustained clinical CR at a median follow-up of 26.3 months (range, 12.4-50.5). Investigators also noted that no patients in the trial have required chemotherapy, radiation therapy, or surgery.

Initial results of the trial were presented at the 2022 ASCO Annual Meeting and showed a 100% clinical CR rate in 14 patients with stage II or III dMMR rectal cancer who received treatment with dostarlimab. The confirmatory, global, single-arm, phase 2 AZUR-1 trial (NCT05723562) is also ongoing and anticipates an estimated enrollment of 150 patients.

"The most relevant news in the field of colorectal cancer [CRC] is the TRANSMET trial…that shows a very significant advantage in the liver transplantation [plus chemotherapy arm vs chemotherapy alone arm] in terms of 5-year OS, which was the primary end point of the study. Even more [benefit was seen] in the per-protocol population [with a HR of 0.16] when compared with the ITT population where there was a HR of 0.37. But a clear benefit [was seen] from this procedure that has never been considered in the treatment armamentarium for patients with metastatic CRC. These data are big news and something that we will need to include in our multidisciplinary evaluations in front of patients with metastatic CRC with liver-limited disease.”

The addition of liver transplantation to chemotherapy significantly improved OS and PFS vs chemotherapy alone in patients with unresectable colorectal liver metastases, according to data from the TRANSMET trial (NCT02597348). Patients who received liver transplantation and chemotherapy (n = 36) experienced a 5-year OS rate of 73% compared with 9% for patients who received chemotherapy alone (n = 38) in the per-protocol population of the trial (HR, 0.16; 95% CI, 0.07-0.33; log-rank 

At a median follow-up of 59 months, the 5-year OS rate in the ITT population was 57% in the transplantation arm (n = 47) vs 13% in the chemotherapy alone arm (n = 47; HR, 0.37; 95% CI, 0.21-0.65;

 = .0003). The 5-year PFS rates were 20% compared with 0%, respectively (HR, 0.34; 95% CI, 0.20-0.57; log-rank 

"As a gastrointestinal radiation oncologist, one of the most important studies was the ESOPEC trial in esophageal cancer. The study showed that there was an improvement in OS for the use of FLOT vs the CROSS regimen. Although FLOT is probably going to be a more commonly used regimen in the US, it’s a very difficult regimen for patients to tolerate, so the CROSS regimen is still a viable option. Also, this study didn’t evaluate the use of CROSS followed by surgery followed by adjuvant nivolumab, which we’ve seen has significantly improved disease-free survival [DFS] for patients who have undergone CROSS followed by surgery. We still have an option with CROSS followed by surgery followed by nivolumab.”

At a median follow-up of 55 months, perioperative chemotherapy with docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT protocol) improved OS compared with neoadjuvant chemoradiation (CROSS protocol) for patients with resectable esophageal cancer. Data from the phase 3 ESOPEC trial (NCT02509286) showed that patients in the ITT population who received the FLOT protocol (n = 221) achieved a median OS of 66 months (95% CI, 36-NE) compared with 37 months (95% CI, 28-43) among those who were treated with the CROSS protocol (n = 217; HR, 0.70; 95% CI, 0.53-0.92; 

Additionally, the 3-year OS rates were 57.4% vs 50.7%, respectively, and the 5-year respective OS rates were 50.6% vs 38.7%.

"Data from the CheckMate 9DW study in HCC could be practice changing using the combination of nivolumab/ipilimumab in the first-line setting against a tyrosine kinase inhibitor [TKI]. It is very important because the first-line setting of HCC is very crowded right now. There are data with atezolizumab [Tecentriq] plus bevacizumab [Avastin] and with durvalumab [Imfinzi] plus tremelimumab [Imjudo], and those 2 regimens are currently approved. We also heard most recently from the phase 3 CARES-310 study [NCT03764293] that you can give a TKI and [an] immuno-oncology agent in this setting, and [there is an] OS benefit. That regimen with camrelizumab plus rivoceranib is not currently approved yet but will hopefully receive approval in the future. With [these] data—now that nivolumab/ipilimumab met it’s OS end point—it [could] be a fourth combination that may get approved in the first-line setting, giving us more options. Then, as clinicians, we have to decide which regimen to choose.”

