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Key Studies in NSCLC: Independent Conference Coverage of the 2021 ASCO Scientific Meeting
  • CME

Zofia Piotrowska, MD, MHS
Karen L. Reckamp, MD, MS
Released: August 20, 2021

Advances in Metastatic NSCLC—Targeted Therapy

CodeBreaK100 Update: Study Design

Zofia Piotrowska, MD, MHS:
We are now going to discuss advances in metastatic NSCLC. In terms of targeted therapies, at ASCO 2021 we saw updates of numerous important studies on drugs that have been previously reported. First, we’ll discuss the CodeBreaK100 study of the KRAS G12C inhibitor sotorasib. Of note, KRAS is the most common mutation in nonsquamous NSCLC at 25%, with KRAS G12C being the most common variant at 13%.

CodeBreaK100 is a registrational, single-arm phase II study of sotorasib in patients with previously treated KRAS G12C–mutated advanced NSCLC. Initial analyses demonstrated durable clinical benefit with an ORR of 37% and a median PFS of 6.8 months.11 On May 28, 2021, sotorasib received accelerated approval from the FDA for treatment of adult patients with locally advanced or metastatic KRAS G12C–mutated NSCLC who have received ≥1 previous systemic therapy.12 The current analysis reports OS and updated safety and efficacy data.13-14

CodeBreaK100 Update: Patient Characteristics and Disposition

Zofia Piotrowska, MD, MHS:
The study population for CodeBreaK100 included 126 patients. As you might expect in a KRAS-mutated population, the majority were current or former smokers. Some patients had received only 1 prior line of therapy, but others were more heavily pretreated, including approximately 22% who had 3 prior lines of therapy. Of importance, almost all of these patients had prior chemotherapy, prior immunotherapy, or both.13-14

CodeBreaK100 Update: Efficacy Summary

Zofia Piotrowska, MD, MHS:
Regarding efficacy, the ORR with sotorasib was 37%, consistent with previous reports we’ve seen from this trial. Median duration of response was a little more than 11 months, and median PFS was 6.8 months.13-14

CodeBreaK100 Update: OS

Zofia Piotrowska, MD, MHS:
At ASCO, we saw OS data from this study. Among 126 patients, the median OS was 12.5 months.13-14

CodeBreaK100 Update: Efficacy in Prespecified Subgroups by Baseline Characteristics

Zofia Piotrowska, MD, MHS:
Efficacy with sotorasib appeared to be fairly consistent among the different prespecified subgroups analyzed in CodeBreaK100.13-14 Of importance, we saw similar response rates regardless of the number of prior lines of therapy. 

CodeBreaK100 Update: Exploratory Efficacy by Molecular Subgroups

Zofia Piotrowska, MD, MHS:
Another important question from the ongoing KRAS G12C trials is the impact of comutations on response to KRAS G12C inhibitors. This study looked at co-occurrence of TP53, STK11, and KEAP1 mutations with KRAS G12C. Efficacy was observed regardless of the presence of these co-occurring mutations, which are indicative of suboptimal outcomes with standard of care therapy. Efficacy also was observed regardless of PD-L1 expression level or tumor mutational burden (TMB) level.13-14

CodeBreaK100 Update: Exploratory Efficacy by Co-occurring Mutations in Both STK11 and KEAP1

Zofia Piotrowska, MD, MHS:
Looking more closely at comutations, we can see that, although patient numbers are small, there is a trend toward improved response rates in patients who had wild-type KEAP1 regardless of STK11 mutational status. Conversely, patients who were KEAP1 mutated were less likely to respond to sotorasib in this study and had a shorter median PFS and OS.13-14

CodeBreaK100 Update: Safety

Zofia Piotrowska, MD, MHS:
The safety profile of sotorasib, which generally seems to be fairly well tolerated, was consistent with previous reports. The most common any-grade TRAEs were gastrointestinal toxicities, including diarrhea and nausea, which were seen in approximately 32% and 19% of patients, respectively. The rate of grade 3 diarrhea was low at 4%, and no patients had grade 3 nausea. We also saw approximately 15% of patients with any-grade alanine aminotransferase or aspartate aminotransferase elevation. These were the most common grade 3 events, which still were relatively low at approximately 6% for both. In total, 7% of patients discontinued treatment due to toxicities, and 22% required dose modification.13-14 Again, the overall safety profile of sotorasib seems fairly favorable.

