CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: June 26, 2024
Expiration: December 25, 2024
EMPOWER-Lung 3 Part 1 – PROs: Study Design
Luis Paz-Ares, MD, PhD:
Moving on to advanced NSCLC, we will start with an analysis of first-line chemoimmunotherapy. Baramidze and colleagues32 presented an interesting analysis of patient‑reported outcomes with a quadruplet regimen comprising cemiplimab plus platinum doublet chemotherapy plus ipilimumab for first‑line treatment of advanced NSCLC in the EMPOWER‑Lung 3 Part 1 trial.
Part 1 recruited patients with previously untreated advanced NSCLC without EGFR, ALK, or ROS1 alterations and PD‑L1 expression less than 50%. Patients were stratified by histology and PD‑L1 expression and then randomized to a control arm of chemotherapy alone for 4 cycles, cemiplimab plus chemotherapy for 4 cycles, or cemiplimab plus chemotherapy for 2 cycles plus ipilimumab for 4 cycles.
The trial earlier met its primary endpoint, demonstrating that first-line treatment with the quadruplet significantly prolonged OS vs chemotherapy alone (HR: 0.615; 95% CI: 0.441-0.857).33
The analysis presented at ELCC 2024 focused on patient-reported outcomes.32 These were collected using the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13). Patient-reported outcomes were assessed at Day 1, the start of each cycle for the first 6 doses, and then the start of every 3 cycles. The investigators compared the TTD for the quadruplet vs chemotherapy alone, where TTD was defined as clinically meaningful deterioration (≥10-point decrease from baseline), excluding death, with deterioration observed across available time points. All of the analyses were nominal with no adjustment for multiplicity.
Zofia Piotrowska, MD:
I would note that first-line cemiplimab plus chemotherapy is approved in the United States. In 2022, positive OS data from Part 2 of this trial led to FDA approval of cemiplimab plus platinum-based chemotherapy for adults with advanced NSCLC without EGFR, ALK, or ROS1 alterations.34
EMPOWER-Lung 3 Part 1 – PROs: Baseline Characteristics
Luis Paz-Ares, MD, PhD:
Looking at the baseline characteristics of the patient population, I would say these are standard characteristics for this type of trial. The median age was approximately 63 years, most of the patients had good ECOG PS, slightly more than half had squamous histology, approximately 7% had brain metastases and, of importance, approximately 15% had locally advanced rather than metastatic disease.32 Of note, half of the patients had PD‑L1–negative (PD-L1 <1%) tumors.
EMPOWER-Lung 3 Part 1 – PROs: TTD (Excluding Death) for GHS/QoL and Functioning Scores
Luis Paz-Ares, MD, PhD:
As you can see here, there was a clear improvement in patient-reported outcomes.32 The investigators reported significant TTD delays with the quadruplet vs chemotherapy alone in terms of global health status/QoL (GHS/QoL) along with multiple QLQ-C30 functions (all P <.05).
Zofia Piotrowska, MD:
It was good to see that patient QoL was maintained overall and that these assessments favored the quadruplet.
EMPOWER-Lung 3 Part 1 – PROs: TTD (Excluding Death) for EORTC QLQ-C30 Symptom Scores
Luis Paz-Ares, MD, PhD:
There was also a clear increase in TTD with the quadruplet vs chemotherapy alone for nearly all symptom scores.32
EMPOWER-Lung 3 Part 1 – PROs: TTD (Excluding Death) for EORTC QLQ-C13 Symptom Scores
Luis Paz-Ares, MD, PhD:
Consistent with the other data, we further saw prolonged TTD with the quadruplet for symptoms specific to lung cancer.32
EMPOWER-Lung 3 Part 1 – PROs: Clinical Implications
Luis Paz-Ares, MD, PhD:
Altogether, this analysis found that first-line cemiplimab plus chemotherapy plus ipilimumab was associated with an improvement in patient-reported QoL vs chemotherapy alone in advanced NSCLC.
QoL can be difficult to assess. A notable challenge is that QoL varies over the course of the study. For example, QoL may be worse during the chemotherapy part of treatment, but once the patient has finished chemotherapy and is benefiting from the activity of the drugs, their QoL may be better than someone who did not undergo chemotherapy. Assessing QoL depends on when you do your measurements; getting meaningful data requires collecting data over time, as the investigators did for this analysis.
Unfortunately, collecting data over time runs the risk of patients becoming exhausted and less engaged with completing questionnaires. There is also the risk that patients with the worst QoL may be the most likely to not complete the questionnaires.
