: Can you comment on current unmet treatment needs in patients with metastatic lung cancer?

To address that question, we need to first talk about all the different populations of metastatic lung cancers, because a big thing that's happened in the last decade is the further subclassification of these tumors. Broadly speaking, small cell lung cancer (SCLC) continues to be its own separate group, but there is some work that will potentially help us subcategorize that.

Fortunately, we've had the benefit of immunotherapy, which has significantly improved outcomes related to first-line therapy. A subgroup of patients has had impressive durable responses to the inclusion of immunotherapy, but, in the second-line setting and beyond, we have a new drug in lurbinectedin. That's adding to the somewhat limited armamentarium of treatment options. There is a lot of work going on with some novel therapies in SCLC, and I'm excited for the future, but the advances thus far have been limited. Therefore, that is an area of real need.

In non–small cell lung cancer (NSCLC), we've had a tremendous subclassification, particularly related to nonsquamous NSCLC. Now, with nonsquamous NSCLC, getting genomic testing is really important, as there are multiple different actionable alterations with approved targeted therapies. When patients get beyond those targeted therapies, then beyond chemotherapy, and, in some cases, beyond immunotherapy, that's the next setting where we need a treatment option.

In patients without an actionable alteration who have a high PD-L1 expression, immunotherapy has been revolutionary. Even in those without high levels of PD-L1 expression, chemotherapy plus immunotherapy has improved outcomes, and we see some patients with years of ongoing durable control. These are some of the big wins that we've seen in the last 5 to 10 years, but once we get beyond any approved targeted therapies and first-line chemotherapy and immunotherapy, we're looking at the setting of second-line chemotherapy, and that's the setting where we really need more options.

It's interesting, because docetaxel was previously a standard second-line option, and we gave a lot of it. Now we have all of these other treatment options that are well-tolerated and, in many cases, quite effective. Docetaxel and other chemotherapy regimens continue to be important treatment options, but once we get to that point, there's a real opportunity for other advances, particularly in later lines of treatment.

: What is the significance of Trop-2 biomarker expression in the prognosis and progression of lung cancers? How might Trop-2-targeted antibody-drug conjugates (ADCs) help address these unmet needs?

There's still a lot for us to learn about Trop-2, and there are some different datasets suggesting that higher Trop-2 expression may indicate a likelihood of a worse prognosis. Not all datasets are completely consistent in that, but there is certainly a suggestion of that from some of the data that exist.

ADCs represent a very exciting new class of drugs that involves an antibody that binds to the cell receptor and then delivers the payload. When the antibody is specific to something that's on just the cancer cells, then this is a mechanism for delivering chemotherapy into cancer cells. This has the potential to substantially reduce toxicities as compared with just infusing the chemotherapy directly.

There have been a handful of different ADCs that have been studied, and there are at least a couple that are specific to Trop-2, so this is an exciting way of potentially delivering that chemotherapy directly to these cells that have Trop-2 expression.

: What are your thoughts on the recent data presented on datopotamab deruxtecan (Dato-DXd) for patients with NSCLC who are enrolling in the ongoing TROPION-PanTumor01 trial? Could you comment on the safety and efficacy of this drug in patients with NSCLC who have actionable genomic alterations?

I've been involved in this trial from very early on, so I've also had the opportunity to treat a number of patients with this drug. This has been exciting so far. There are a number of patients who have benefitted from the drug, and some of them that have gotten an impressive, durable response to treatment.

As far as outcomes, the drug has, fortunately, been very well-tolerated. The dose escalation went as high as 10 mg/kg, but, unfortunately, at that dose, patients did have mucositis and rash. When dropping the dose back down to 8 mg/kg and then even 6 mg/kg, the drug was more well-tolerated.

On top of that, we've seen some nice responses to therapy, as well. The TROPION-PanTumor01 study was looking at tolerability, but we do have some patients with durable responses, as well. I have a patient who has tolerated the drug for about 2 years. It is incredibly meaningful to have patients with early progression on first-line chemotherapy and immunotherapy go on to have such a durable response with a generally well-tolerated drug, where they can continue to work full time and carry on with their lives.

It's encouraging that we're seeing responses across all of these populations. Whether patients have an identified actionable genomic alteration or not, we're still seeing responses to therapy. Of course, that's the kind of thing we would expect with chemotherapy. When talking about these ADCs and Trop-2-directed ADCs in particular, it raises the question as to whether we might see difference within responses if there are differences in the availability of Trop-2. To see responses across them is encouraging as to the potential utility of these ADCs in the way that we would use next-line chemotherapy, which is across the whole population.

: Regarding the TROPION-Lung02, TROPION-Lung04, and TROPION-Lung08 clinical trials, what impact do you think combination regimens may have on treatment selection and patient outcomes if they are FDA-approved?

The first part in answering this is the speculation concerning these trials being done and leading to approval. Assuming that happens, then, of course, further evaluation of the details of those trials would be overwhelmingly important as far as determining potential clinical utility.

For the exercise of speculating on what would potentially be meaningful, each of these trials are looking at a combination of Dato-DXd, a Trop-2 ADC, plus checkpoint inhibitor immunotherapy. We've seen this have an impact on the standard of care when looking at chemotherapy plus immunotherapy vs chemotherapy alone.

In patients with a high PD-L1 expression, immunotherapy works well enough that, in many cases, immunotherapy is used alone in that population, so we tend to focus on patients with a PD-L1 expression below 50% when looking at chemotherapy plus immunotherapy. In the setting of Dato-DXd plus immunotherapy, broadly, if the outcomes of the study are better than immunotherapy alone in those with higher than 50% PD-L1 expression, that would be quite meaningful. The combination of chemotherapy plus immunotherapy is something that we certainly use, but if we can get away without using the chemotherapy, then that is preferable. One aspect of this combination study that's a bit different than what we would expect of chemotherapy plus immunotherapy is that Dato-DXd seems to be better tolerated. Broadly, if we're talking about the inclusion of a drug with substantial benefit and little toxicity, then that becomes quite compelling.

