CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: July 25, 2023
Expiration: July 24, 2024
IMMU-132-01: Sacituzumab Govitecan-hziy in Previously Treated Advanced NSCLC
Stephen Liu, MD:
Let us talk a bit about the early clinical data available for the TROP-2‒directed ADCs. Dr Heist, could you start by telling us about what the clinical data show for sacituzumab govitecan-hziy?
Rebecca S. Heist, MD, MPH:
The open-label phase I/II IMMU-132-01 basket trial was a test of safety, tolerability, and efficacy of sacituzumab govitecan-hziy in adult patients with refractory metastatic epithelial cancers (N = 495).19 All patients were enrolled without regard to their TROP-2 expression level. The cohort of patients with NSCLC (n = 54) was heavily pretreated (median of 3 prior lines of therapy); all had received prior platinum-based chemotherapy, and approximately one third had received a prior ICI (eg, anti‒PD-1 or anti‒PD-L1) or EGFR inhibitor.20
Primary endpoints of the study included safety and objective response rate (ORR), and secondary endpoints were PFS and OS.
IMMU-132-01 NSCLC Cohort: Efficacy
Rebecca S. Heist, MD, MPH:
Participants in the NSCLC cohort had a median age of 64 years, and 80% were White. In the patients who received a starting dose of 10 mg/kg (n = 46), ORR was 17%, with a median PFS of 4.4 months (95% CI: 2.5-5.4) and median OS of 7.3 months (95% CI: 5.6-14.6).19
TROPION-PanTumor01 NSCLC Cohort With Datopotamab Deruxtecan
Stephen Liu, MD:
Dr Johnson, could you talk a little about the early clinical data for datopotamab deruxtecan?
Melissa L. Johnson, MD:
The phase I TROPION-PanTumor01 trial was a first-in-human look at the safety and tolerability of datopotamab deruxtecan for treatment of patients with advanced solid tumors. One cohort looked specifically at adult patients with relapsed/refractory advanced/metastatic NSCLC (N = 180).21 In total, 61% of participants had received ≥3 prior lines of therapy, 84% had received immunotherapy, and 96% had received platinum-based chemotherapy. Patients were enrolled regardless of their TROP-2 expression level. The primary objectives were to determine safety and maximum tolerated dose of datopotamab deruxtecan, and secondary endpoints included efficacy, pharmacokinetics, and antidrug antibody testing.
The maximum tolerated dose was established in part 1 of the study (dose escalation) to be 8 mg/kg every 3 weeks, and 6 mg/kg every 3 weeks was chosen as the dose for future development. In part 2 of the study (dose expansion), patients were assigned to groups receiving either 4 mg/kg (n = 50), 6 mg/kg (n = 50), or 8 mg/kg (n = 80) every 3 weeks.
TROPION-PanTumor01—Updated NSCLC Cohort: Antitumor Activity
Melissa L. Johnson, MD:
Antitumor activity was observed in all doses tested, with an ORR range of 22% to 26%, and responses in general were durable (median duration of response [DoR] for 6-mg/kg group: 10.5 months; 95% CI: 5.6-26.5).21 No relationship was observed between TROP-2 expression and response.
Efficacy of TROP-2‒Directed ADCs
Stephen Liu, MD:
As we just saw, sacituzumab govitecan-hziy and datopotamab deruxtecan have shown ORR in the range of 17% to 26% in patients with heavily pretreated disease. Dr Levy, what are your thoughts on this?
Benjamin Levy, MD:
Keep in mind that development of TROP-2‒directed ADCs is in the early stages, and we are still figuring out how to best use them. It really depends on what line of therapy you are looking at and then what drugs you are combining them with. It is possible that increased efficacy will be seen as we move these drugs into earlier stages of disease.
Melissa L. Johnson, MD:
I personally do not consider all ADCs to be targeted therapy, so it may be unrealistic to expect response rates above 50% in the second line and beyond. However, some patients have a great, deep response that can last a very long time, and it is exciting when you look at the scans. These TROP-2‒directed ADCs are capable of impressive responses, with a significant benefit in at least a small number of patients.
Stephen Liu, MD:
Although these are exciting drugs and they are somewhat targeted, we should not have the same expectations as we do for other truly targeted therapies, such as the tyrosine kinase inhibitors, ALK inhibitors, or EGFR inhibitors. Clearly, we need to keep working to learn how best to position ADCs in our treatment paradigm.
Strategies for Effective Use of TROP-2‒Directed ADCs
Stephen Liu, MD:
So, let us talk about the ongoing clinical trials that are evaluating how best to use these agents. Do the ADCs work best as monotherapy, perhaps in early disease settings? Should we think of them in combination?