Zofia Piotrowska, MD:
These are important data because we are often concerned about increased toxicities with quadruplet regimens that include CTLA-4 inhibition. The FDA has approved several other quadruplet regimens (ie, those from CheckMate 9LA35 and POSEIDON36) that incorporate both PD-1/PD-L1 and CTLA-4 inhibition.
Data from this analysis provide some reassurance that patient QoL is not negatively affected by a quadruplet regimen and further support use of a quadruplet regimen for select patients. The challenge is, how do we select those patients? Thoracic oncologists are proficient at determining who is a good candidate for platinum-doublet chemotherapy. But we are still learning how to identify which patients may be most appropriate for a dual ICI approach or a quadruplet approach.
For now, we must use our same tried-and-true metrics to assess which patients are eligible for these escalated treatment approaches. For the quadruplet regimen, I would consider a patient who is younger, generally healthy, and has no history of autoimmune disorders, given the greater risk of serious irAEs that comes with dual checkpoint blockade. Data indicate that patients with a history of autoimmune disease have both an increased risk of flare of that underlying autoimmune disorder and an increased risk of irAEs.37-40
Phase Ib/IIa Trial of Tuvusertib, an ATR Inhibitor, Plus Cemiplimab in Patients With Advanced NSCLC That Progressed on Prior Anti–PD-(L)1 and Platinum-Based Therapies
Luis Paz-Ares, MD, PhD:
While on the topic of cemiplimab-based therapy, we will briefly discuss a trials-in-progress poster that my colleagues and I41 presented at ELCC 2024.
An ongoing challenge in advanced NSCLC is how to treat patients who experience disease progression on PD-1/PD-L1 inhibition and platinum-based therapies. One potential approach is to combine PD-1/PD-L1 inhibition with ATR inhibition, because blocking ATR prevents the repair of DNA, increasing the presence of cytosolic DNA fragments.42 These fragments are sensed by the cGAS‑STING pathway, leading to activation of the type I interferon response and upregulation of PD-L1 expression on tumor cells. Thus, the hope is that combining an ATR inhibitor such as tuvusertib with a PD-1 inhibitor such as cemiplimab will lead to synergistic antitumor activity that overcomes either primary or acquired resistance to PD-1/PD-L1 inhibition.
We have planned a phase I/IIa trial (NCT05882734) evaluating the safety and antitumor activity of tuvusertib plus cemiplimab in patients with advanced nonsquamous NSCLC who already progressed through 1 prior PD‑1/PD-L1 inhibitor in combination or sequentially with platinum‑based therapies. This trial excludes patients with actionable EGFR/ALK alterations but does permit those with clinically stable brain metastases. The plan is to recruit 180 patients from sites in the United States, Japan, and Korea.
FLAURA2: Study Design
Zofia Piotrowska, MD:
We will next discuss an analysis of postprogression outcomes and OS from the FLAURA2 trial of first-line osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC (NCT04035486).43 This phase III study enrolled patients with previously untreated, EGFR-mutated advanced nonsquamous NSCLC. These are the classic EGFR mutations, specifically exon 19 deletions or L858R mutations. Stable central nervous system metastases were permitted.
The study randomized patients to first-line treatment with either osimertinib alone, which is our current standard of care, or the combination of osimertinib with carboplatin and pemetrexed for 4 cycles followed by maintenance osimertinib and pemetrexed until disease progression.
As was previously reported, this study met its primary endpoint, demonstrating that first-line osimertinib plus chemotherapy significantly improved the median PFS to 25.5 vs 16.7 months with osimertinib alone (HR: 0.62; 95% CI: 0.49-0.79; P <.001).44
The current analysis focused on how patients fared after their first-line treatment, which can include the time when patients were able to remain on the first-line treatment even after initial disease progression.43 We will often continue that first-line treatment beyond disease progression as long as patients are continuing to have clinical benefit. Thus, the current analysis covers secondary endpoints including OS as well as subsequent treatment outcomes, including time to first subsequent treatment (TFST), time to second subsequent treatment (TSST), and PFS2.
FLAURA2 Post Progression: TFST, TSST, and PFS2
Zofia Piotrowska, MD:
Overall, these postprogression outcomes were improved with osimertinib plus chemotherapy vs osimertinib alone.43 We would expect postprogression improvement like this when a treatment is extending that first PFS. That being said, these results are reassuring to see.