The combination of nivolumab and ipilimumab was superior to both lenvatinib (Lenvima) and sorafenib (Nexavar) in unresectable hepatocellular carcinoma (HCC), demonstrating a statistically significant OS benefit and higher response rates. Findings from the phase 3 CheckMate 9DW trial (NCT04039607) showed that the median OS among patients treated with nivolumab plus ipilimumab (n = 335) was 23.7 months (95% CI, 18.8-29.4) compared with 20.6 months (95% CI, 17.5-22.5) with lenvatinib/sorafenib (n = 333; HR, 0.79; 95% CI, 0.65-0.96; 

Further, the overall response rate (ORR) was 36% (95% CI, 31%-42%) in the immunotherapy arm with a median duration of response (DOR) of 30.4 months (95% CI, 21.1-NE) vs 13% (95% CI, 10%-17%) in the lenvatinib/sorafenib arm with a median DOR of 12.9 months (95% CI, 10.2-31.2).

"The CORE-001 study has certainly made a big impact; it’s brought this option for patients who [may be] fearful of developing progressive disease while on treatment. We have a very viable and tolerable drug combination going forward.”

The long-term durable responses experienced by patients with BCG–unresponsive, high-risk non–muscle-invasive bladder cancer with carcinoma in situ who received treatment with cretostimogene grenadenorepvec (CG0070) plus pembrolizumab (Keytruda) suggest that the doublet may be a novel bladder-sparing strategy, according to investigators of the phase 2 CORE-001 trial (NCT04387461).

In CORE-001, 82.9% of patients who received the conditionally replicating, intravesically delivered adenovirus plus pembrolizumab (n = 335) experienced a CR at any time. Additionally, the 12-month CR rate was 57.1% (95% CI, 39.5%-73.2%) and the 24-month CR rate was 54.3% (95% CI, 36.9%-70.8%). The PFS rate was 100%; no patients experienced disease progression to muscle-invasive bladder cancer or metastatic urothelial carcinoma.

"Although this study was negative, afterward investigators looked at subpopulations of patients who might benefit from therapy [with atezolizumab]. Vincent Wenxin Xu, MD, has done remarkable work on the circulating protein KIM-1 and has shown that it is predictive of diagnosis of kidney cancer vs a benign entity, [and that] it’s associated with worse outcomes after resection of a tumor in the metastatic setting. [When investigators then] looked at this in the setting of IMmotion010, results were markedly different based on KIM-1 levels. In the KIM-1–low setting there was no benefit, it mimicked the overall trial with no benefit whatsoever for atezolizumab. But patients with high KIM-1 levels after surgery experienced a significant and clinically meaningful benefit [with] atezolizumab treatment. That’s not going to change atezolizumab’s [use] specifically, it’s not going to make that a viable therapy today, but it’s proof of concept that we’re starting to develop biomarkers to be able to rationally select patients. Because right now, with adjuvant therapy, we undertreat some patients and overtreat others. If we have a rational way to select who’s going to benefit the most from these therapies, we’re going to do our patients a great service, so this study is a very important contribution to the literature.”

An exploratory analysis of data from the phase 3 IMmotion010 trial (NCT03024996) found that high postnephrectomy KIM-1 serum levels showed potential as a circulating protein biomarker for minimal residual disease and disease recurrence in patients with RCC in the adjuvant setting. Atezolizumab also improved DFS vs placebo in patients with high-baseline KIM-1 serum levels, and a baseline KIM-1 level of 86 pg/mL was identified to define high vs low expression.