If Dato-DXd with immunotherapy ends up improving outcomes and continues to have a tolerable adverse effect profile, then it becomes more compelling to add that drug to immunotherapy. One aspect to Dato-DXd that would need to be taken into account is that some patients end up losing their hair, and some of them quite substantially, so this is part of the complex discussion of risk vs benefit. Sometimes, it's easy to talk about hair loss as not necessarily being important to the overall picture, but, for some patients, that's overwhelmingly meaningful. If the drug itself has tremendous efficacy and durability, then that tradeoff is different than if it adds some, but not overwhelming, durable benefit. This all just factors into that overall discussion with patients.

: What other data from ongoing trials in Trop-2-targeted ADCs are you looking forward to seeing?

 There are a lot of studies currently underway looking at Dato-DXd, and there are also studies on sacituzumab govitecan. These are the 2 leading Trop-2 ADCs that are being studied. Fortunately, we’re seeing a suggestion that Trop-2 ADCs are well-tolerated and likely to have efficacy across a broad population of patients with NSCLC. They are being evaluated in other tumor types, as well. Of course, sacituzumab govitecan is being used with breast cancer, but this is something that will hopefully pan out across multiple tumor types

: Regarding enrollment in clinical trials, what factors might you consider when recommending patients with lung cancer to take part? What kinds of challenges would you anticipate these patients to possibly encounter?

Participation in clinical trials is extremely important for most patients, but, unfortunately, not all patients qualify for trials. There are some big misconceptions about clinical trials. Many patients believe clinical trials are something that they're doing for future populations, but they believe that they will not benefit from them. There is a broad belief that clinical trials are an option only for people who have no options. I hear people say they think of it as being a guinea pig, or there's this misconception that we're just throwing drugs in and seeing what sticks.

When I meet with patients early on, I speak to them about the value of clinical trials and focus on how best to treat them to help dispel some of these misunderstandings early on. In speaking with any patient who may qualify, and even more broadly … about a clinical trial or any treatment, our conversation is 100% around what is best for that individual. Any drug that gets to the point of even just a phase 1 study has to have tremendous justification based on earlier data, and that's after we see how it's tolerated. There needs to be some suggestion of this agent working in patients with that cancer to then expand that further and enroll patients in a phase 2 study. Individuals enrolling in a trial are essentially getting a potential future standard of care, and they're getting it today. I have had patients who are currently doing exceptionally well years after receiving a checkpoint inhibitor before that was available as a standard of care. That’s because they were on trials and, fortunately, did exceptionally well. Unfortunately, not every trial ends up having the exceptional outcomes we hope for, but these are … promising options that would be discussed. Any trial that I discuss with a patient would be because I think that that particular drug is a good option for that individual.

On top of that, I also make the point that anyone enrolling on a trial would get at least the best standard of care if there's a randomized trial. Broadly, patients often have the expectation that they're at risk of getting a placebo and, therefore, are essentially not getting any treatment but not knowing it. People are understandably quite afraid of that, so I also make a point to them very early on that nobody would enroll in a trial and get less than what is the current standard of care, and, in most cases, many trials now don't even have a placebo. If there's a placebo, patients on the study are getting the best-known standard of care plus either the experimental drug or placebo.

I try to allay patients' fears about this first by reassuring them that anything we do is about what's best for them. If they're on a trial and I think it's no longer the best for them, I would take them off of it. We're not bound to anything. We're not doing anything just for the future of science. This is all about their own treatment, and, hopefully, the treatment works well for them and goes on to help a lot of other people, as well. But the focus is around them and their care. Second, they would never end up on a placebo by itself; that's not how this works. Third, by going on clinical trials, we still have the standard-of-care options available. We're just adding in something else that might end up working for them. For all of these reasons, we use clinical trials to help out with an individual's care and, hopefully, get more out of treatment. This is not just a way of looking at drugs but rather of treating those individuals.

Clinical trials are another reason that it's important for patients to see an academic oncologist at one of the big centers. In some cases, clinical trials are available to the population in the first-line setting, where there still are plenty of treatment options and there's good proven therapy. But there's reason to believe that incorporating another drug in that first-line setting may help treatment options even more. One of the trials that you asked about earlier is first-line Dato-DXd plus pembrolizumab vs pembrolizumab alone in those with a high PD-L1 expression. Giving pembrolizumab alone in that population is approved, and it generally works well and is well-tolerated. The question is, does Dato-DXd add more in that setting? That's not something that would necessarily be known unless the oncologist has that trial open, so it's good for patients to get a second opinion just to have a sense of what other trials might be available.

Now, in some cases, I have patients who drive hours to come to see me. Although I may have a trial, it might not be worth the many hours of driving, particularly if its follow-up is once a week; in some cases, however, it is. For example, before the FDA approval of 2 different drugs for 

 fusion. When I saw patients who qualified but who had driven hours to see me, I told them, “I know this is an inconvenient journey, but, in this case, the drug itself is really worth it based upon the outcomes we're seeing. I fully expect this to be a drug that ultimately ends up being approved, because the responses are really pretty consistent, and the drug has been well-tolerated.”

In fact, I have 1 patient who drives about 45 minutes who has now continued to be on an initial trial for one of these 

 fusion–targeted therapies. He's been on this for years. It's now an FDA-approved therapy. He saw me the day before he was to start chemotherapy as his first-line treatment; instead, he's been on a pill now for years with ongoing excellent control without adverse effects. We were only able to put him on that trial because he happened to come in for an opinion and hadn't yet started treatment. This is one of the reasons it's important to be seen at one of the big academic centers before starting therapy, because, sometimes, there are some compelling trials that might not be known unless the oncologist is well plugged in to some of these centers that have these options.

: If Dato-DXd is approved for use in lung cancer, would you anticipate an issue with accessibility for use with patients?

