CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: October 25, 2022
Expiration: October 24, 2023
Wade T. Iams, MD, MSCI:
Our current standard of care regimens for patients with advanced NSCLC without actionable biomarkers, such as EGFR or ALK alterations, includes immune checkpoint inhibitor therapy with or without chemotherapy. The duration of immune checkpoint inhibitor therapy varies; for example, you can stop pembrolizumab at 2 years based on the trials supporting the use of this agent. A recurring question in the clinic that patients invariably ask is, “What happens if my cancer grows after I stop pembrolizumab?”
This next study was a dataset compiled from patients with advanced NSCLC who received a second course of single-agent pembrolizumab after cessation in 5 prospective clinical trials.8 I think this is a practical and important dataset to review.
From these data, you can see that there is a low percentage of patients who received a second-course pembrolizumab. In clinical practice, I provide a lot of reassurance for my patients when they are stopping pembrolizumab; I tell them that there is a very low risk that they will have tumor growth. With this dataset, we now also have data on efficacy when you retreat with pembrolizumab.
In an analysis of the objective response rate (ORR) with pembrolizumab retreatment by PD‑L1 expression in cohort 1 (first-line pembrolizumab monotherapy), the ORR for the overall population was 19.3%, 17.4% for patients with PD-L1 TPS ≥50%, and 27.3% for patients with a PD-L1 TPS of 1% to 49%. The CIs were large, especially for the PD‑L1 1% to 49% group, so it is difficult to interpret these data with certainty.
The median DoR with pembrolizumab retreatment was not reached at data cutoff, but the 6-month DoR rate was 79%. The median PFS with pembrolizumab retreatment was 10.3 months after previous pembrolizumab monotherapy and 7.7 months after pembrolizumab plus chemotherapy. The median OS with pembrolizumab retreatment was 27.5 months after previous pembrolizumab monotherapy and not yet reached after pembrolizumab plus chemotherapy.
There were no surprising safety signals and pembrolizumab retreatment seems like a manageable option for patients.
Wade T. Iams, MD, MSCI:
This pooled analysis of patients who received a second course of pembrolizumab as a part of 5 different clinical trials is an important dataset that can help inform discussions with patients in the clinic when completing a course of pembrolizumab at 2 years. We now know that a second-course pembrolizumab can be a good option to regain disease control in a majority of patients.
When we look at the efficacy data, it is important to consider additional context with second-course pembrolizumab as it relates to recent data from the Lung-MAP S1800A substudy presented at ASCO 2022. In this trial, patients previously treated with an immune checkpoint inhibitor and platinum-based chemotherapy who had progressive disease showed a similar objective response and PFS but improved OS with pembrolizumab plus ramucirumab compared with changing to a standard-of-care cytotoxic chemotherapy.9 There appears to be a subset of patients who are still deriving benefit from immune checkpoint inhibitor therapy even after progression and this can result in durable survival results.
Heather Wakelee, MD:
This has been a critical clinical question. I had a patient in clinic yesterday with this exact scenario, where he was approaching 2 years on pembrolizumab therapy and we were questioning whether we should stop or continue pembrolizumab therapy. If pembrolizumab therapy is discontinued, what do you do next?
Cohort 1 consisted of patients from KEYNOTE-024, KEYNOTE-042, and KEYNOTE-598 who had a PD‑L1 TPS of ≥1% or ≥50%. In these trials, 1160 patients were enrolled to receive pembrolizumab monotherapy. Only 223 patients completed 35 cycles of pembrolizumab and 123 experienced progression after therapy was stopped. Cohort 2 consisted of patients from KEYNOTE-189 and KEYNOTE-407 regardless of PD‑L1 expression. In these 2 trials, 763 patients were enrolled to receive pembrolizumab plus chemotherapy. In this subset, 125 patients completed 35 cycles of pembrolizumab and 57 experienced progression after therapy was stopped.
This is one of the things I emphasize with my patients who approach 2 years of therapy with pembrolizumab: if we stop therapy, there is approximately a 50% chance the cancer is not going to return, but a 50% chance it could.
We do not know what happens if you continue pembrolizumab therapy beyond 2 years, but these data do suggest that restarting with a second course of pembrolizumab can help regain control of the disease.
Many of the patients from these trials have had a complete response to initial therapy or have minimal disease at progression, so it can be difficult to define a meaningful response. It is unclear whether a CR or PR is more meaningful than simply having the disease under control; however, the fact that a large percentage of these patients were able to see their disease back under control with pembrolizumab retreatment is great.