KIM-1–high status was associated with worse DFS outcomes, as patients with KIM-1–high disease (n = 300) experienced a median DFS of 35.88 months compared with 57.23 months for those with KIM-1–low disease (n = 452; HR, 1.75; 95% CI, 1.40-2.17). Further, in the KIM-1–high subgroup, DFS outcomes were improved for patients who received atezolizumab (n = 151) vs placebo; the median DFS was NE vs 21.16 months (n = 149; HR, 0.72; 95% CI, 0.52-0.99), respectively.

"The impressive results of ADRIATIC demonstrated that [there was a] reduction in risk of mortality by 27%. There were 10% gains in 2- and 3-year OS that coupled with PFS. [Although] more than 50% of patients had disease progression at 2 years, this is only the beginning of being able to study novel and combination immunotherapies. ADRIATIC has not read out its combination arm of durvalumab plus tremelimumab, and there are a number of other investigational studies that are seeking to improve on [these data].”

The administration of durvalumab as consolidation treatment following concurrent chemoradiotherapy significantly improved OS and PFS vs placebo in patients with limited-stage small cell lung cancer (LS-SCLC). This represents a critical finding as no major advancements have occurred with systemic treatment for LS-SCLC in decades, according to investigators of the phase 3 ADRIATIC study (NCT03703297).

Data from the first planned interim analysis at a median follow-up of 37.2 months (range, 0.1-60.9) in censored patients demonstrated that the median OS was 55.9 months (95% CI, 37.3-NE) for patients treated with the immunotherapy (n = 264)vs 33.4 months (95% CI, 25.5-39.9) with placebo (n = 266; HR, 0.73; 95% CI, 0.57-0.93; 

The University of Texas MD Anderson Cancer Center

This roundup includes exclusive insights from nearly 20 clinicians and key data on the top abstracts coming out of the 2024 ASCO Annual Meeting.

ASCO 2024 Data Shake Up Standards and Shed Light on Biomarkers

As the lung cancer treatment paradigm continues to evolve and advance, investigators continue to develop increasingly effective therapies for patients in specific, and in some cases previously underserved, disease subtypes. Although the disease remains the leading cause of cancer-related death worldwide, there is great hope among experts in the field that outcomes for patients with lung cancer will only continue to improve in the coming years.

“It’s a very exciting time for patients with lung cancer because of the availability of targeted and immunotherapy treatment options,” Suresh S. Ramalingam, MD, FACP, FASCO, executive director of Winship Cancer Institute of Emory University and associate vice president for cancer at Woodruff Health Sciences Center in Atlanta, Georgia, said in an interview with 

. “We’re seeing improvements in patients with small cell lung cancer [SCLC] and with non–small cell lung cancer [NSCLC]. Overall, patients with lung cancer are living better and living longer, and that is thanks to the amazing therapeutic advances that have been made in the past few years.”

NSCLC is the most common type of lung cancer, representing approximately 85% of cases. Despite the overall poor prognosis the disease carries—the 5-year overall survival (OS) rate is approximately 17%—a variety of targeted approaches and immunotherapeutics have gained traction in the space and improved upon outcomes seen with traditional surgery, chemotherapy, and/or radiotherapy.

Since 2020, 16 agents have been approved by the FDA in various disease settings of NSCLC.

On the other hand, patients with SCLC have not experienced as many robust advances in recent years. SCLC remains a highly aggressive subtype that represents approximately 15% of all lung cancer diagnoses; although it is often initially responsive to chemotherapy, most patients relapse, and the 5-year OS rate is less than 7%.

Specifically, patients with limited-stage SCLC (LS-SCLC) have not seen a major treatment advance beyond the standard of care for decades. The current standard treatment, concurrent chemoradiotherapy, confers a median OS that ranges between 25 and 30 months.

During the plenary session at the 2024 American Society of Clinical Oncology Annual Meeting (ASCO 2024), in June in Chicago, Illinois, investigators presented findings from 3 phase 3 clinical studies with the potential to rewrite the standard of care in patients with oncogene-driven NSCLC and LS-SCLC.