If it were approved, I would expect that there would be an effort to ramp up production to make sure that they're getting that to all cancer centers. This is a drug that has not been difficult to give to patients, so I would expect that to be widely available. Of course, that's pending full FDA approval.

Articles

In this expert interview, Jacob Sands, MD, shares key insights on unmet needs in the treatment of lung cancer, comments on the role of clinical trials investigating Trop-2-targeted therapy, and considers the potential impact of datopotamab deruxtecan (Dato-DXd) on the treatment landscape if it receives FDA approval for use in lung cancer. 

Expert Perspectives on Trop-2 Biomarker Expression in Lung Cancer and the Potential Role of Dato-DXd


Targeting Trop-2 Overexpression in Breast Cancer and Non-Small Cell Lung Cancer

The transmembrane glycoprotein Trop-2 is involved in cancer progression and metastasis due to its role as a key regulator of the hallmarks of cancer, including cell growth, proliferation, migration, invasion, and survival.

 A variety of human epithelial cancers (eg, malignancies of the breast, lung, bladder, stomach, colon, rectum, pancreas, prostate, cervix, head and neck, and ovary) are characterized by Trop-2 overexpression.

 The overexpression of Trop-2 has been associated with more aggressive disease and worse overall survival (OS) and progression-free survival (PFS) in patients with solid tumors.

In breast cancer (BC), increased Trop-2 mRNA has been demonstrated to be a strong predictor of lymph node involvement, distant metastasis, and poor OS.

 Although Trop-2 is expressed across all BC subtypes, overexpression is more commonly observed in certain disease subtypes, including hormone receptor­–positive/HER2 (also known as ERBB2)-negative (HR+/HER2-) BC, and triple-negative breast cancer (TNBC).

For lung cancer, the correlation of Trop-2 overexpression with prognosis can vary with lung cancer subtype.

 More specifically, high Trop-2 expression is associated with a worse prognosis, higher patient mortality, and shorter OS in patients with lung cancer having an adenocarcinoma histology.

 Interrogation of human samples has also demonstrated high levels of Trop-2 expression to correlate with a high tumor, node, and metastasis stage and a worse disease course in adenocarcinoma.

 Additionally, lower rates of survival have been observed in patients with high-grade neuroendocrine tumors, including small cell carcinoma.

 Conversely, high Trop-2 expression does not appear to be associated with mortality in squamous cell carcinoma.

Favorable safety and efficacy study data leading to the FDA approval of sacituzumab govitecan-hziy—an antibody-drug conjugate (ADC) that targets Trop-2—in metastatic TNBC and urothelial cancer established the use of Trop-2–targeting therapeutics as a viable strategy for treating solid tumors.

 Moreover, drug modalities targeting Trop-2 offer a novel approach for treating TNBC, estrogen receptor–positive (ER+)/HER2- BC, and NSCLC, which may help to fill existing gaps in the current treatment landscape.

Unmet Needs in TNBC and ER+/HER2- Metastatic BC

Approximately 10% to 15% of all BC cases, and a disproportionate number of BC-related deaths, are related to TNBC, an aggressive form of invasive BC.

 Its prevalence is particularly high in premenopausal women and Black and Hispanic populations.

 TNBC is characterized by a lack of estrogen and progesterone receptors and low expression of HER2. Therefore, TNBC cannot be effectively treated with standard hormone-based therapies and HER2-targeted agents.

 Chemotherapy has produced promising results in early TNBC; however, the majority of patients relapse within the first 3 to 5 years after initial treatment.

 Management of metastatic TNBC remains a clinical challenge, so participation in clinical trials of new treatments often is a good option for patients, regardless of their disease stage.

 Consequently, there is an urgent unmet need for effective treatment options in patients with metastatic TNBC.

The most common metastatic BC (MBC) subtype is ER+/HER2-, which has a median PFS of 11 to 24.8 months.

 The 2022 National Comprehensive Cancer Network (NCCN) guidelines indicate that endocrine therapy (ET) using aromatase inhibitors, selective ER modulators, or selective ER down regulators is the preferred first-line treatment for patients with ER+ MBC.

 Despite demonstrated efficacy of ET as first-line treatment for such advanced disease, only an estimated 40% of patients initially respond to ET, and all responders ultimately develop resistance with time.

 Furthermore, notable decreases in efficacy between first- and second-line ETs have been observed.

 Many patients with ER+/HER- MBC eventually require treatment with chemotherapeutic agents, and a loss of efficacy with subsequent lines of chemotherapy has been demonstrated.

 Thus, there is a pressing need for additional biomarkers and correlating targeted therapies to help improve survival outcomes for this patient population.

Breast Cancer: FDA-Approved and Investigational ADCs targeting Trop-2

Several ongoing clinical trials for Trop-2–targeting therapies are showing signs of efficacy in patients with TNBC and HR+/HER2- BC.

 Datopotamab deruxtecan (Dato-DXd) is an investigational anti–Trop-2 ADC containing DXd, a potent topoisomerase I inhibitor, coupled to a Trop-2–directed monoclonal antibody via a tetrapeptide-based cleavable linker.

 Sacituzumab govitecan is an anti–Trop-2 ADC that contains SN-38, a water insoluble active metabolite of irinotecan.

 Encouraging efficacy and safety trial data investigating sacituzumab govitecan in the treatment of TNBC have demonstrated meaningful clinical activity and a manageable safety profile.

In this ongoing phase 1, multicenter, open-label, 2-part study, investigators are assessing the preliminary safety and efficacy of using Dato-DXd in patients with previously treated solid malignancies.

 TROPION-PanTumor01 (NCT03401385) includes patients with advanced/metastatic TNBC as well as those with HR+/HER2- BC that has relapsed or progressed on other standard-of-care treatments. Preliminary data on overall response rate (ORR) according to the RECIST guideline, version 1.1, by blinded independent central review (BICR) were presented in December 2021 at the 2021 San Antonio Breast Cancer Symposium.