CodeBreaK100 Update: Clinical Implications

Zofia Piotrowska, MD, MHS:
We know that sotorasib was just approved in May 2021 based on the CodeBreaK100 data. Dr. Reckamp, how do you view these updates relative to the data we’ve seen before, and how are you incorporating sotorasib into your clinical practice?

Karen L. Reckamp, MD, MS:
This is an update that confirms what we’ve seen before, and it is exciting to have the approval of sotorasib for our patients with KRAS G12C–positive NSCLC. With KRAS being the largest subtype of oncogenic drivers in NSCLC, there has been a need for therapeutic options for our patients with KRAS-mutant disease, and this is the first step forward. I will definitely incorporate sotorasib into my practice following chemoimmunotherapy in the frontline setting.

We need to learn more and do better for these patients. KRAS is not your typical oncogenic driver mutation. The response rate with sotorasib is in the 30% range rather than the 60% to 70% range, as we have seen with targeted therapies against other oncogenic drivers, so we’re looking at comutations and other biologic aspects to understand why. I believe understanding the impact of comutations and mechanisms of resistance will be incredibly important in this space. Furthermore, in hopes of giving our patients longer benefit, combination therapies, such as with immunotherapy and other modulators of the RAS pathway, are currently being evaluated.

Zofia Piotrowska, MD, MHS:
I completely agree. We’ve so long considered KRAS to be an undruggable target, and this is the first approval of a KRAS-targeted therapy, which is really exciting—but it definitely falls into the category of targeted therapies that I would say have good but not great activity and leave lots of room for improvement. Clinical trials with sotorasib and numerous other investigational KRAS inhibitors are ongoing, and my hope is that the sum of all of these studies will provide us with the opportunity to learn how we can tailor therapy—whether it’s biomarker selection of comutations or other patient factors, or using combination therapy—to improve patient outcomes. But for now, the FDA approval is for the second-line and beyond setting, and I certainly will use this drug for patients with a KRAS G12C mutation who have progressed on first-line therapy in my clinic.

Karen L. Reckamp, MD, MS:
Another important point to make is that KRAS G12C should now be included as part of initial comprehensive next-generation sequencing (NGS) for patients with newly diagnosed advanced NSCLC. Or, if you don’t have KRAS G12C test results prior to starting first-line therapy, it’s definitely an oncogenic driver you will want to test for before starting second-line therapy, which as you said is where sotorasib is indicated. It’s also important to highlight the fact that sotorasib is applicable to only a subset of KRAS-mutant disease. So not only is testing for mutations in KRAS going to be important, it also is important to be able to identify patients as having a G12C mutation—where you can give sotorasib—vs a non-G12C mutation, for which we hope to have better therapies in the future. But right now, we have a targeted therapy only for the KRAS G12C mutation specifically.

BOS172738 in RET-Altered Cancers: Study Design

Zofia Piotrowska, MD, MHS:
The second study in the realm of targeted therapies for the treatment of advanced NSCLC is a phase I dose-escalation study evaluating BOS172738 (zeteletinib), a novel selective RET inhibitor, in patients with advanced solid tumors with RET gene alterations. Of note, RET gene arrangements can be found in 1% to 2% of nonsquamous NSCLC, and in 2020, the FDA approved 2 selective RET inhibitors—selpercatinib and pralsetinib—for treating RET fusion–positive advanced NSCLC, and these have since become the standard of care in this setting.15-16 Of importance, this phase I study was of patients who had not received prior selective RET inhibitors, although prior treatment with multikinase inhibitors was allowed. In total, 67 patients were treated in various dose-escalation cohorts.17 