The phase 3 LAURA trial (NCT03521154) was a double-blind, placebo-controlled study that enrolled adult patients with locally advanced, unresectable, stage III NSCLC with an EGFR exon 19 deletion or L858R mutation whose disease did not progress following definitive chemoradiotherapy. Eligible patients were randomly assigned 2:1 to receive oral osimertinib (Tagrisso) 80 mg or placebo once daily. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR) per RECIST v1.1; secondary end points included overall survival (OS), central nervous system PFS, and safety.

“Presently in this group of patients, concurrent chemoradiation followed by immunotherapy has been the standard of care. But that is not something that works well for patients with an EGFR mutation, [and] that is why we conducted this study,” Ramalingam, who was the lead study author, explained.

Findings from the primary analysis of LAURA presented during ASCO 2024 by Ramalingam demonstrated that the median PFS per BICR in the osimertinib arm (n = 143) was 39.1 months (95% CI, 31.5-not calculable [NC]) vs 5.6 months (95% CI, 3.7-7.4) in the placebo arm (n = 73). Treatment with osimertinib conferred an 84% reduction in the risk of progression or death compared with placebo (HR, 0.16; 95% CI, 0.10-0.24; 

 < .001). The 12- and 24-month PFS rates were 74% and 65%, respectively, in the investigational arm vs 22% and 13%, respectively, in the control arm.

The objective response rates (ORR) by BICR in the osimertinib and placebo arms were 57% (95% CI, 49%-66%) vs 33% (95% CI, 22%-45%), respectively. The median duration of response (DOR) was 36.9 months (95% CI, 30.1-NC) vs 6.5 months (95% CI, 3.6-8.3), respectively. OS data were 20% mature at the time of the presentation, but favored the osimertinib arm (HR, 0.81; 95% CI, 0.42-1.56; 

“We found that the [PFS] benefit was seen across all key subgroups of patients enrolled to the study,” Ramalingam added. “It is widely applicable to this patient population regardless of age, gender, or the specific type of mutation. We [also] saw that the safety profile was consistent with what we would expect with osimertinib alone.”

Osimertinib was well tolerated over the course of LAURA; most adverse effects (AEs) in the investigational arm were low grade with 1 patient experiencing an AE leading to death that was deemed possibly related to treatment. Patients in the osimertinib and placebo arms experienced grade 3 or higher AEs (35% vs 12%), AEs leading to death (2% vs 3%), and serious AEs (38% vs 15%). The most common any-grade AEs reported in at least 10% of patients in the osimertinib arm included radiation pneumonitis (48%), diarrhea (36%), and rash (24%).

“This will have an immediate impact on management of patients with stage III locally advanced 

-mutated [NSCLC],” Ramalingam said. “Right now, we [prescribe] chemotherapy and radiation and then we just follow [patients]. The LAURA study showed that if patients do not get any further therapy, within 5 to 6 months, half of the patients have disease progression. Using osimertinib in this setting, a drug that is approved and available for stage IV disease and earlier resected lung cancer, would be an easy integration into standard treatment algorithms. We believe this trial will change the standard of care for this subset of patients.”

-positive NSCLC, findings presented during ASCO 2024 from the phase 3 CROWN trial (NCT03052608) displayed the longest PFS ever reported in advanced NSCLC. CROWN enrolled patients with stage IIIB/IV 

-positive NSCLC who did not receive prior systemic therapy for metastatic disease and randomly assigned them 1:1 to receive lorlatinib (Lorbrena) 100 mg once daily or crizotinib (Xalkori) 250 mg twice daily. The primary end point was PFS by BICR; secondary end points included ORR, OS, and safety (

At a median PFS follow-up of 60.2 months (95% CI, 57.4-61.6) in the lorlatinib arm (n = 149) vs 55.1 months (95% CI, 36.8-62.5) in the crizotinib arm (n = 147), the median PFS was not reached (NR; 95% CI, 64.3-NR) compared with 9.1 months (95% CI, 7.4-10.9), respectively (HR, 0.19; 95% CI, 0.13-0.27). The 5-year PFS rates were 60% vs 8%, respectively.