At the data cutoff point (April 2021), 43 patients with TNBC were treated with at least 1 dose of Dato-DXd. Of these, 95% were treated with at least 2 prior lines of therapy, 44% were given immunotherapy, and 16% were previously treated with sacituzumab govitecan. With a median follow-up of 3.9 months (range, 0.3-9.2 months), the median treatment duration was 2.8 months (range, 0.7-6.9 months).

 In all, 38 patients were evaluable for response; the disease was controlled in 84%, and ORR by BICR was noted in 39% showing evidence of a PR (12 confirmed, 3 pending confirmation). In the 12 patients having a confirmed PR, the median time to response (TTR) was 1.35 months (range, 1.2-3.2 months).

Preliminary safety data showed that all-cause treatment-emergent adverse events (TEAEs) of any grade occurred in 95% of patients, and 35% of patients experienced those of grade 3 or higher. None of the patients discontinued treatment due to AEs. Any-grade TEAEs most commonly reported included nausea (58%), stomatitis (53%), alopecia or vomiting (35% each), and fatigue (33%). The TEAEs occurring at grade 3 or higher included stomatitis (9%), fatigue (7%), and vomiting (2%); information on alopecia of at least grade 3 was not available. No diarrhea of grade 3 or higher was reported, and 1 patient experienced a decreased neutrophil count of grade 3.

 Additionally, there were no reported instances of treatment-related interstitial lung disease (ILD) as adjudicated by an independent committee. Serious TEAEs occurred in 12% of patients, and there were no TEAEs associated with death. Dose reductions due to stomatitis, fatigue, mucosal inflammation, dry eye, retinal exudates, and blurred vision occurred in 9 patients, with each TEAE being reported multiple times. Further, 3 patients experienced dose interruptions as a result of stomatitis, mucosal inflammation, bronchitis, and musculoskeletal chest pain.

The phase 3 SASCIA trial (NCT04595565) is a prospective, international, multicenter, randomized, open-label, parallel group study investigating the ADC sacituzumab govitecan given to patients with centrally confirmed HER2- BC. The patients’ tumors also were either HR-negative (HR-) with any residual invasive disease measuring greater than 0.1 cm 

 HR+ with a clinical and pathologic stage (CPS) and ER status and histologic grade (EG) (CPS + EG score) of at least 3 or a CPS + EG score of 2 and lymph-node metastases. To be eligible for enrollment, patients had received prior taxane-based neoadjuvant chemotherapy for 16 weeks, which needed to include 6 weeks of a taxane.

The study is evaluating 1200 patients. Patients will be randomly assigned 1:1 to receive 10 mg/kg of sacituzumab govitecan on days 1 and 8 every 3 weeks for 8 cycles or a treatment of physicians choice (eg, capecitabine or platinum-based chemotherapy); ET will be given to patients with HR+ BC per appropriate guidelines.

Trial enrollment started in December 2020; as of June 2021, 57 patients were enrolled in Germany, and these patients were randomly assigned to one of the treatment arms. The primary end point is invasive disease–free survival, and the key secondary end point is OS. Additional secondary end points include safety, compliance, distant disease–free survival, locoregional recurrence–free interval, and patient-reported outcomes and quality of life.

The safety and efficacy of sacituzumab govitecan was also studied in IMMU-132-01 (NCT01631552), a phase 1/2, single-arm, open-label, multicenter basket trial. To be eligible for enrollment in the study, adult patients had received a diagnosis of advanced epithelial cancer that was relapsed or refractory to at least 1 standard treatment regimen.

 Patients were given sacituzumab govitecan on days 1 and 8 of each 21-day cycle at a dose of 8, 10, 12, or 18 mg/kg until disease progression, unacceptable toxicity, or death occurred. Prophylactic growth factor support was not permitted before the first day of cycle 1; otherwise, preinfusion medications could be given at the investigator’s discretion.

Patients were assessed for treatment duration, total number of doses received, and all treatment cycles completed to determine exposure to sacituzumab govitecan. Treatment interruptions and discontinuations were also included in the analysis, as were treatment delays of greater than 3 weeks (> 28 days between dose 1 and 2 in a single cycle 

 > 35 days between dose 2 in a given cycle and dose 1 of the next cycle).

 End points for treatment efficacy included PFS, duration of response (DOR), OS (per Kaplan-Meier analysis), ORR (ie, confirmed PR and complete response [CR] per RECIST, version 1.1), and clinical benefit rate (CBR; defined as CR, PR, or stable disease for ≥ 6 months).

The IMMU-132-01 basket trial of sacituzumab govitecan included patients with metastatic TNBC who received the drug at the clinically selected dose of 10 mg/kg in the third or later lines of therapy and were selected for analysis of updated results.

 Eligible patients needed to meet enrollment criteria for the full basket trial.

 The 108 patients enrolled were heavily pretreated with a median of 3 prior cancer regimens (range, 2-10 regimens); previous treatment in 106 participants included taxanes (98%) and anthracyclines (86%).

The objective response rate was 33.3% (PR, 30.6%; CR, 2.8%), with a median TTR of 2.0 months (range, 1.6-13.5 months) and a median DOR of 7.7 months (95% CI, 4.9-10.8). Additionally, the CBR (including stable disease for 6 months) was 45.4%.

 At the time of data cutoff, the median PFS was 5.5 months (95% CI, 4.1-6.3) with an estimated PFS probability of 41.9% at 6 months and of 15.1% at 12 months. Median OS was 13.0 months (95% CI, 11.2-13.7), with estimated 6- and 12-month PFS probabilities of 78.5% and 51.3%, respectively.

Safety analysis showed that the mean number of doses received was 18.7 (range, 1-102 doses) across an average of 9.6 cycles (range, 1-51 cycles); the median duration of exposure was 5.1 months (range, 0.03-36.1 months).