Hossein Borghaei, MS, DO:
To some extent, I think it depends on the specific agent. The activity of ADCs for NSCLC can vary widely, from an approximately 50% response rate for trastuzumab deruxtecan in patients with HER2 mutations all the way down to a 17% to 26% response for TROP-2‒directed ADCs in the second or third line.
To justify a drug as monotherapy, I consider a high response rate to be in the range of 40% to 50%. I look at the durability of the response—like Dr Johnson mentioned she has seen in clinic for some patients—to see whether the disease can stay under control for long enough. If the response is low and durability is lacking, which seems to be the case with TROP-2‒directed ADCs, my next thought is to find some sort of combination therapy.
Benjamin Levy, MD:
Two ongoing trials are testing the TROP-2‒directed ADCs against standard-of-care docetaxel (taxane) in the second line. The open-label phase III TROPION-Lung01 trial is evaluating datopotamab deruxtecan, and the open-label phase III EVOKE-01 trial is evaluating sacituzumab govitecan-hziy in adult patients with advanced/metastatic NSCLC.17 In both studies, patients must have progressed on platinum-based chemotherapy and anti‒PD-1/PD-L1 therapy (in combination or sequentially), and those with actionable genomic alterations must have progressed on ≥1 prior line of appropriate targeted therapy to be enrolled. Also, these trials do not require TROP-2 testing prior to enrollment.
We are desperate—practically begging for alternatives to current second-line options in our patients—so we hope that TROP-2‒directed ADCs will land in the second line and enable us to investigate how to further leverage these drugs in combination.
Melissa L. Johnson, MD:
Also, keep in mind that these pivotal second line trials have enrolled patients with nonsquamous and squamous NSCLC vs docetaxel. I tend to consider TROP-2‒directed ADCs akin to a taxane in terms of selectivity for both cancer types.
Hossein Borghaei, MS, DO:
We have many needs in the second line setting right now, so I would prefer to have well-tolerated, active drugs that can stand alone in terms of response, PFS, and OS. However, the initial data suggest that the TROP-2‒directed ADCs may require a partner to extend their clinical activity and improve on the response rate.
I would hope to see improvements in clinical efficacy in trials combining these drugs with the standard-of-care drugs in a frontline setting. I think this is going to be very much dependent on the individual ADC.
Stephen Liu, MD:
I agree that it appears the data are telling us that the best way to use TROP-2‒directed ADCs will be as part of combination therapy in the future.
TROPION-Lung02: Datopotamab Deruxtecan + Pembrolizumab ± Platinum CT in Advanced NSCLC
Stephen Liu, MD:
Dr Levy, you led a study that looked at combining datopotamab deruxtecan with immunotherapy. Can you describe the rationale for the combination? Why do you expect a TROP-2‒directed ADC to pair well with immunotherapy?
Benjamin Levy, MD:
Sometimes synergistic phenomena are witnessed in the clinic, and then you have to work backward to explain why. There is a biological rationale for the synergy; when the ADC payload is delivered, antigens and neoantigens are released that can directly stimulate the immune system. Another key to possible synergy with immunotherapy is antibody-dependent cellular toxicity, triggered by the Fc component of the ADC once it binds to the target antigen. This process can attract natural killer cells and other types of immune cells to the tumor microenvironment, further augmenting the response to immunotherapy. That is the theory, which obviously needs to be tested in controlled clinical trials, perhaps not only with ICIs (anti‒PD 1/PD L1), but also with dual checkpoint blockade or even TIGIT. Despite some disappointment with TIGIT, there may be a rationale to combine it with TROP-2‒directed ADCs. We still have so much to learn about how to best use these drugs.
Stephen Liu, MD:
Dr Levy, you presented the first data of a TROP-2‒directed ADC plus immunotherapy combination trial at the 2022 World Conference on Lung Cancer. Can you please tell us what you have seen so far?
Benjamin Levy, MD:
The phase Ib TROPION-Lung02 trial is a dose-escalation and dose-expansion study looking at datopotamab deruxtecan in combination with pembrolizumab (anti‒PD-1 antibody) and platinum chemotherapy in patients with advanced NSCLC (N = 88).22,23 “Doublet” (datopotamab deruxtecan plus pembrolizumab) and “triplet” (doublet plus platinum-based chemotherapy) cohorts were evaluated, with each being a mix of patients who were pretreated and who were treatment naive. Primary endpoints were safety and tolerability, with secondary endpoints of efficacy, pharmacokinetics, and antidrug antibodies.