Notably, lorlatinib provided a significant PFS benefit vs crizotinib both in patients with (HR, 0.08; 95% CI, 0.04-0.19) and without (HR, 0.24; 95% CI, 0.16-0.36) brain metastases. Additionally, lorlatinib significantly extended time to intracranial progression compared with crizotinib (HR, 0.06; 95% CI, 0.03-0.12).

“[The CROWN data] were outstanding; maybe some of the best targeted data we have seen in lung cancer,” David R. Spigel, MD, medical oncologist and chief scientific officer at Sarah Cannon Research Institute, in Nashville, Tennessee, said in an interview with 

. “I would argue it is some of the best data ever seen in oncology, in terms of patients living for 5 years without their cancer returning. That really is quite amazing.”

During ASCO 2024, Spigel presented findings from the phase 3 ADRIATIC study (NCT03703297), which examined the PD-L1– directed antibody durvalumab (Imfinzi) as consolidation therapy following concurrent chemoradiation in patients with stage I to III LS-SCLC who did not experience disease progression after chemoradiation. Patients were randomly assigned to receive durvalumab 1500 mg every 4 weeks, placebo every 4 weeks, or durvalumab 1500 every 4 weeks plus tremelimumab (Imjudo) 75 mg every 4 weeks for 4 doses followed by durvalumab monotherapy. The co–primary end points were OS and PFS by BICR per RECIST v1.1 for durvalumab vs placebo.

“[Chemoradiation] has been the standard of care for decades, but most patients have their cancer come back within 2 years, and [approximately] less than a third of patients will make it beyond 5 years,” Spigel noted. “Our current standard of treatment is just not good enough to help patients when your goal is to cure them. ADRIATIC was designed to see if using immunotherapy after chemotherapy and radiation can improve [outcomes].”

During the presentation, Spigel shared results from the durvalumab monotherapy and placebo arms, noting that data from the combination arm will be shared at a later date. At a median follow-up of 37.2 months (range, 0.1-60.9) patients treated with durvalumab (n = 264) achieved a median OS of 55.9 months (95% CI, 37.3-not evaluable) vs 33.4 months (95% CI, 25.5-39.9) among patients who received placebo (n = 266), leading to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.57-0.93; 

 = .0104). At a median follow-up of 27.6 months (range, 0.0-55.8), the median PFS was 16.6 months (95% CI, 10.2-28.2) vs 9.2 months (95% CI, 7.4-12.9), respectively (HR, 0.76; 95% CI, 0.61-0.95; 

The 24- and 36-month OS rates were 68.0% and 56.5%, respectively, in the durvalumab arm; these rates were 58.5% and 47.6% in the placebo arm. The 24- and 36-month PFS rates were 48.8% and 46.2% respectively, in the durvalumab arm; these rates were 36.1% and 34.2% in the placebo arm.

Findings from a subgroup analysis showed that the OS benefit of durvalumab over placebo was observed regardless of patient characteristics. The most pronounced benefit with durvalumab was reported in patients who were randomly assigned to the drug less than 14 days after concurrent chemoradiation (HR, 0.47; 95% CI, 0.24-0.91), those who achieved stable disease following concurrent chemoradiation (HR, 0.54; 95% CI, 0.25-1.13), and those with a World Health Organization performance status of 0 (HR, 0.55; 95% CI, 0.38-0.79).

“The study met both of its primary end points,” Spigel commented. “This is a new standard of care, and durvalumab will hopefully have its label expanded where it is already available. This will be something doctors, patients, and families will want to get access to as soon as possible. I believe this will change care for us starting today, and that is good news for our patients.”