 Common AEs of any grade included nausea (67%), diarrhea (62%), fatigue and asthenia (55%), neutropenia (64%), and anemia (50%), while those of higher grade included neutropenia (grade 3, 26%; grade 4, 16%), anemia (grade 3, 11%; grade 4, 0%), and decreased white blood cell count (grade 3, 8%; grade 4, 3%). Serious AEs were seen in 32% of patients, with febrile neutropenia (7%), vomiting (6%), nausea (4%), and diarrhea and dyspnea (3% each) reported; AEs leading to death were noted in 4% of patients.

 In all, 44% of patients experienced dose interruptions due to AEs (most often, neutropenia). In total, 3 patients discontinued treatment due to AEs (related to treatment, 2 patients; not related to treatment, 1 patient.

As part of the IMMU-132-01 basket trial, patients with HR+/HER2- MBC were selected for a prespecified subpopulation analysis to assess the safety and clinical activity of 10 mg/kg of sacituzumab govitecan. Adult patients with HR+/HER2- MBC were eligible if they demonstrated disease progression following at least 2 systemic regimens, including 1 or more ETs and 1 chemotherapy, for metastatic disease.

In this subpopulation analysis, the primary efficacy end point was objective response rate per RECIST, version 1.1; other efficacy end points included TTR, DOR, and CBR. Median OS and PFS were also included in the efficacy assessment.

 With a median duration of follow-up of 11.5 months (range, 0.7-38.4 months) at the data cutoff, a median of 13.5 doses (range, 1.0-84.0 doses) were received; the median relative dose intensity was 99.8% (range, 47.4%-107.3%).

 An objective response was achieved in 31.5% of patients (PR, 17 patients; 95% CI, 19.5%-45.6%). In these patients, the median TTR was 2.1 months (95% CI, 1.4-7.8), and the median DOR was 8.7 months (95% CI, 3.7-12.7). Stable disease was the best response achieved in 33.3% of patients; therefore, the CBR for this subpopulation was 44.4% (95% CI, 30.9%-58.6%).

 The efficacy results also showed that the median OS and PFS, respectively, were 12.0 months (95% CI, 9.0-18.2) and 5.5 months (95% CI, 3.6-7.6).

The most common all-grade, treatment-related hematologic AEs included neutropenia (72.2%), anemia (37.0%), and decreased white blood cell count (14.8%); these were of grade 3 or higher in 50.0%, 11.1%, and 9.3% of patients, respectively. All-grade gastrointestinal (GI) AEs related to treatment were nausea (66.7%), diarrhea and vomiting (both 46.3%), and constipation (25.9%). The GI AEs of at least grade 3 were diarrhea (7.4%), vomiting (3.7%), and nausea (1.9%). Other AEs of any grade included fatigue (50.0%), alopecia (44.4%), decreased appetite (31.5%), and headache (18.5%); the only other AE of at least grade 3 noted was fatigue (1.9%).

 Overall, 24.1% of patients required dose reductions, and 7% of patients discontinued therapy due to AEs (only 2 patients discontinued therapy due to treatment-related AEs).

A Trop-2–directed ADC, SKB264, is being investigated in an open-label, global, first-in-human study of patients with locally advanced or metastatic solid malignancies. The dose escalation study is ongoing. As of March of 2021, 18 adult patients with unresectable solid tumors that relapsed or are refractory to standard treatment have been enrolled. For study inclusion, patients must also show measurable disease according to RECIST, version 1.1.

Initial safety results demonstrated that all-cause TEAEs occurred in all 18 patients. The most common were of grades 1 and 2 in severity (nausea [72.2%], alopecia [66.7%]). The most common TEAEs of at least grade 3 in severity included decreases in neutrophil count (27.8%) and white blood cell counts (22.2%) and anemia (16.7%). Patients who experienced TEAEs of grade 3 or higher recovered after receiving treatment; no TEAE led to death.

Pharmacokinetic results showed no drug accumulation after multiple doses were given, and exposure to SKB264 increased in proportion to the dose. The dose schedule of every 2 weeks is supported by the half-lives of SKB264 (36 hours) and the free payload (49 hours). In the first cycle, the serum-free payload of total SKB264 peak serum concentration and area under the curve (AUC) were 6% and 5%, respectively, suggesting that the novel linker is stable in the serum.

A preliminary efficacy evaluation was performed for the 17 patients having at least 1 tumor assessment. Efficacy was noted at doses from 2 to 6 mg/kg (ORR, 35.5%; disease control rate, 70.6%). A PR according to RECIST, version 1.1, was achieved in 6 patients, which including 2 of 5 participants with TNBC, 2 of 4 with ovarian cancer, 1 with HER2+ BC, and 1 with gastric adenocarcinoma.

Lung cancer remains the leading cause of cancer-related death in the United States, accounting for approximately 22% of all cancer deaths among men and women.

 Lung cancer can be classified according to 4 subgroups, including adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and large cell carcinoma, with adenocarcinoma being the most common histology observed.

 NSCLC accounts for the majority of lung cancer diagnoses (80% to 85%) and is responsible for an estimated 85% of lung cancer-associated deaths.

 At the time of diagnosis, approximately 4 in 5 US patients with NSCLC will have metastases upon presentation or during the course of their disease.

 Diagnosis of NSCLC at advanced stages can often lead to greater treatment challenges and an increased risk for disease recurrence and treatment failure.

 For patients with metastatic NSCLC, median survival following standard treatment with platinum-based chemotherapy is 8 to 10 months.

 Despite advanced therapeutic approaches for NSCLC, newer treatments often are effective only for patients with nonsquamous subtypes (5-year relative survival rate, 21.7%), indicating an unmet need within the current treatment landscape.

Approximately 15% of lung cancer diagnoses involve SCLC, which is associated with one of the lowest 5-year survival rates (6%).

 Due to the aggressive nature of this cancer, roughly two-thirds of patients present with metastatic disease at the time of diagnosis.