Luis Paz-Ares, MD, PhD:
I agree, there was a clear improvement in these relevant endpoints. I particularly want to call out the improvement in PFS2, for which there was an HR of 0.70 (95% CI: 0.52-0.93)—meaning that adding chemotherapy to osimertinib decreased the risk of PFS2 by 30% vs osimertinib alone.
FLAURA2 Post Progression: Second Interim OS Analysis
Zofia Piotrowska, MD:
Although the primary analysis demonstrated that adding chemotherapy to osimertinib significantly prolonged median PFS by approximately 9 months, there was also concern about the increased toxicity with the combination vs osimertinib alone.43,44 Unsurprisingly, adding chemotherapy increased the rates of chemotherapy-related toxicities, including hematologic toxicities and fatigue. Adding chemotherapy also adds to the burden of treatment for patients because receiving chemotherapy requires infusions every 3 weeks along with more frequent clinic visits.
These risks and burdens must be weighed against the PFS improvement with adding chemotherapy to osimertinib. When we have a treatment that improves outcomes but also adds toxicities, we turn to OS to help decide. Are we actually helping patients to live longer by giving them that more effective—but more toxic—treatment upfront?
The initial OS analysis was performed with the primary analysis of PFS.44 At that time, the OS data were at 27% maturity, and the HR was 0.90 (95% CI: 0.62-1.24; P = .52). At ELCC 2024, we saw the second interim OS analysis when the data maturity was 41%.43 Despite the OS data still being immature, we did see indications that the HR is improving. The second interim HR was 0.75 (95% CI: 0.57-0.97), with a P value of .0280 that did not reach the required threshold of ≤.000001 for significance in this analysis. We must wait to see how these OS data will turn out in the final analysis.
Luis Paz-Ares, MD, PhD:
I considered these OS results to be the key finding from this updated analysis, which had a median follow-up exceeding 30 months. Although the OS data are only 41% mature and did not reach statistical significance, there was a numerical trend towards better OS when adding chemotherapy to osimertinib.
FLAURA2 Post Progression: Clinical Implications
Zofia Piotrowska, MD:
I considered these to be important data. In my practice, the FLAURA2 regimen is an option for my patients. It is now approved by the FDA and is in the National Comprehensive Cancer Network guidelines.15,45
However, the FLAURA2 regimen is not necessarily right for every patient. We are still learning to identify the patients who are most likely to benefit from this approach vs the current standard of care of osimertinib monotherapy. Osimertinib monotherapy is very effective and well tolerated while reducing the treatment burden on patients, as it is purely oral and only requires coming to clinic every few months. Osimertinib monotherapy is still a very reasonable standard of care for many patients. We will need more follow-up to see the final OS data from FLAURA2.
Luis Paz-Ares, MD, PhD:
Despite the OS data not being fully mature, the primary PFS results, trend for OS improvement, and these postprogression outcomes do suggest that adding chemotherapy to first line osimertinib could prolong OS.
FLAURA2 is 1 of 2 trials comparing osimertinib monotherapy vs combination therapy, the other being the phase III MARIPOSA trial. MARIPOSA compared the combination of amivantamab, an EGFR-MET bispecific antibody, plus lazertinib, a third-generation EGFR TKI that crosses the blood–brain barrier, vs osimertinib alone in patients with previously untreated advanced NSCLC harboring EGFR ex19del or L858R mutation.46 Both trials demonstrated that the combination significantly improved PFS vs osimertinib alone, with an HR of 0.62 (95% CI: 0.49-0.79; P <.001) in FLAURA and 0.70 (95% CI: 0.58-0.85; P <.001) in MARIPOSA.44,46 However, the OS data for both trials remain immature.
Zofia Piotrowska, MD:
Along with waiting for the final OS data, we also need to better understand who is most likely to benefit from adding chemotherapy to first-line osimertinib. At the European Society for Medical Oncology 2023, Planchard and colleagues47 presented very compelling data from FLAURA2 indicating that patients with baseline brain metastasis strongly benefited from the combination regimen. This subgroup had both an improved intracranial response rate and a greater improvement in PFS vs the overall population with the combination regimen.
In my clinic, I also consider the FLAURA2 regimen for patients with very high disease burden and those who are having more disease-related symptoms—essentially, patients who need the quickest and deepest initial response. The primary analysis of FLAURA2 demonstrated that adding chemotherapy to osimertinib improved the overall response rate (ORR) and deepened the response.47
Luis Paz-Ares, MD, PhD:
I agree. We need further information to help determine the best treatment for each individual patient, whether that would be osimertinib monotherapy or one of these combination therapies.