Durvalumab also displayed a tolerable safety profile in LS-SCLC; patients discontinued treatment due to AEs at a rate of 16.4% vs 10.6% in the monotherapy and placebo arms, respectively, and death due to AEs was reported at respective rates of 2.7% vs 1.9%. Patients in both arms experienced serious AEs (29.8% vs 24.2%), any-grade immune-mediated AEs (32.1% vs 10.2%), and grade 3 or 4 immune-mediated AEs (5.3% vs 1.5%). The most common any-grade AEs in the durvalumab arm included radiation pneumonitis (22.9%), decreased appetite (16.8%), and hypothyroidism (16.0%).

“There is this wave of other drugs coming, [including] antibody-drug conjugates, bispecifics, and other immunotherapy combinations,” Spigel said in conclusion. “These are naturally going to be things we want to study in earlier treatment settings like first-line extensive-stage SCLC and LS-SCLC. This is kind of a stair-step approach. Now that durvalumab has shown benefit and we have other drugs showing benefit, can you combine them? Do you use them in sequence? These will be the next big questions.”

Araghi M, Mannani R, Heidarnejad Maleki A, et al. Recent advances in non-small cell lung cancer targeted therapy; an update review. Cancer Cell Int. 2023;23(1):162. doi:10.1186/ s12935-023-02990-y

FDA approvals in lung cancer treatment. Lung Cancer Research Foundation. Accessed June 6, 2024. https://www.lungcancerresearchfoundation.org/research/why-research/treatment-advances/

Patel SR, Das M. Small cell lung cancer: emerging targets and strategies for precision therapy. 

. 2023;15(16):4016. doi:10.3390/cancers15164016

Spigel DR, Cheng Y, Cho BC, et al. ADRIATIC: durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). 

. 2024;42(suppl 17):LBA5. doi:10.1200/JCO.2024.42.17_suppl.LBA5

Ramalingam SS, Kato T, Dong X, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor- mutated (EGFRm) NSCLC: primary results of the phase 3 LAURA study. 

. 2024;42(suppl 17):LBA4. doi:10.1200/ JCO.2024.42.17_suppl.LBA4

Solomon BJ, Liu G, Felip E, et al. Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK + non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study. 

. 2024;42(suppl 17):LBA8503. doi:10.1200/JCO.2024.42.17_suppl.LBA8503

Lung cancer treatment is advancing with new therapies targeting specific subtypes, improving patient outcomes. NSCLC, the most common type, has seen significant progress with 16 FDA-approved agents since 2020. SCLC, however, remains challenging with fewer advancements. Recent phase 3 trials, LAURA and CROWN, have shown promising results for EGFR-mutated and ALK-positive NSCLC, respectively. The ADRIATIC study suggests durvalumab as a new standard for LS-SCLC. These findings highlight the potential for improved survival and quality of life for lung cancer patients.

As the lung cancer paradigm continues to advance, increasingly effective therapies are under development for previously underserved disease subtypes.

Key Data Updates From ASCO May Advance the Treatment Landscapes of 3 Lung Cancer Subtypes

Several recent studies examining novel mTOR inhibitors in combination with various agents, from inhibitors of VEGF, Aurora A kinase, and PD-1 to an antidiabetic agent, have shed light on how mTOR inhibitors may be combined safely with additional therapies for patients with solid tumors. Sapanisertib (CB-228), a dual inhibitor of mTORC1 and mTORC2, is an mTOR inhibitor of particular interest, and findings from phase 1 studies showed promising safety signals when combination therapy with the agent was evaluated in various solid tumors, including cervical and pancreatic cancer.

“mTOR exists in 2 physically and functionally distinct protein signaling complexes—one with Raptor, which is sensitive to the mTOR inhibitor rapamycin, and the other with Rictor, which is rapamycin insensitive,” Vivek Subbiah, MD, chief of early-phase drug development at Sarah Cannon Research Institute in Nashville, Tennessee, said in an interview with 

). “The currently approved rapalogs such as rapamycin or everolimus [Afinitor] exert that inhibitory effect predominantly via the mTORC1 pathway, while the inhibitory effect of mTORC2 is very limited or weak. Consequently, there is continued signaling through significant pathway and feedback loops resulting in upregulation of other pathways like AKT, which has an undesirable effect of accelerating not only the cell proliferation but antagonizing the antiproliferative effects of the original mTOR inhibition.”