 Despite high initial response rates of 60% to 75% among patients with stage IV metastatic SCLC, associated outcomes are poor (PFS, 5.5 months; median OS, < 10 months), and most patients experience relapse within a year after treatment with a platinum-based chemotherapy

 Moreover, with no new therapeutics for SCLC approved since 1998, there is an urgent need for additional treatment options and targeted therapies that may help improve outcomes in this patient population.

Lung Cancer: Investigational ADCs Targeting Trop-2

TROPION-PanTumor01 Trial: Dose Analysis in Overall NSCLC Cohort

As part of the TROPION-PanTumor01 trial, data from patients with advanced NSCLC were analyzed.

 To inform dose selection, population pharmacokinetics and exposure-response modeling were performed across doses in 175 patients.

As of the September 2020 data cutoff, all-grade TEAEs were higher among the 80 patients receiving 8 mg/kg of Dato-DXd than among the 45 participants receiving 6 mg/kg or 50 patients receiving 4 mg/kg of the drug.

 Rates of drug-related TEAEs of at least grade 3 also were higher among patients given the 8-mg/kg dose (34%) than among those given 6- or 4-mg/kg doses (16% and 10%, respectively). Serious TEAEs occurred at higher rates among those given 8 mg/kg of Dato-DxD (20%) than among those given the lower doses (6 mg/kg, 9%; 4 mg/kg, 8%). Drug-related ILD was more frequently seen in patients in the 8-mg/kg cohort (15%) than among the cohorts receiving 6 mg/kg (2%) and 4 mg/kg (2%), as confirmed by an independent adjudication committee. Grade 5 ILD was observed in 3 patients in the 8-mg/kg group.

 Across the 8-, 6-, and 4-mg/kg cohorts, all-grade TEAEs included vomiting (34% vs 18% vs 12%, respectively), anemia (28% vs 16% vs 4%), diarrhea (20% vs 11% vs 6%), and mucositis (29% vs 13% vs 6%).

 Patients given the 8-mg/kg dose were more likely than were those in the 6- and 4-mg/kg cohorts to experience dose interruptions (20% vs 20% vs 4%, respectively) and dose reductions (31% vs 9% vs 2%) due to TEAEs. Treatment discontinuation due to AEs also occurred more frequently in the 8-mg/kg group than in patients receiving 6- or 4-mg/kg doses (15% vs 7% vs 4%).

Preliminary efficacy data for patients with NSCLC showed an ORR of 25% in the 8-mg/kg cohort, of 21% in the 6-mg/kg cohort, and of 23% in the 4-mg/kg cohort, as determined by BICR. Across the 3 groups, preliminary mean PFS was 5.4 months (95% CI, 4.1-7.1), 8.2 months (95% CI, 1.5-11.8), and 4.3 months (95% CI, 2.0-not estimable), respectively, although data were limited by an immature duration of follow-up of 3 months or less in each cohort (46%, 67%, and 66%, respectively).

Pharmacometric analysis showed a positive correlation between exposure to Dato-DXd (AUC) with probability of CR or PR and change in tumor size from baseline. A positive correlation was also observed between Dato-DXd exposure and both stomatitis or mucositis of at least grade 2 and incidences of dose reduction. Trends derived from these projected probabilities were confirmed in a virtual population bootstrapped from population pharmacokinetic data of patients with NSCLC.

TROPION-PanTumor01 Trial: NSCLC Cohort With Actionable Genomic Alterations

An analysis of Dato-DXd use in patients with NSCLC with actionable genomic alterations (AGAs) was conducted as part of the ongoing TROPION-PanTumor01 trial population.

 In all, 34 patients were included in this analysis; investigator-reported AGAs involved 

in 1 patient each. Overall, 82% of these patients were treated with at least 3 prior regimens, and 85% had prior exposure to tyrosine kinase inhibitor therapy. Notably, osimertinib had been used in 69% of patients with 

Patients remained on study for a median duration of 13 months, and the median DOR was 8.5 months (95% CI, 3.3-not estimable). The BICR-confirmed ORR was 35% across treatment doses (95% CI, 19.7-53.5). Nausea (62%) and stomatitis (56%) were the most commonly reported any-grade AEs, and hematologic toxicities were noted infrequently. Grade 5 treatment-related ILD occurred in 1 patient with NSCLC associated with AGAs who was in the 8-mg/kg cohort.

An analysis was conducted of patients within the IMMU-132-01 basket trial to assess the safety and antitumor activity of sacituzumab govitecan in patients with metastatic NSCLC with measurable disease that had progressed following 1 or more lines of treatment for stage 4 disease.

 In addition to meeting enrollment criteria for the phase 1 basket trial, eligible patients also needed an ECOG performance status of 0 or 1 and adequate bone marrow, hepatic, and renal function. Patients also were required to have completed systemic therapy 4 or more weeks before enrollment.

 Patients had a median of 3 prior lines of therapy (range, 2-7 lines), and all patients were treated previously with at least 1 platinum-containing regimen; 74% received prior treatment with platinum-based chemotherapy and a taxane, and the remaining 26% of patients also had prior exposure to pemetrexed and/or gemcitabine.

 Additionally, 33% of patients had received immunotherapy (PD-1 or PD-L1 inhibitor), and 32% had been treated with an EGFR inhibitor.

Among 54 patients with metastatic NSCLC enrolled, 8 patients received the 8-mg/kg dose offered in the full basket trial, and 46 participants received the offered 10-mg/kg dose.

 Of 47 patients evaluable for response, 19% showed a confirmed PR. In the intent-to-treat (ITT) population, the ORR was 17%, with a median TTR of 3.8 months (range, 1.8-11.6 months) and a median DOR of 6.0 months (95% CI, 4.8-8.3).

 Stable disease was observed in 49% of patients, and the CBR was 32%.

 Median PFS in the ITT population was 5.2 months (95% CI, 3.2-7.1), and the median OS was 9.5 months (95% CI, 5.9-16.7), both based on Kaplan-Meier estimates.