I think an important source of information for individualizing treatment decisions will come from biomarker studies of the FLAURA2 and MARIPOSA data. For example, how relevant is the presence of comutations such as P53? Could we decide whether to add chemotherapy or amivantamab after several cycles of osimertinib based on the ctDNA response—meaning that patients with a very good response could skip the combination, whereas those with a poor response would intensify to combination therapy? At American Association for Cancer Research 2024, we saw some preliminary data on a ctDNA response monitoring panel for advanced NSCLC.48
There are some data suggesting that certain genomic signatures may identify which patients are more likely to progress or have disease particularly sensitive to platinum.49,50 Having this information at baseline may help us to decide between adding chemotherapy vs amivantamab to osimertinib.
Zofia Piotrowska, MD:
Another interesting question about the FLAURA2 results is whether we could consider reducing the treatment burden and toxicity risk by giving patients osimertinib only as maintenance. The safety analysis presented at ESMO 2023 reported that the median exposure to pemetrexed was 8.3 months, meaning that patients still achieved a significant PFS benefit despite not receiving chemotherapy for the entire time they were on treatment.47 I do think these data support adding chemotherapy upfront to induce the deepest response. However, if the patient is experiencing cumulative fatigue, renal toxicity, or other issues on maintenance osimertinib plus pemetrexed, then I would feel comfortable moving the patient to osimertinib alone based on the FLAURA2 data.
PALOMA — Amivantamab SC Q4W: Study Design
Zofia Piotrowska, MD:
For our next study, we will discuss early results from a cohort in the phase Ib PALOMA trial, which is assessing the pharmacokinetics and safety of a subcutaneous formulation of amivantamab administered at different dosing intervals.51,52 Amivantamab is a bispecific antibody targeting both EGFR and MET, and is currently approved by the FDA for patients with advanced NSCLC harboring EGFR exon 20 insertions, either as first-line treatment in combination with carboplatin/pemetrexed or as second-line monotherapy after platinum-based chemotherapy.53 We have also seen positive data for amivantamab in patients with classic EGFR mutations from MARIPOSA and MARIPOSA-2.46,54
The current FDA approvals are both for the intravenous formulation of amivantamab. However, intravenous amivantamab is associated with a high rate of low-grade infusion-related reactions (IRRs), which were reported in 67% of clinical trial participants (grade ≥3 in 2%).51,53 To reduce the risk of IRRs, the first dose of amivantamab is split over 2 days with an average infusion time of approximately 4 hours—thereby increasing the treatment burden for both patients and infusion centers.52
The subcutaneous formulation of amivantamab was developed to try to mitigate the risk of IRRs and is under investigation in both the phase Ib PALOMA trial and in combination with lazertinib in the phase III PALOMA-3 trial (NCT05388669), which was recently presented at the American Society of Clinical Oncology 2024. We had already seen PALOMA safety data for subcutaneous amivantamab given at Q2W and Q3W intervals.51 This presentation focused on the Q4W schedule in patients with unresectable or metastatic solid tumors that progressed after prior standard of care treatment.52
PALOMA—Amivantamab SC Q4W: Baseline Characteristics
This was a relatively small dataset comprising 19 patients treated with the Q4W schedule of subcutaneous amivantamab.52 Most patients (17/19; 89%) had NSCLC, were Asian (13/19; 68%), and weighed less than 80 kg (16/19; 84%). Slightly more than half were women.
PALOMA—Amivantamab SC Q4W: Pharmacokinetic Analysis and Dose Refinement
Zofia Piotrowska, MD:
As shown in the table, the investigators initially studied a Q4W dose of 3200 mg (≥80 kg: 4320 mg), which they refined to 3520 mg (≥80 kg: 4640 mg) to better match the pharmacokinetic parameters of the approved intravenous Q2W dose. Overall, the pharmacokinetic parameters were comparable between the refined and approved doses, with similar exposures, Ctrough, and AUC.
Of note, the subcutaneous formulation only required 7 to 10 minutes for administration. This is much shorter and easier than the long infusions and split dosing necessary to mitigate IRR risk with the intravenous formulation.