Previously, sapanisertib received fast track designation from the FDA in October 2022 for use as monotherapy in patients with unresectable or metastatic squamous non–small cell lung cancer harboring an 

 mutation who previously received platinum-based chemotherapy and immune checkpoint inhibition.

 Studies have also suggested that combination therapy may enhance the antitumor activity of sapanisertib.

“We needed next-generation mTOR inhibitors that not only target mTORC1 which is a Raptor pathway, but also target the Richter pathway. We have next-generation dual inhibitors of mTORC1 and mTORC2 and these have been developed, and preclinical models have supported the potency of the dual inhibitor strategy. Sapanisertib is a potent, selective ATP competitive dual inhibitor of mTORC1 and mTORC2 regulated by upstream tyrosine kinases such as IGF1R, and in early phase clinical trials, sapanisertib was shown to have preliminary anti-tumor activity,” Subbiah added.

Sapanisertib Plus the Antidiabetic Agent Metformin

“Metformin is a common antidiabetic medication that has been repurposed as an antineoplastic medication to enhance the effect of chemotherapy in multiple cancers,” Subbiah explained. “Metformin inhibits the mTOR pathway through upstream activation of AMPK, which results in the phosphorylation and activation of the tumor suppressor gene 

; this decreases the downstream AKT activation and exerts an inhibitory effect on mTOR.”

Subbiah noted that when the combination of mTOR inhibitors and metformin was used in preclinical models, “metformin induced activation of AMPK, which has been shown to disrupt the cross talk between IGF1R and G protein–coupled receptors in many cancers.”

In a phase 1 study (NCT03017833) that evaluated the combination of sapanisertib and metformin, 79% of response-evaluable patients with locally advanced or metastatic solid tumors (n = 19/24) achieved disease control. Partial responses (PRs) occurred in 17% of patients among those with leiomyosarcoma (n = 2), breast cancer (n = 1), and endometrial cancer (n = 1). The median progression-free survival (PFS) was 6.0 months (95% CI, 2.8-14.6) at a median follow-up of 19 months, and the median overall survival was 18 months (95% CI, 7.2-not evaluable).

“We need to analyze the responders deeply,” Subbiah noted. “Three out of the 4 patients who achieved a PR had a double mutation in the pathway; patients had documented alterations in 

, suggesting perhaps hyperactivation of the pathway is responsible for the responses to the combination. Interestingly, no objective responses were seen in patients harboring only 

The maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination was sapanisertib 4 mg plus metformin 1000 mg daily (dose level 3). One patient experienced a dose-limiting toxicity (DLT) of grade 3 diarrhea when treated with sapanisertib 3 mg and metformin 1000 mg (dose level 2), which was managed with supportive therapies and without the need for dose reduction. Further, treatment with sapanisertib 4 mg given in combination with metformin 1500 mg (dose level 4) resulted in 2 DLTs of grade 3 fatigue in 1 patient and grade 3 rash in another patient; both patients were able to continue therapy following dose modification. In total, 13.3% of the 30 patients treated in the trial required a dose adjustment of either drug, and 10.0% needed a dose reduction of sapanisertib.

Among patients treated in the study, sarcoma (n = 6) was the most common cancer, followed by breast (n = 4), ovarian (n = 4), and head and neck (n = 3) cancers; 2 patients each also had colorectal, lung, renal cell, and endometrioid cancers, and 1 patient each had gastroesophageal junction, prostate, stomach, bladder, and cervical cancers.