Serious AEs of grade 3 or higher that occurred in at least 5% of patients included neutropenia (28%), leukopenia and pneumonia (9% each), diarrhea and nausea (7% each), and fatigue (6%). Two patients (4%) experienced febrile neutropenia. Grade 3 or 4 neutropenia was more common with use of the 10-mg/kg dose (30%) than the 8-mg/kg dose (13%), although only 8 patients in this study received the lower dose.

 Dose reductions due to neutropenia occurred in 43% of patients, and AEs led to premature discontinuation of treatment in 2 patients.

Another part of the IMMU-132-01 basket trial analysis evaluated the activity of sacituzumab govitecan in patients with metastatic SCLC who had measurable tumors by CT scan and were relapsed or refractory to 1 or more lines of standard therapy for metastatic disease.

 Patients needed to meet full enrollment criteria for the phase 1 basket trial at-large. Further eligibility criteria included an ECOG performance status of 0 or 1; adequate renal, hepatic, and bone marrow function; and completion of prior therapy 2 or more weeks before trial enrollment.

 A majority of patients had extensive disease that included multiple-organ metastases. The median number of prior lines of therapy was 2 (range, 1-7 lines). All patients on trial had received cisplatin or carboplatin plus etoposide and were considered chemoresistant or chemosensitive to their first-line treatment.

A total of 53 patients with metastatic SCLC were included, with 38 participants receiving the 10-mg/kg dose and 15 receiving the 8-mg/kg dose.

 In the ITT population of 50 patients, PR was achieved in 6 of 36 patients (17%) in the 10-mg/kg group and 1 of 14 patients (7%) in the 8-mg/kg group, resulting in an overall ORR of 14%.

 The median DOR by Kaplan-Meier estimate was 5.7 months (95% CI, 3.6-19.9). Stable disease was achieved as the best response in 42% of patients, with a median duration of 5.6 months (95% CI, 5.2-9.7). The median PFS in the ITT population was 3.7 months (95% CI, 2.1-4.3), and the median OS was 7.5 months (95% CI, 6.2-8.8).

This article surveils key advancements in the role of antibody-drug conjugates in solid tumors by examining important clinical trial findings on targeting Trop-2 in breast and lung cancers. 

Clinical Advancements of Targeted Antibody-Drug Conjugates in Breast and Lung Cancer


The oncology treatment landscape has evolved with the clinical development of precision-based therapeutic approaches and the growing availability of targeted agents.

 Over the last decade, targeted therapeutics have increasingly become an attractive method for improving tumor selectivity and reducing the systemic toxicity associated with traditional chemotherapy.

 Monoclonal antibodies (mAbs) specifically recognize and target cellular surface antigens, which is a valuable mechanism for the delivery of drugs to tumor cells while minimizing off-target toxicity to normal tissues.

 Antibody-drug conjugates (ADCs) allow for improved drug delivery and reduced toxicity. They are designed to combine the targeting ability of mAbs with the cell damaging effects of potent cytotoxic agents.

 ADCs, in particular, represent a rapidly expanding therapeutic drug class specifically designed to overcome these shortfalls associated with chemotherapeutic agents.

The clinical success achieved with a particular ADC is contingent upon several key factors including the target antigen, antibody framework, cytotoxic payload, type of linker, method of conjugation, and target indication.

Target antigens should be preferentially and homogeneously expressed at high levels on the surface of tumor cells relative to normal tissues, rapidly internalize upon antibody binding, and be minimally present in the circulation.

Antigens expressed exclusively on the surface of tumor cells are ideal targets for ADCs.

 Lineage-specific antigens expressed by hematological malignancies have been investigated to a large extent as ideal targets for ADC development.

 Solid tumors express mostly tumor-associated antigens rather than those that are tumor- or lineage-specific, which can lead to an increased potential for off-target toxicity and decrease the level of intratumoral drug delivery.

ADC targets for the treatment of solid tumors with United States Food and Drug Administration (FDA)-approved options include HER2, poliovirus receptor-related protein 4 (nectin-4), and trophoblast cell-surface antigen 2

(Trop-2). Additional potential ADC targets for solid tumors that are under investigation include HER3, carcinoembryonic antigen-related cell adhesion molecule (CEACAM), mesenchymal-epithelial transition factor (c-Met), mesothelin, LIV-1, folate receptor α, and tissue factor.

Since the advent of mAb-associated technologies, the continued pursuit to improve tissue penetration and uptake has led to the development of a variety of antibody frameworks.

 The type and size of antibody utilized can affect multiple ADC-associated properties including cross-linking capabilities, complement-dependent cytotoxicity effector functions, cellular uptake, clearance rates, structure, and overall biological activity.

 ADC-associated mAbs should possess a strong binding affinity for the target antigen with low immunogenicity and cross-reactivity.

While the target antigen and corresponding mAb are important factors contributing to tumor selectivity, the cytotoxic payload is essential in eliciting a cell apoptotic effect.

 It is estimated that 1% to 2% of ADC payloads reach their cellular target, which has led to the utilization of more potent agents, including those with anti-tubulin polymerization and DNA-damaging activity.

 Agents with high plasma stability, low immunogenicity, a smaller molecular weight, and a longer drug half-life are preferred characteristics for ADC-associated payloads.

Essential in connecting the ADC-associated mAb and payload, chemical linkers are classified as either cleavable or noncleavable based on their mechanism of drug release.

 Cleavable linkers allow the payload to be cleaved from the parent antibody structure in the presence of acid, proteases, or reducing agents such as glutathione.

 Glutathione-sensitive disulfide linkers have greater plasma stability and can be advantageous for oncology applications due to the high glutathione concentration present in the intracellular compartment of cancer cells.

 Conversely, noncleavable linkers form stable, nonreducible bonds with amino acid residues of their mAb counterparts, which may contribute to greater plasma stability, a longer half-life, and decreased potential for off-target toxicity.