BOS172738 in RET-Altered Cancers: Baseline Characteristics

Zofia Piotrowska, MD, MHS:
Among the 67 patients treated, 34 (51%) had NSCLC, approximately one third had medullary thyroid cancer, and 18% had other tumors.17 Although 28% of patients had received a prior multikinase inhibitor, none had been given a selective RET inhibitor, such as selpercatinib or pralsetinib, as I mentioned above.

BOS172738 in RET-Altered Cancers: Safety

Zofia Piotrowska, MD, MHS:
In terms of safety, BOS172738 appeared to be fairly well tolerated. The most common adverse event was increased creatine phosphokinase, which was grade ≥3 in 25% of patients but largely asymptomatic. Approximately 40% of patients had dyspnea, but only 1% was grade ≥3. It does not appear that this dyspnea was necessarily attributed to interstitial lung disease (ILD) or pneumonitis, but it would be interesting to see more detail on its etiology. Approximately one third of patients had aspartate aminotransferase increases, diarrhea, or anemia, but again all of those appeared to be largely low grade.17

One important point about this drug is that it was developed to be specific against RET and have less activity against VEGFR. This has been a challenge with even the selective RET inhibitors that are now approved, where we do see some patients having VEGF-related AEs such as hypertension. In this study, any-grade hypertension and grade ≥3 hypertension were seen in only 19% and 3% of patients, respectively. In comparison, the selective RET inhibitors selpercatinib and pralsetinib led to grade ≥3 hypertension in approximately 12% of patients.18-19

BOS172738 in RET-Altered Cancers: Efficacy and Pharmacokinetics

Zofia Piotrowska, MD, MHS:
In terms of efficacy, the ORR with BOS172738 was 31% among the 54 evaluable patients. When we look at the 30 patients with NSCLC, the ORR was 30%.17 The median duration of response has not been reached. The study presented one case of intracranial activity, but overall the efficacy data are still preliminary.

BOS172738 in RET-Altered Cancers: Clinical Implications

Zofia Piotrowska, MD, MHS:
Putting these data into context, the ORR of 30% seen in patients with NSCLC with BOS172738 is lower than that for pralsetinib and selpercatinib, for which response rates are in the 60% to 70% range. Dr. Reckamp, what do you think about these data?

Karen L. Reckamp, MD, MS:
Given the response rate of 30%, it doesn’t measure up to the current selective RET inhibitors that we have in the clinic, so unless it shows something that is beneficial for our patients or overcomes resistance, this drug doesn’t appear to meet the mark that we have set for RET fusion–positive patients in NSCLC. An important point you mentioned is that BOS172738 may spare VEGFR and have less hypertension, so a toxicity benefit may be one of the advantages that sets this drug apart. However, it doesn’t otherwise appear to be significantly different from the approved selective RET inhibitors, so there isn’t a reason to think this drug could overcome resistance to those inhibitors, and this trial didn’t answer that question.

Zofia Piotrowska, MD, MHS:
I agree with that completely. Fortunately, that mark has been set quite high by selpercatinib and pralsetinib in terms of ORR, duration of response, and intracranial efficacy. It’s a really high bar to meet, and I’m glad to have the agents that are approved for RET fusion–positive disease to use in the clinic.

Karen L. Reckamp, MD, MS:
Also, in terms of toxicity, both of the approved selective RET inhibitors are very well tolerated drugs.

Zofia Piotrowska, MD, MHS:
Absolutely. In general, I don’t think hypertension is a huge issue with them. It’s generally manageable, in my experience. But there may be some patients with underlying hypertension for whom drugs that spare VEGFR could potentially be clinically appealing in the future.