Now, we need to try to address the question of who should stay on pembrolizumab indefinitely and who can stop safely and know that restarting a second course of pembrolizumab can regain tumor control.
Heather Wakelee, MD:
So far, we have discussed immune checkpoint inhibitor–based treatment options for patients with NSCLC and no actionable genomic alterations. Although treatment with an immune checkpoint inhibitor with or without chemotherapy has improved outcomes for these patients, disease progression does occur and treatment options become more limited.
TROP2 is a transmembrane glycoprotein associated with poor prognosis in NSCLC.10 Datopotamab deruxtecan (Dato-DXd) is an antibody–drug conjugate (ADC) with a humanized anti‑TROP2 antibody linked to a topoisomerase I inhibitor payload, and it has had some earlier data showing encouraging activity in advanced NSCLC.11
The primary endpoint was safety and tolerability and the secondary endpoints included efficacy, pharmacokinetics, and presence or absence of antidrug antibodies.
Most patients were men (70%) and had nonsquamous histology (70%-85%). In the doublet cohorts, the median number of previous lines of therapy was 1 and 33% received Dato-DXd and pembrolizumab as their first line of therapy. In the triplet cohorts, the median previous lines of therapy was 0 and 63% received Dato-DXd and pembrolizumab plus a platinum agent as their first line of therapy.12
Drug‑related pneumonitis or interstitial lung disease is something healthcare professionals need to be mindful of with any ADC. In this trial, drug-related interstitial lung disease was reported in 8% of patients receiving Dato-DXd and pembrolizumab (3% were grade 3) and 2% of patients receiving Dato-DXd and pembrolizumab plus a platinum agent (all grade 3). Stomatitis also occurred in 48% of patients receiving doublet therapy and 23% of patients receiving triplet therapy, and this is not something often reported with pembrolizumab plus platinum therapy. Other adverse events were as expected.
There were 3 deaths on the trial (5% of patients receiving doublet therapy and 2% of patients receiving triplet therapy) but these were advanced‑stage patients, and most were not believed to be drug related.
For patients who received therapy as first-line treatment, the response rate was 62% with the doublet and 50% with the triplet. In addition, 39% of patients receiving Dato-DXd and pembrolizumab and 40% receiving Dato-DXd and pembrolizumab plus a platinum agent achieved stable disease, making the disease control rate 100% and 90%, respectively.12
In the second-line population, intriguingly enough, the response rate for Dato-DXd and pembrolizumab was 24% and was 29% with Dato-DXd and pembrolizumab plus a platinum agent.12
Heather Wakelee, MD:
Overall, these data suggest that there is some advantage to combining the TROP2 ADC, Dato-DXd, with immune checkpoint inhibitor therapy with or without chemotherapy. The doublet with Dato-DXd and pembrolizumab resulted in response rates that were somewhat higher than you would expect with pembrolizumab alone in first-line and second-line metastatic NSCLC. When you add a platinum agent along with Dato-DXd and pembrolizumab, there is added toxicity and it is not clear if it significantly improves response rates. This may be a reasonable strategy to consider, but more data are needed to confirm these results.
In general, we consider ADCs to be a new class of therapy, but they are basically using antibodies for target delivery of some of our standard chemotherapeutic modalities. One question is whether the substitution of an ADC in place of one of our standard chemotherapies, such as a taxane or pemetrexed, is making a big leap forward for patient outcomes. At this point, it is not clear, but there are a few phase III trials currently recruiting to help answer some of these questions. For example, the TROPION-Lung08 trial will compare Dato‑DXd plus pembrolizumab vs pembrolizumab alone as first‑line therapy for patients with metastatic NSCLC who have high PD‑L1 expression (TPS ≥50%). The TROPION-Lung07 trial will compare Dato‑DXd plus pembrolizumab vs Dato-DXd plus pembrolizumab plus platinum chemotherapy vs pembrolizumab plus pemetrexed plus platinum chemotherapy for patients with metastatic NSCLC who have a PD‑L1 TPS <50%. I think these are reasonable studies to ask the question of whether adding a single‑agent chemotherapy with an ADC to pembrolizumab can make a meaningful impact on patient outcomes.