 Linker chemistry may also be used to balance hydrophobicity between the mAb and drug payload to help reduce potential aggregation.

 Selection of the ADC-associated linker can be influenced by the mechanism of action (MOA) sought in the end drug design.

In addition to the linker, the conjugation method used to attach payloads to their respective mAb framework plays a crucial role in controlling the potency and homogeneity of the end drug product.

 Conventional methods have used lysine and interchain cysteines sites for conjugation.

 However, conjugation with these methods occurs randomly and leads to heterogeneous drug-to-antibody ratios (DARs) associated with variability in pharmacokinetics, efficacy, and safety profiles.

 The abundance of lysine and inability to control conjugation at these sites can result in lower binding efficiency and cytotoxicity of the ADC.

 While higher DARs can lead to more potent ADCs, they may also decrease stability and increase the potential for aggregation, off-target toxicity, and greater drug clearance.

 Novel site-specific strategies involve installing natural or unnatural amino acids, carbohydrate moieties, or aldehyde tags for drug conjugation to overcome these shortfalls and achieve a more homogeneous product.

ADCs in the Solid Tumor Treatment Landscape

As of February 2022, 4 ADCs targeting 1 of 3 specific biomarker are FDA approved for the treatment of solid tumors: ado-trastuzumab emtansine (HER2), trastuzumab deruxtecan (HER2), enfortumab vedotin (Nectin-4), and sacituzumab govitecan (Trop-2).

HER2 overexpression is present in approximately 25% to 30% of breast cancer (BC) and has been further identified in other types of malignancy including gastric and gastroesophageal junction (GEJ) cancers, biliary tract cancer, colorectal cancer (CRC), non–small cell lung cancer (NSCLC), bladder cancer, and uterine cancer.

Ado-trastuzumab emtansine (T-DM1) received FDA approval in 2013 for the treatment ofpatients with HER2-positive (HER2+) metastatic BC who have been previously treated with trastuzumab and a taxane.

 T-DM1 employs a noncleavable thioether linker to bind the anti-HER2 antibody trastuzumab to a potent anti-tubulin payload with an associated DAR of 3.5:1.

 While T-DM1 has demonstrated favorable efficacy, some HER2+ BCs are nonresponsive or are minimally responsive to T-DM1.

 Multiple mechanisms of resistance to T-DM1 have been identified, and patients can eventually experience disease progression following treatment.

 In addition to elucidating the mechanisms of resistance to T-DM1, there is a need to identify other targetable biomarkers for the development of additional treatment options.

Another anti-HER2 ADC, trastuzumab deruxtecan (T-DXd), received FDA approval in 2019 for the treatment of patients with unresectable or metastatic HER2+ BC who have previously received 2 or more anti-HER2–based regimens in a metastatic setting.

 T-DXd is also indicated for the treatment of locally advanced or metastatic HER2+ gastric or GEJ adenocarcinoma in patients who have received a prior trastuzumab-based therapy.

 T-DXd shares the same anti-HER2 targeting vehicle present in T-DM1 for drug delivery, but it uses a cleavable linker design to attach a topoisomerase I inhibitor. Cysteine conjugation methods employed in T-DXd drug design also allow for a more homogeneous product with a higher associated DAR (8:1).

 During the process of internalization, T-DXd undergoes intracellular cleavage via lysosomal enzymes, releasing the membrane-permeable cytotoxic payload.

Consequently, T-DXd elicits a greater bystander killing effect, which may allow for increased cytotoxic effects on proximal antigen-negative cells and improve clinical activity in patients with low or heterogeneous HER2 expression.

Nectin-4 is an immunoglobulin-like adhesion molecule that is involved in calcium-independent cell-to-cell adhesion.

 High levels of nectin-4 expression have been reported in approximately 70% to 90% of urothelial cancers with higher levels more commonly seen in non-invasive subtypes.

Enfortumab vedotin is an ADC composed of an anti-tubulin payload attached to an anti–nectin-4 IgG1 antibody via a protease cleavable linker.

 It received FDA approval in 2019 indicated for the treatment of patients with locally advanced or metastatic urothelial cancer who have previously received treatment with a PD-1 or PD-L1 inhibitor and platinum chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting.

The cell surface glycoprotein Trop-2 is thought to serve an important role in cell proliferation and transformation.

 Trop-2 overexpression accelerates the cancer cell cycle and drives tumor progression.

 Trop-2 is overexpressed in many epithelial solid tumors versus normal tissue, including BC and lung cancer as well as gynecological, urothelial, and gastrointestinal carcinomas among others, which has led to the investigation of anti–Trop-2 agents in other malignancies.

 In some cancers, Trop-2 overexpression has been shown to be associated with increased tumor aggressiveness, metastases, and poor prognosis, which highlights Trop-2 as a valid target for ADC development that will expand treatment options and fill unmet needs within the current treatment landscape.

Therapeutic resistance continues to be an ongoing challenge in the management of solid tumors, and there remain unmet needs in the current treatment landscape.

 Among BC subtypes, triple-negative BC (TNBC) continues to demonstrate the worst outcomes with an associated median overall survival of approximately 13 months.

 Although some patients with TNBC initially respond to standard systemic treatment with chemotherapy, nearly half of these patients will develop resistance to treatment.

 The lack of well-defined molecular targets for TNBC further highlights the need to identify biomarkers that can be utilized in the development of novel targeted therapeutics.

This article provides an overview of antibody-drug conjugates for the treatment of solid tumors and examines emerging evidence demonstrating Trop-2 as a potential target in breast and lung cancers.

Trop-2 Directed Antibody-Drug Conjugates for the Treatment of Solid Tumors | Supplements and Featured Publications

Expert Perspectives on Trop-2 Biomarker Expression in Lung Cancer and the Potential Role of Dato-DXd

Clinical Advancements of Targeted Antibody-Drug Conjugates in Breast and Lung Cancer

Trop-2 Directed Antibody-Drug Conjugates for the Treatment of Solid Tumors