CHRYSALIS: Study Design

Zofia Piotrowska, MD, MHS:
To close the section on targeted therapies for advanced NSCLC, we will discuss 2 studies in the setting of resistance to first-line osimertinib in the treatment of advanced EGFR-mutated NSCLC. Development of resistance to osimertinib is inevitable, and there is an unmet need for new therapies in this setting.

Let’s start first with the open-label phase I CHRYSALIS trial, which is a multicohort study evaluating the combination of amivantamab, a bispecific antibody targeting EGFR and MET, and lazertinib, an oral third-generation EGFR TKI, in patients with EGFR mutation–positive NSCLC and progression on osimertinib without intervening chemotherapy (N = 45).20 Of importance, amivantamab is a drug that recently received FDA approval for adult patients with locally advanced or metastatic NSCLC and EGFR exon 20 insertion mutations following platinum-based chemotherapy, which are not part of the current study population being reported on.

CHRYSALIS: Baseline Characteristics

Zofia Piotrowska, MD, MHS:
Among the 45 patients treated with amivantamab plus lazertinib, approximately half were nonsmokers, 29% had a history of prior brain metastases, and—of importance—100% had progressed on the third-generation EGFR TKI osimertinib. Approximately 70% of patients also had been treated with a first- or second-generation EGFR TKI. Finally, approximately two thirds of these patients had an EGFR exon 19 deletion, and one third had an EGFR L858R mutation.20

CHRYSALIS: Updated Efficacy and Safety

Zofia Piotrowska, MD, MHS:
The combination of amivantamab plus lazertinib achieved an ORR of 36%. The median duration of response was 9.6 months, and the median PFS was 4.9 months.20 This level of efficacy is actually quite compelling in the post-osimertinib space, where we don’t have many treatment options besides chemotherapy outside of clinical trials, so I was encouraged by these data. 

I’ve also generally been encouraged by the safety profile with amivantamab plus lazertinib. Most AEs were grade 1/2, and the most common was infusion‑related reactions, seen in 78% of patients, which is important to be aware of with amivantamab. These infusion reactions occur most commonly on cycle 1, Day 1 and can be mitigated with split dosing between cycle 1, Day 1 and Day 2 in pretreatment. The majority of patients then are able to be treated successfully, even if they do have an initial reaction. It also is important to note that approximately 50% of these patients had acneiform rash and 27% had other forms of rash. This is perhaps expected knowing that both amivantamab and lazertinib have skin toxicities related to the inhibition of wild‑type EGFR. That said, this combination was fairly well tolerated, with only 4% of patients discontinuing treatment due to AEs.20

CHRYSALIS: Response in Patients With EGFR/MET-Based Resistance

Zofia Piotrowska, MD, MHS:
One of the most interesting findings in this dataset was regarding potential biomarkers of response to combination therapy with amivantamab plus lazertinib. When they looked at patients by resistance mechanism to prior EGFR inhibition, they saw that, among patients who had resistance driven through EGFR- or MET‑based mechanisms, including patients who had MET amplification or secondary EGFR mutations such as C797S and others, the response rate of 47% was higher than in the overall population. Median duration of response was similar at 10.4 months.20 This starts to suggest that looking at resistance mechanisms may be a potential biomarker of response to this combination and may help distinguish patients who might benefit from this combination more than, for example, patritumab deruxtecan, which we’ll talk about shortly.

CHRYSALIS: Response in Patients Without EGFR/MET-Based Resistance

Zofia Piotrowska, MD, MHS:
Looking at the 28 patients in the study who did not have an EGFR- or MET‑based resistance mechanism, the response rate of 29% was a little lower than in the overall population, with a median duration of response of 8.3 months.20 Many of these patients had other resistance mechanisms that were independent of EGFR and MET pathways. However, the majority of responses seen in this particular cohort were among patients for whom the resistance mechanism had not been identified. So when you do a biopsy or send for a liquid biopsy after first‑line osimertinib and don’t see a resistance mechanism, amivantamab plus lazertinib still may have a potential role, although other agents can be considered in this setting, as well.