TROPION-Lung02: Antitumor Activity
Benjamin Levy, MD:
Including results in all response-evaluable patients, response was similar in the doublet (ORR: 38%; disease control rate: 84%; n = 61) and triplet (ORR: 49%; disease control rate: 87%; n = 71) cohorts. This was the first study evaluating doublet/triplet therapy with an ADC on the front line for NSCLC. The ORR was determined in patients who were treatment naive (doublet: 50%, n = 34; triplet: 57%, n = 53). It is not clear whether this result was due to the pembrolizumab or addition of platinum-based chemotherapy.
When TROP-2‒directed ADCs are moved up to the first line, we may start to see more efficacy, but it may be because patients in the treatment naive setting have tumors with less heterogeneity, and you are able to treat them longer because they are relatively healthier. We need more studies in the first line, looking at these drugs in a particularly enriched group of patients, either as single agent or in combination with immunotherapy.
TROP-2‒Directed ADCs and CNS Penetration
Rebecca S. Heist, MD, MPH:
Regarding the use of TROP-2‒directed ADCs in the first line setting, I am enthusiastic about their potential inclusion as part of a chemotherapy backbone. However, we must be thoughtful about the optimal dose and how much maintenance to give, if any. When choosing a maintenance strategy, which we typically do up front with chemotherapy/immunotherapy, how long will it last when combining an ADC and immunotherapy? Keep in mind that the most common partner for platinum-based chemotherapy in patients with nonsquamous NSCLC is pemetrexed, which has the quite meaningful advantages of good long-term tolerability and central nervous system (CNS) penetration. We also need to determine whether the TROP-2‒directed ADCs have comparable levels of CNS penetration. These are all things that need to be established as the first line studies are carried out.
Benjamin Levy, MD:
The CNS penetration of these drugs is an important point, and as we learn more, perhaps we can look to other tumor types for inspiration. If you follow the breast cancer literature, you will see how trastuzumab deruxtecan works in the brain for leptomeningeal disease.24 We do not know if it could work the same way in lung cancer, but it is remarkable to see this activity in breast cancer. Is there a difference in the blood‒brain barrier in lung cancer vs breast cancer? Are different ADCs metabolized differently? To me, these are very exciting questions.
Rebecca S. Heist, MD, MPH:
I would love to see CNS penetration data for the TROP-2‒directed ADCs. I think most of the studies have excluded active or growing CNS metastases, but it is an unanswered question that really needs to be looked at.
Select Ongoing Trials of Sacituzumab Govitecan-hziy in Advanced or Metastatic NSCLC
Stephen Liu, MD:
Several trials are underway that look to build from the standard of care and hopefully show the efficacy of TROP-2‒directed ADCs in the earlier-line settings. What are the ongoing trials on which our learners can consider enrolling their patients?
Rebecca S. Heist, MD, MPH:
Two studies are evaluating sacituzumab govitecan-hziy in patients with advanced/metastatic NSCLC and no prior therapy.
The randomized phase II EVOKE-2 study is looking at sacituzumab govitecan-hziy plus pembrolizumab with or without platinum-based chemotherapy in patients without actionable genomic alterations. Cohorts for doublet therapy will be stratified by PD-L1 tumor proportion score (TPS) status (<50% vs ≥50%), and cohorts for triplet therapy will be stratified by cancer type (squamous vs nonsquamous) regardless of PD-L1 TPS. The primary endpoints are ORR and percentage experiencing dose-limiting toxicities.
The randomized phase III EVOKE-3 trial will compare sacituzumab govitecan-hziy plus pembrolizumab vs pembrolizumab alone. Eligible patients must have PD-L1 TPS ≥50% and no actionable genomic alterations in EGFR, ALK or ROS1. Primary endpoints include PFS and OS.
As mentioned previously, the open-label phase III EVOKE-01 trial is comparing sacituzumab govitecan-hziy with docetaxel in adult patients with advanced/metastatic NSCLC previously treated with platinum chemotherapy and an ICI.
Select Ongoing Trials of Datopotamab Deruxtecan in Advanced or Metastatic NSCLC
Benjamin Levy, MD:
Two studies are looking at datopotamab deruxtecan in patients with advanced/metastatic NSCLC and no prior therapy.
In the phase III TROPION-Lung07 study, patients will be randomized 1:1:1 to receive datopotamab deruxtecan plus pembrolizumab with or without platinum-based chemotherapy, or pembrolizumab plus platinum-based chemotherapy with pemetrexed. Eligible patients must have PD-L1 TPS <50%. The primary endpoints are PFS (blinded independent central review) and OS. The phase III TROPION-Lung08 study will compare datopotamab deruxtecan plus pembrolizumab vs pembrolizumab alone in patients with PD-L1 TPS ≥50%. The primary endpoints are PFS (blinded independent central review) and OS. Of importance, neither of these studies is accepting patients with actionable genomic alterations in EGFR, ALK, ROS1, NTRK, BRAF, RET, or MET.