It was also intriguing and encouraging was that there no antidrug antibodies observed with the subcutaneous formulation. Antidrug antibodies can be a resistance mechanism to bispecific antibodies.55
PALOMA—Amivantamab SC Q4W: IRRs and Related Symptoms
Zofia Piotrowska, MD:
When we compare the safety profile of intravenous amivantamab vs the subcutaneous formulation given Q4W, the most notable difference is the markedly lower rate of IRRs with the subcutaneous formulation.52 Whereas 67% of clinical trial participants experienced IRRs with intravenous amivantamab, only 3/19 patients (16%) experienced IRRs with subcutaneous amivantamab. Furthermore, these 3 IRRs were all low grade. This is an encouraging observation.
That being said, the safety profile of the subcutaneous formulation was otherwise consistent with the intravenous formulation. Patients treated with the subcutaneous formulation still experienced the dermatologic toxicities associated with EGFR inhibition and the toxicities associated with MET inhibition.
PALOMA—Amivantamab SC Q4W: Clinical Implications
Zofia Piotrowska, MD:
My takeaway from this analysis is that the subcutaneous formulation of amivantamab has several key advantages over the intravenous formulation. First, subcutaneous administration requires much less “chair time.” Second, it requires less monitoring. Third and of particular importance, subcutaneous amivantamab would improve the patient experience by lowering the risk of IRRs that are so prevalent with the intravenous formulation.
However, administering amivantamab subcutaneously does not mitigate the other toxicities related to EGFR-MET inhibition, particularly the dermatologic toxicities. We would have to continue to closely monitor patients for those toxicities if this subcutaneous formulation enters practice.
Luis Paz-Ares, MD, PhD:
I agree. This small study suggests that subcutaneous amivantamab could be a potential alternative with benefit for patients in the future. I would consider these phase I data a bit too early to immediately bring the subcutaneous formulation into the clinic. These early safety data favor the subcutaneous formulation, but we still need to confirm that this formulation has equivalent efficacy to the intravenous formulation.
Zofia Piotrowska, MD:
Yes. The subcutaneous formulation is under investigation in other studies, notably PALOMA-3, a randomized phase III noninferiority study (NCT05388669). PALOMA-3 demonstrated the pharmacokinetic noninferiority of third-line treatment with subcutaneous amivantamab given Q2W in combination with lazertinib, a third-generation EGFR inhibitor similar to osimertinib, vs intravenous amivantamab plus lazertinib in patients with NSCLC harboring classic EGFR mutations.
DeLLphi-300 Long-term Follow-up: Study Design
Luis Paz-Ares, MD, PhD:
For our final study, we will be looking at developments in SCLC. I was one of the authors on this study, which focused on long‑term outcomes, including intracranial activity, of patients with previously treated SCLC who received tarlatamab at ≥10 mg in the phase I first-in-human DeLLphi‑300 trial.56 Tarlatamab is a bispecific T-cell engager (BiTE) that binds to CD3 on the T‑cell and DLL3 on the SCLC cell, thereby activating and directing T‑cells to kill the cancer cells.57,58 We should note that this trial permitted patients to have stable, asymptomatic brain metastases after having completed definitive therapy.
Earlier, we had published data from the initial patients treated with tarlatamab at doses ranging from 0.003 to 100 mg.59 That analysis reported an ORR of 23% and manageable safety profile across those doses studied.
Zofia Piotrowska, MD:
We should note that on May 16, 2024, the FDA granted accelerated approval to tarlatamab for treatment of patients with extensive-stage SCLC who had disease progression either on or after platinum-based chemotherapy.60,61 The accelerated approval was based on the phase II DeLLphi-301 trial, which reported an ORR of 40% and median duration of response of 9.7 months in this setting.
DeLLphi-300 Long-term Follow-up: Baseline Characteristics
Zofia Piotrowska, MD:
Returning to the DeLLphi-300 trial, we can see that this was a sizable dataset for a phase I trial, involving 157 patients.56 Many had received multiple prior therapies, as shown by a median of 2 prior lines of therapy (range: 1-3).
DeLLphi-300 Long-term Follow-up: Overall Survival
Luis Paz-Ares, MD, PhD:
After a median follow-up of 12.1 months, the median OS was 17.5 months for all patients treated with tarlatamab at ≥10 mg.56 Remarkably, for those 17 patients treated at the 10-mg dose, the median OS was 20.3 months. This is consistent with results from the phase II DeLLphi‑301 trial, which randomized participants to 2 doses of tarlatamab (10 mg vs 100 mg) and reported that the 10-mg dose offered the optimal balance between response vs safety.58
Zofia Piotrowska, MD:
Despite the small numbers in this analysis, there does seem to be a “tail” on this OS curve. These are encouraging results.