CHRYSALIS: Response in Patients With EGFR/MET Expression by IHC

Zofia Piotrowska, MD, MHS:
Finally, IHC staining for EGFR and MET was done in a small number of patients. Among 10 patients positive for EGFR/MET by IHC, the response rate was 90%, suggesting that an IHC‑based assay eventually may be developed to select patients most likely to benefit from this combination.20 You can see that sometimes these IHC‑positive patients did not necessarily overlap with those who were genomically identified to have EGFR- or MET‑driven resistance. So it may be that a combination of IHC and a genomic assay will allow us to identify the patient population most likely to benefit from this combination.

CHRYSALIS: Clinical Implications

Zofia Piotrowska, MD, MHS:
Dr. Reckamp, how do you approach treating your patients with EGFR‑mutated NSCLC who are progressing on osimertinib, and what are your thoughts about these data on amivantamab plus lazertinib?

Karen L. Reckamp, MD, MS:
First, I think that patients progressing on osimertinib are a challenging group without a defined best treatment strategy. We are only now beginning to understand that resistance mechanisms to first-line osimertinib are much more complex than what we saw with first- and second-generation EGFR TKIs. Furthermore, we are just starting to see patients with disease progression who have been receiving osimertinib for 2 years or more. Up until now, most of the data in the setting of osimertinib resistance have been from patients with more rapid disease progression, which may represent a different patient population than the longer-term patients we are now seeing.

In the clinic, I consider how rapidly the patient is progressing on osimertinib, and I think about whether they have brain metastases, which is very important to me when making treatment decisions. The combination of amivantamab plus lazertinib has activity in the brain due to the inclusion of lazertinib, so I would consider this combination for patients with brain metastases even though we don’t have data specifically for this group of patients. The data showing response rates across multiple resistance mechanisms also are appealing, especially in cases where we don’t know the specific mechanism of resistance. The median PFS is modest but reasonable at nearly 5 months. Although this combination could be an option for patients if it is approved, it is still not quite good enough. I’d like to see drugs that have higher response rates or that are specific to particular resistance mechanisms. So I think we’ve still got a ways to go, but this is a promising first step.

Zofia Piotrowska, MD, MHS:
I completely agree with you. I think the point you raised about central nervous system (CNS) metastases is a very important one. We certainly have many patients in our clinic who had brain metastases at their initial diagnosis and go on to osimertinib and have really good CNS control, and even when they progress systemically, their CNS disease continues to be controlled. For those patients, when selecting second‑line therapy, I think it is important to try to keep them on osimertinib or another similar drug to maintain that CNS control, which can be a challenge, particularly when enrolling patients on clinical trials. I worry about stopping EGFR TKIs in those patients and what will happen in the CNS. This type of combination where you continue a drug that’s very similar to osimertinib and has good CNS penetration—in this case lazertinib—and then add a novel therapy to it seems like a good way to treat these patients.

I also would add that we are starting to see early evidence that maybe it’s going to be biomarker selection that helps us select the patients most likely to benefit from the combination of amivantamab plus lazertinib. Mechanistically, it would make sense that the patients who have resistance driven through EGFR and MET would be the most likely to benefit from this antibody, which targets both of those molecules. In the future, I anticipate that—whether through molecular testing or an IHC‑based assay—we’ll be able to identify the patients who preferentially benefit from this combination, including patients with CNS disease vs those who may be better candidates for alternative therapeutic approaches—such as patritumab deruxtecan, which we’ll discuss next—or chemotherapy.