As mentioned before, the open-label phase III TROPION-Lung01 trial is comparing datopotamab deruxtecan with docetaxel in adult patients with advanced/metastatic NSCLC either previously treated with platinum chemotherapy and ICI or, in the case of actionable genomic alterations, previously treated with targeted therapies with or without chemotherapy and an ICI. A recent press release indicated that this trial met the dual primary endpoint of improved PFS, with results to be presented at a future meeting.
Hossein Borghaei, MS, DO:
We also are testing datopotamab deruxtecan in combination with other immunotherapies for treatment of patients with advanced/metastatic NSCLC and no actionable genomic alterations. The ongoing phase Ib TROPION-Lung04 trial (NCT04612751) is looking at safety and tolerability of datopotamab deruxtecan (4 mg/kg or 6 mg/kg) plus durvalumab (anti‒PD-L1 antibody), with or without platinum-based chemotherapy. Part 1 (dose escalation) allows patients with ≤2 prior lines of systemic therapy. However, for part 2 (dose expansion), patients in doublet cohorts must not have had prior ICI therapy (1 line of platinum-based chemotherapy is allowed), and those in triplet cohorts are not allowed any prior systemic cancer therapy. The primary endpoint is number of patients with dose-limiting toxicities.
Neoadjuvant/Adjuvant Usage for TROP-2‒Directed ADCs in Lung Cancer
Benjamin Levy, MD:
I also wanted to mention neoadjuvant/adjuvant use of TROP-2‒directed ADCs in early-stage NSCLC.
Neoadjuvant nivolumab plus chemotherapy demonstrated significant clinical benefit in patients with resectable NSCLC.25 Given the potential for synergy between ADCs and immunotherapy, it will be interesting to test TROP-2‒directed ADCs plus immunotherapy in the neoadjuvant setting.
For example, 1 arm of the phase II NeoCOAST-2 trial (NCT05061550) will evaluate datopotamab deruxtecan plus durvalumab and single-agent platinum-based chemotherapy as neoadjuvant therapy in patients with resectable early-stage (II-IIIb) NSCLC. The primary endpoints are number of patients with complete response and safety. Patients with actionable genomic alterations in EGFR or ALK are not eligible, nor are those who have received prior immunotherapy or TROP-2‒directed ADCs. It will be interesting to see the results from this study. It may be important to look at TROP-2‒directed ADCs in different settings, perhaps even in the consolidation setting for stage III NSCLC. These drugs potentially have more toxicity, so we need different dosing and interval strategies, even in the neoadjuvant or consolidation settings.
TROP-2‒Directed ADCs for Advanced NSCLC With Actionable Driver Alterations
Stephen Liu, MD:
Most of the ongoing trials mentioned so far do not allow patients with actionable genomic alterations. Do you think TROP-2‒directed ADCs are just as likely to work in a driver positive cancer?
Rebecca S. Heist, MD, MPH:
With oncogene drivers such as EGFR/ALK/ROS/RET, there is the possibility that a drug such as datopotamab deruxtecan would work with any of those. It is an area of interest that is definitely being studied. Many of the patients with actionable genomic alterations are sensitive to chemotherapy, and as we said, TROP-2‒directed ADCs are a kind of targeted chemotherapy.
TROPION-PanTumor01: NSCLC With Actionable Genomic Alterations—Antitumor Activity
Melissa L. Johnson, MD:
There was some early indication of activity for datopotamab deruxtecan in patients with driver-positive NSCLC. A subanalysis of the phase I TROPION-PanTumor01 trial described earlier focused on participants with actionable genomic alterations.26 In 34 heavily pretreated patients (82% had received ≥3 prior lines of therapy) with actionable genomic alterations, confirmed ORR was 35% (95% CI: 19.7%-53.5%), with a DoR of 9.5 months (95% CI: 3.3 to not evaluable).
The TROPION-Lung01 and EVOKE-1 trials allowed patients with advanced/metastatic NSCLC and driver mutations (eg, EGFR, ALK, ROS1, RET, MET, NTRK, and BRAF) if they had progressed on a targeted therapy. Now there are some ongoing studies directly targeting this same patient population, including the single-arm phase II TROPION-Lung05 trial (NCT04484142), which is looking at efficacy, pharmacokinetics, and safety of datopotamab deruxtecan. The primary endpoint is ORR, and secondary endpoints include DoR, PFS, OS, pharmacokinetics, and safety.
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