Regarding dosing, the FDA approved the 10-mg dose of tarlatamab.60
DeLLphi-300 Long-term Follow-up: Safety and Tolerability (Primary Endpoints)
Luis Paz-Ares, MD, PhD:
There were no new safety signals in this analysis,56 which was consistent with the safety profile reported in previous analyses and the phase II DeLLphi-301 trial.58
Zofia Piotrowska, MD:
We do have to keep in mind that tarlatamab is part of a drug class new to thoracic oncologists. Cytokine-release syndrome (CRS) and immune effector cell‒associated neurotoxicity syndrome (ICANS) are important toxicities that we will have to learn how to monitor and manage as a community. These toxicities are unique and different from the safety profiles of our established targeted therapies and immunotherapies.
CRS was quite common, occurring in 59% of patients treated with tarlatamab at 10 mg and in 67% with more than 10 mg. Reassuringly, most CRS events were grade 1/2.
We also saw ICANS and associated neurologic events in 5.9% of patients treated with 10 mg and in 12.6% treated with more than 10 mg of tarlatamab. Fortunately, there was only 1 low-grade event at the 10-mg dose. Among the 17 patients (12.6%) who developed ICANS with more than 10 mg, 7 patients (5.2%) had a grade 3 event and 1 (0.7%) had a grade 4 event.
Luis Paz-Ares, MD, PhD:
We also saw that among those treated with the 10-mg dose, most cases of ICANS occurred in cycles 1 and 2. To help mitigate and monitor for ICANS and CRS, we used step dosing and in-hospital monitoring for 2 days with the initial doses in this study.
There has been concern about whether patients with brain metastases may be at greater risk of ICANS. So far, we have not seen a clear increase in tarlatamab-related AEs, including ICANS, among those with brain metastases.
Zofia Piotrowska, MD:
Personally, I am more concerned about the risk of CRS than of ICANS. In this report, approximately two thirds of patients treated with tarlatamab at more than 10 mg experienced CRS. CRS is further concerning because patients with SCLC often have poorer health and more comorbidities associated with tobacco use. In general, patients with SCLC tend to be sicker overall and to have less physical reserve.
DeLLphi-300 Long-term Follow-up: Response and Intracranial Activity
Luis Paz-Ares, MD, PhD:
This analysis reported an ORR of 35.3% in patients treated with tarlatamab at 10 mg and 25.0% with tarlatamab at more than 10 mg.56 The median duration of response was 14.9 and 11.2 months, respectively.
In addition, we also presented some relevant data on the efficacy of tarlatamab in patients with brain metastases. Among the 16 evaluable patients with ≥1 brain lesion ≥10 mm at baseline, tarlatamab was associated with intracranial disease control in 87.5%, which lasted for a median duration of 7.4 months.
DeLLphi-300 Long-term Follow-up: Clinical Implications
Luis Paz-Ares, MD, PhD:
I think it is important to remark on 2 key findings from this analysis. First, these long‑term data indicate that tarlatamab is active in SCLC, including in patients with baseline brain metastases. We should note that patients with brain metastases were required to have been treated with radiation before study entry.
Second—but more relevant—are the OS results. In the initial report of this study, the ORR was 23% and the median OS was 13.2 months.59 This is quite remarkable in the pretreated setting of SCLC, where you would expect a median OS of approximately 6 to 8 months.62 More remarkably, we reported that with longer follow-up and with more patients treated at 10 mg or more, the median OS exceeded 17 months.[Hummel 2024] That is at least doubling the expected survival in this setting and suggests that more patients are benefiting from tarlatamab than those who are having a response as well as those free of progression, because median PFS was only 3.7 months in our earlier analysis.59 There is a disconnect somehow between the more moderate effect of tarlatamab on PFS and response vs its notable OS benefit.
Zofia Piotrowska, MD:
Now that tarlatamab is approved by the FDA for relapsed extensive-stage SCLC, we need to learn as a community how to incorporate this agent into our clinical practice. We will need to learn how to monitor for and manage CRS and ICANS so that our patients can benefit from this agent, which does seem to be an effective therapy in this setting.
Incorporating this drug into practice will be a new experience. We could learn from our colleagues caring for patients with hematologic malignancies, where therapies with a risk of CRS and ICANS have been standard of care for multiple years.
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