Patritumab Deruxtecan in EGFR-Mutated NSCLC: Study Design

Zofia Piotrowska, MD, MHS:
Let’s now move to patritumab deruxtecan (formerly known as U31402), an ADC targeting HER3, which is expressed in most EGFR‑mutated lung cancers. Here we see the updated results of an open‑label phase I trial of patritumab deruxtecan in patients with advanced EGFR‑mutated NSCLC who have failed prior EGFR TKI therapy.21 The dose-escalation phase established 5.6 mg/kg IV every 3 weeks to be the recommended phase II dose. This report moves into the dose-expansion phase, looking at all 57 patients treated at the recommended phase II dose.

Patritumab Deruxtecan in EGFR-Mutated NSCLC: Baseline Characteristics

Zofia Piotrowska, MD, MHS:
In this table, we can see that approximately half of the patients had a history of CNS metastases, emphasizing the point that CNS metastases are an important consideration for this group. This was quite a heavily pretreated population, with a median of 4 prior lines of therapy and—in some cases—up to 9 prior lines of therapy. Of importance, all of these patients were required to have been treated with a prior EGFR TKI, and the majority had received prior osimertinib, which is reflective of the population that we are interested in looking at in our practices.21

Patritumab Deruxtecan in EGFR-Mutated NSCLC: Efficacy According to Prior Treatment

Zofia Piotrowska, MD, MHS:
If we look first at all 57 patients who received a prior EGFR TKI with or without platinum‑based chemotherapy, patritumab deruxtecan achieved a response rate of 39%, with a median duration of response of 6.9 months and median PFS of 8.2 months. When we look specifically at patients who received prior osimertinib and platinum‑based chemotherapy, we see similar outcomes.21 A 40% response rate with a median PFS of 8 months in such a heavily pretreated population seems quite promising.

Patritumab Deruxtecan in EGFR-Mutated NSCLC: Efficacy by History of CNS Metastases

Zofia Piotrowska, MD, MHS:
For the 25 patients with a prior history of brain metastases, the ORR with patritumab deruxtecan was 32%, which numerically is a little lower than the ORR of 41% seen in the 27 patients who did not have a history of brain metastases. However, the median PFS was comparable between the 2 groups.21 No data were presented about the sites of progression in these patients, although I wonder whether the patients with prior brain metastases may have had less CNS control given that they had to stop their CNS‑penetrant EGFR TKI when enrolling on this study.

Patritumab Deruxtecan in EGFR-Mutated NSCLC: Additional Efficacy Outcomes

Zofia Piotrowska, MD, MHS:
Antitumor activity with patritumab deruxtecan was seen across a diverse variety of mechanisms of resistance to EGFR TKIs, which to me was one of the most important take-home messages from this study. We saw responses to this drug in patients with known resistance mechanisms, regardless of what those resistance mechanisms may have been, and in those without a known resistance mechanism.21 This drug appears to be modestly active in patients across various resistance mechanisms and thus may be an option for our patients regardless of whether they have an identifiable resistance mechanism.

Furthermore, responses were seen across a range of baseline HER3 expression levels, so it is yet unknown whether HER3 expression will be the right biomarker to select patients for this treatment or what the right biomarker will be.

Patritumab Deruxtecan in EGFR-Mutated NSCLC: Safety

Zofia Piotrowska, MD, MHS:
Considering safety, approximately 10% of patients had to discontinue patritumab deruxtecan due to toxicity, and approximately 20% required dose reductions.21 Approximately half of patients had grade ≥3 treatment-emergent AEs—mostly hematologic toxicities such as decreased platelet counts, white blood cell counts, lymphocyte counts, or neutrophil counts—presumably related to the chemotherapy payload of the ADC. 

I also will point out that there is some incidence of ILD in this study. In total, 5% to 7% of patients had ILD, including 1 patient with grade 3 ILD. It’s interesting to note that we have seen ILD with other ADCs using the deruxtecan chemotherapy payload, and it’s definitely important to watch for this when treating patients with patritumab deruxtecan.