“The next step should be to use these mTORC1/2 inhibitors in combination in specific biomarker-driven and targeted populations of patients, as we saw activity mainly in patients enriched with these pathway alterations,” Subbiah added.

Combining Sapanisertib With the Aurora A Kinase Inhibitor Alisertib

An expansion cohort of a phase 1b study (NCT02719691) evaluating sapanisertib with the Aurora A kinase inhibitor alisertib (MLN8237) in patients with refractory solid tumors found modest benefit with the combination, but correlative studies have the potential to shed light on select patients who did respond to the agents, according to lead study author S. Lindsey Davis, MD. Following initial efficacy demonstrated in the phase 1 dose-finding portion of the study (n = 18), where 1 patient with hormone receptor–positive, HER2-negative breast cancer and 1 patient with castrate-resistant prostate cancer experienced prolonged stable disease (SD), Davis noted the expansion cohort enrolled 20 more patients with refractory solid tumors to receive the combination at the RP2D.

The RP2D was determined as alisertib 30 mg twice daily on days 1 through 7 of a 21-day cycle and sapanisertib 2 mg daily on a continuous schedule. Patients in the solid tumor expansion cohort received a 7-day lead-in of alisertib or sapanisertib prior to administration of the combination.

In the expansion cohort, 1 PR was seen in a patient treated in the alisertib lead-in group with hormone receptor–positive HER2-negative breast cancer, and 1 patient with refractory pancreatic adenocarcinoma experienced prolonged SD for approximately 11 months; therefore, 11 patients were enrolled to a pancreatic cancer expansion cohort.

In both lead-in groups, evaluable patients (n = 16) experienced a disease control rate (DCR) of 44% with a SD rate of 38% and an overall response rate (ORR) of 6%. Of the 6 evaluable patients in the pancreatic cancer expansion cohort, 67% experienced SD, and the remaining 33% experienced progressive disease; 1 patient experienced SD for more than 6 months.

“Our hope was that we could use this as a jumping-off point to move into a particular tumor type or do additional work in individual disease sites, [but] unfortunately, we didn’t see that signal enough to take this to a large phase 2 clinical trial in a certain disease state,” Davis, an oncologist at the University of Colorado Cancer Center and associate professor of medicine-medical oncology at the University of Colorado Anschutz Medical Campus in Aurora, explained.

“The importance of these findings is also further evaluated in those additional correlatives where we looked at tissue testing because there seem to be some standout patients. There are examples in our work of 3 patients in this group of [31] where we see outlying responses in a positive way. It speaks to the need for us to dig down into why those patients are the standouts and how we can tailor further treatments using sapanisertib and other mTOR inhibitors, either in this combination or others, to drive better benefit.”

Recent studies have explored the combination of novel mTOR inhibitors with various agents, showing promising safety and efficacy in treating solid tumors. Sapanisertib, a dual mTORC1/2 inhibitor, has demonstrated potential in combination therapies, including with metformin, alisertib, and ziv-aflibercept. These combinations have shown disease control and manageable toxicity profiles in early-phase trials. Future directions emphasize the need for biomarker-driven approaches to optimize the therapeutic benefits of mTOR inhibitors in specific patient populations.

Recent studies of novel mTOR inhibitors in combination with various agents have shown how these combinations may be used for patients with solid tumors. 

Vol. 25 No. 9 | Oncology Live®

DESTINY-Breast03 and DESTINY-Breast06 Data Shape Metastatic Breast Cancer Treatment

340B Drug Pricing Program Ostensibly Improves Cancer Care but Carries Unforeseen Consequences

ASCO 2024 Data Shake Up Standards and Shed Light on Biomarkers

Key Data Updates From ASCO May Advance the Treatment Landscapes of 3 Lung Cancer Subtypes

Dual Targeting of the mTOR Pathway May Enhance Antitumor Activity in Solid Malignancies

New Data Augment the Treatment Paradigm in HR+/HER2– Breast Cancer

Hope: A Critical Concept in Oncology, but Open to Interpretation