Wade T. Iams, MD, MSCI:
I agree, this is not yet practice changing, but these data do warrant further evaluation and I am most interested to see additional results with the Dato‑DXd plus pembrolizumab doublet. When having a conversation with a patient, the discussion often centers around the tradeoff between the likelihood of durable disease control compared with the potential for toxicity. The adverse events associated with Dato-DXd is not negligible, so it is important to be cognizant of this when deciding on treatment approaches and to consider whether we see enough of an improvement in durable disease control to warrant additional potential toxicity.
Wade T. Iams, MD, MSCI:
In addition to exploring new treatment options for patients with advanced NSCLC whose disease has progressed on or after immune checkpoint inhibitor therapy, other studies are trying to address mechanisms of resistance to PD‑1 or PD‑L1 inhibitors by evaluating potential drivers of resistance and treatment options that can exploit these drivers.
The HUDSON trial is a phase II umbrella study that used molecular screening to match patients with various potential driver mutations to targeted therapy combinations. Cohorts include those that are biomarker matched (eg, patients with ATM mutations who received the ATR inhibitor ceralasertib in combination with durvalumab) and those that were not matched.
The mechanisms that were assessed included those that target the DNA damage repair pathways, such as ATM mutations and homologous recombination as well as HER2 expression or mutations. The most successful approach to date was the use of the ATR inhibitor ceralasertib, particularly among patients with ATM mutations. Other strategies that were evaluated used a PARP inhibitor, olaparib; an epigenetic modifier STAT3 inhibitor, danvatirsen; an anti‑CD73 monoclonal antibody, oleclumab; and the HER2-targeted ADC trastuzumab deruxtecan. Since ceralasertib is being further evaluated in subsequent trials, we will focus on these results in our discussion.
Patients who were biomarker matched (group A) included those with homologous recombination repair mutations and received durvalumab plus olaparib; with LKB1 aberrations and received durvalumab plus olaparib; with ATM mutations and received durvalumab plus ceralasertib or ceralasertib alone; were CD73high and received durvalumab plus oleclumab; or with HER2 expression or mutations and received durvalumab plus trastuzumab deruxtecan.
Patients who were not matched by a specific biomarker (group B) were divided into those with primary resistance or acquired resistance (progression ≤24 or >24 weeks, respectively) and received durvalumab in combination with olaparib, danvatirsen, ceralasertib, oleclumab, or cediranib.
The primary endpoint was ORR and secondary endpoints included disease control rate, PFS, and safety.13
Wade T. Iams, MD, MSCI:
The baseline characteristics were pretty well matched among different cohorts. The median age was approximately 65 years and a little more than one half were men. Most had adenocarcinoma, and between 25% and 55% were PD-L1 positive. There was a moderate number of patients in each cohort ranging from 45 to 87 patients.13
Each subgroup had a fair number of patients for making some conclusions.
In the 21 patients who were biomarker matched with an ATM mutation, the ORR was 29%, the median PFS was 8.4 months, and the median OS was 22.8 months. In the patients who were nonmatched with primary resistance (n = 20) or acquired resistance (n = 25), the ORR was 15% and 8%, the median PFS was 4.9 months and 4.6 months, and the median OS was 11.8 months and 19.1 months, respectively.13
For patients who received durvalumab plus ceralasertib, there was a moderate-to-large amount of grade ≥3 treatment‑emergent adverse events (50% of patients treated with ceralasertib plus durvalumab). Treatment‑emergent adverse events resulted in discontinuation in 12% of patients and, unfortunately, 2 patients (3%) experienced treatment‑emergent adverse events resulting in death.
The most common (≥20%) treatment-related adverse events included nausea, vomiting, decreased appetite, and anemia with this combination.13
Wade T. Iams, MD, MSCI:
The HUDSON trial was a well-designed umbrella study that aimed to test various potential mechanistic strategies to address acquired resistance to PD‑1/PD-L1 checkpoint inhibitors, both in a biomarker-informed and biomarker-agnostic fashion. The key cohort that emerged from this study was the cohort of patients treated with durvalumab plus the ATR inhibitor ceralasertib, particularly the improved clinical efficacy among patients with ATM mutations.
Heather Wakelee, MD:
I thought that was a great idea to do this type of umbrella trial to explore different agents that target mechanisms that are not specifically a driver but may be modifying other important targets in lung cancer. It was disappointing that we only had 1 strategy that has the potential to move forward, and even the data with the ceralasertib combination does not clearly have a positive risk–benefit profile. The ceralasertib combination is worth further exploration; however, there is a phase III trial planned to study that (LATIFY; NCT05450692). Perhaps of most importance, this trial can act as a framework for ways to assess other potential treatment strategies in the future.
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