HERTHENA-Lung01: Patritumab Deruxtecan in Previously Treated Metastatic EGFR-Mutated NSCLC

Zofia Piotrowska, MD, MHS:
As follow-up to the promising phase I results, HERTHENA‑Lung01 is an open-label, randomized phase II study looking at 2 patritumab deruxtecan dosing strategies in patients with advanced NSCLC and activating EGFR mutations who have progressed on prior osimertinib and ≥1 prior chemotherapy regimen.21 Patients are randomized to either the flat dosing of 5.6 mg/kg every 3 weeks or an uptitration regimen starting at 3.2 mg/kg and then increasing, which is thought to mitigate some of the hematologic toxicities seen above. This study is ongoing, and it will be interesting to see what the results show.

Patritumab Deruxtecan in EGFR-Mutated NSCLC: Clinical Implications

Zofia Piotrowska, MD, MHS:
Dr. Reckamp, what are your thoughts on the patritumab deruxtecan data? How do you anticipate incorporating patritumab deruxtecan into your clinical practice for patients progressing on osimertinib and perhaps also on chemotherapy, if it is approved?

Karen L. Reckamp, MD, MS:
I think patritumab deruxtecan is a promising agent. I agree with you that the response rates and PFS seen in this heavily pretreated population are reasonable and anticipate that they would be even higher in a patient population that’s less heavily pretreated. Considering the discussion we had above about the importance of addressing brain metastases in these patients, I thought it was interesting that the patients who had a history of brain metastases had similar PFS to those who did not. However, I would imagine that patritumab deruxtecan does not penetrate the brain like our small-molecule EGFR TKIs do.

The toxicities with patritumab deruxtecan are still a challenge, so I think, head to head, at this moment, the combination of amivantamab plus lazertinib is probably a little more tolerable in that it doesn’t have the cytopenias and chemotherapy toxicities observed with patritumab. That said, I like the idea of having multiple choices for our patients, so think it would be great to have both of these regimens as options in the clinic in the setting of osimertinib resistance. I also would like to see a biomarker to help us identify those patients most likely to benefit from patritumab deruxtecan, but it looks like HER3 is expressed so highly in EGFR-mutated disease that it will not effectively differentiate people—at least for now.

Zofia Piotrowska, MD, MHS:
I absolutely agree that it would be great to have both patritumab deruxtecan and the combination of amivantamab plus lazertinib as options in the clinic. Despite some safety signals to watch out for, patritumab deruxtecan is a great option for our patients who have progressed on osimertinib and chemotherapy, and it is certainly something I would consider for patients who have good performance status and are looking for further lines of therapy. It also will be interesting to see whether these regimens can be sequenced. Will patients be able to go on to amivantamab plus lazertinib and then, subsequently, still respond to patritumab deruxtecan, or vice versa? 

Karen L. Reckamp, MD, MS:
I would imagine that would be true because they have very different mechanisms of action.

Zofia Piotrowska, MD, MHS:
I also think it’s really important to emphasize the point you made about patritumab deruxtecan and CNS disease. An ongoing study combining patritumab deruxtecan with osimertinib will be important to watch (NCT04676477).

Karen L. Reckamp, MD, MS:
Many osimertinib combinations also are being evaluated in the setting of osimertinib resistance. Osimertinib is an excellent drug for the brain, and many patients continue to have disease control in their brain even when they have systemic progression, so having options that maintain disease control in the brain, such as continuing osimertinib (or switching to another selective EGFR TKI such as lazertinib), along with adding another agent that blocks a different signaling pathway, will be important for these patients.

TROPION-PanTumor01 Update: Study Design

Zofia Piotrowska, MD, MHS:
We also saw an update of TROPION‑PanTumor01, which is a phase I study evaluating datopotamab deruxtecan, a TROP2-targeting ADC, in previously treated advanced NSCLC. This study included dose escalation and then dose expansion at several dose levels, including 4 mg/kg, 6 mg/kg, and 8 mg/kg. Of note, patients were not selected by TROP2 expression in this particular study.22

TROPION-PanTumor01 Update: Baseline Characteristics

Zofia Piotrowska, MD, MHS:
There was a fairly sizeable number of patients in each expansion cohort: 50 each in the 4-mg/kg and 6-mg/kg cohorts and 80 in the 8-mg/kg cohort. The vast majority of patients had nonsquamous histology. Many were heavily pretreated, and nearly all had received prior chemotherapy and/or immunotherapy. It was intriguing to see that 16% to 20% of patients had an EGFR mutation and had been treated with an EGFR TKI.22

TROPION-PanTumor01 Update: Safety

Zofia Piotrowska, MD, MHS:
Grade ≥3 TRAEs with datopotamab deruxtecan were highest in the 8-mg/kg cohort at 35% and approximately half that in the 6-mg/kg and 4-mg/kg cohorts at 16% and 14%, respectively.22 ILD, which is important to monitor for with these drugs, was seen in 15% of patients at 8 mg/kg, and grade 5 treatment‑related ILD/pneumonitis led to death in 3 patients (4%). However, at the 2 lower dose levels, there was only 1 case of grade ≥3 ILD.

TROPION-PanTumor01 Update: TEAEs With Dato-DXd in ≥15% of Patients

Zofia Piotrowska, MD, MHS:
The most common toxicities seen with this compound included nausea, stomatitis, and alopecia, which were seen even at the lower doses of 4 mg/kg and 6 mg/kg.22 However, in general, the 8-mg/kg dose was most toxic overall.

TROPION-PanTumor01 Update: Efficacy Summary

Zofia Piotrowska, MD, MHS:
Despite some differences in the safety profiles of datopotamab deruxtecan at these different dose levels, we saw similar efficacy outcomes across all 3 dose cohorts. ORR was 24% in the 4-mg/kg and 8-mg/kg cohorts and 26% in the 6-mg/kg cohort. The median duration of response was not evaluable at the lowest dose level, and it was 10.5 months and 9 months in the 6-mg/kg and 8-mg/kg cohorts, respectively. Median PFS was between 4 and 7 months.22

TROPION-PanTumor01 Update: Best Change in Sum of Diameters by BICR

Zofia Piotrowska, MD, MHS:
Looking at the waterfall plot, responses were seen at all 3 dose levels. There did not seem to be a trend toward higher response rates with the higher dose levels, which is encouraging.22

TROPION-PanTumor01 Update: Clinical Implications

Zofia Piotrowska, MD, MHS:
Datopotamab deruxtecan may provide yet another treatment option for our pretreated patients, albeit one with some toxicities. Dr. Reckamp, what’s your take on the TROPION‑PanTumor01 data, and how do you think the development of this drug will move forward?

Karen L. Reckamp, MD, MS:
We lack good therapies for patients who have received both chemotherapy and immunotherapy, whether together or sequentially. Here we saw moderate response rates and decent PFS with datopotamab deruxtecan in this setting, so I am looking forward to seeing data from the ongoing phase III TROPION-LUNG01 trial (NCT04656652) evaluating this agent in patients with advanced NSCLC without oncogene‑driven tumors who have been previously treated with platinum-based chemotherapy and an immune checkpoint inhibitor.

Zofia Piotrowska, MD, MHS:
I would agree. It’s always important to keep in mind that for our patients without oncogenic drivers who have progressed on chemotherapy and immunotherapy, the response rates to later lines of single‑agent palliative chemotherapy are quite low. Novel therapies like this, even if the efficacy is modest, could have a big clinical impact in these patient populations, so datopotamab deruxtecan is definitely a therapy to watch going forward.

Karen L. Reckamp, MD, MS:
This agent also is being looked at in patients with advanced NSCLC with oncogene‑driven tumors after treatment with TKI therapy and platinum-based chemotherapy in the phase II TROPION-LUNG05 trial (NCT04484142). I suspect this drug will be active in both groups.

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