Conference to Clinic: Expert Analysis of the Top Abstracts From the 2025 Oncology Meeting in Chicago

It was an exciting ASCO for small-cell lung cancer with 2 positive phase III trials, which we will discuss, and then several updates and key trials also in both early-stage lung cancer and in targeted therapies for lung cancer.

SCLC

[00:09:07]

We will get started with small-cell lung cancer.

[00:09:11]

IMforte: Lurbinectedin + Atezolizumab vs Atezolizumab as First-line Maintenance in ES-SCLC

The IMforte trial was a phase III trial comparing lurbinectedin maintenance plus atezolizumab vs atezolizumab in extensive-stage small-cell lung cancer. The background here is we know is that lurbinectedin received accelerated approval for extensive-stage small-cell lung cancer in the second- or third-line setting. It has been an option now for several years, and this is a study with the goal of validating that approval; however, in the maintenance setting. It enrolled patients with treatment-naive, extensive-stage small-cell lung cancer who did not have brain metastases at diagnosis.

Patients received induction standard therapy with platinum etoposide plus atezolizumab for up to 4 cycles. They were then reevaluated in those patients with a complete response, partial response to stable disease, and preserved performance dashes were randomized to a control arm of atezolizumab at the standard dose every 3 weeks, or atezolizumab plus lurbinectedin at the 3.2 mg/m² dose. The co-primary endpoints were progression-free survival and overall survival.

[00:10:23]

IMforte: IRF-PFS and OS (From Randomization to Maintenance Therapy)

Here are the results of this study. This study was positive both for progression-free survival showing a benefit going from 2.1 months with atezolizumab alone to 5.4 months with lurbinectedin plus atezolizumab for a hazard ratio of 0.54 and an absolute difference at 1 year of about 8%. Also, positive for overall survival, again with a significant benefit here at 1-year follow-up, approximately 12% more patients alive. This is one of the first positive phase III trials. For a long time in the history of small-cell lung cancer, we have not had positive trials. Now we have a positive phase III trial in maintenance.

[00:11:05]

IMforte: IRF-PFS by Subgroup

Let us look at some of the subgroups. While it did appear that nearly all of the subgroups in this study derived benefit here, and perhaps more benefit for those patients who did not have prior PCI. Also, perhaps enhanced benefit for those patients who had liver metastases. Perhaps those patients with poorer prognosis might benefit more from more intensified treatment.

[00:11:29]

IMforte: OS by Subgroup

Here is the overall survival by subgroup. Again, benefit across most of the subgroups very similar. Perhaps those patients with no prior PCI might derive more benefit than those who have PCI. Otherwise, it seems as if most groups derived benefit.

[00:11:47]

IMforte: ORR and DoR During Maintenance Phase

Looking at response rates. As you might expect, when you add a chemotherapy to an immunotherapy, you do see enhanced responses here. Even in the maintenance setting, going from 19% with the atezolizumab alone from 10% with atezolizumab up to 19% with the combination. You also see some enhancement in stable disease as well, so, delaying at least progression. The median duration of response was quite good for the combination. Nine months for lurbinectedin plus atezolizumab vs 5.6 months with atezolizumab.

[00:12:24]

IMforte: ORR and DoR During Maintenance Phase

A concern though when you add a chemotherapy drug to immunotherapy is toxicity. We do see some increase in grade 3 and 4 toxicities, as you might expect, going from 22% with atezolizumab alone to 38% with lurbinectedin plus atezolizumab. There were also some grade 5 toxicities here, going from 2.5% with atezolizumab to 5%.

I think this is a therapy where we have to individualize some of the treatment choices to the patient in front of us in the clinic.

[00:12:56]

IMforte: All-Cause AEs Occurring in ≥ 10% in Either Arm

Here we see some of the specific toxicities seen in the trial. We do see increased myelosuppression, as you might expect, from adding chemotherapy to immunotherapy. Also, the grade 3, 4, and 5 events were predominantly infection related. I think that is something we have to monitor closely in patients where we are going to get prolonged courses of chemotherapy along with immunotherapy. Overall, for this treatment option, I think it is a new option for patients in terms of maintenance. It may forestall patients who would have rapid progression of disease and not get to second-line therapy, I think is what we are seeing here. It is a welcome advance in small-cell lung cancer.

[00:13:43]

ACHILES: Atezolizumab vs Observation After Chemotherapy for Limited-Stage SCLC

Moving on to another trial, the ACHILES trial, which was an international open-label phase II trial, looking at the use of atezolizumab after definitive chemoradiation for limited-stage small-cell lung cancer. We know that at last year's ASCO and published shortly afterwards, durvalumab showed an overall survival benefit in this setting. You might have expected this study might show a similar result, but unfortunately, not. This study enrolled patients with limited-stage small-cell lung cancer who were not eligible for surgery. They received up to 4 cycles of platinum etoposide chemotherapy with radiation, PCI was permitted. Patients without progression at the end of chemoradiation were then randomized to observation or atezolizumab with the primary endpoint of two-year overall survival.

[00:14:37]

ACHILES: PFS and OS

Here we see the results. While there was a numerical increase in progression-free survival, this was not statistically significant. Also, we do not see a statistically significant overall survival benefit. Somewhat surprising results here. One of the ideas put forward by the co-authors of this publication were that perhaps it was a more select population enrolled in this trial compared to the durvalumab trial. However, I do not think this regimen is going to move forward further in limited-stage small-cell lung cancer.

[00:15:17]

DeLLphi-304: Tarlatamab vs CT in Patients With SCLC After Progression During or After Platinum-Based CT

Moving on to the third of our small-cell trials, and this was DeLLphi-304. This is another drug which has had accelerated approval in small-cell lung cancer. Tarlatamab, which is the DLL3 T-cell engager therapy. In this study, it was a randomized phase III, enrolling patients with confirmed small-cell lung cancer who had relapsed after initial platinum doublet chemotherapy and had measurable disease by RECIST. They were randomized to standard chemotherapy, which could be topotecan or in East Asia it could be amrubicin or to tarlatamab. The primary endpoint of the study was overall survival.

[00:16:03]

DeLLphi-304: OS (Primary Endpoint) and Other Efficacy Outcomes

Here we see there was a significant overall survival benefit favoring tarlatamab, going from 8.3 months in the control arm of single-agent chemotherapy to 13.6 months with tarlatamab with a hazard ratio for death of 0.6 and a significant P value. Looking at some of the other efficacy metrics, the response rate was also higher, going from 20% to a single-agent chemotherapy to 35% with tarlatamab. The median duration of response was also prolonged, and median progression-free survival also favored tarlatamab.

[00:16:36]

DeLLphi-304: Safety

In terms of safety, well, these are 2 very different treatments in terms of toxicities. Chemotherapy toxicity, we are very familiar with. Tarlatamab is a T-cell engager. It has some risks of cytokine release syndrome and the neurological syndrome ICANS. Overall, numerically, the numbers favor tarlatamab. If anything, in terms of grade 3 and above toxicity, 62% with chemotherapy, down to 27% with tarlatamab. Tarlatamab is a challenging treatment in some ways and requires adjustment of how we manage our clinics and how we administer it. I think this trial in particular is a big advance in small-cell lung cancer and is something we will have to adopt into our clinics on as broad a base as possible over the next few years.

[00:17:28]

Posttest 1: In consultation with a patient with previously untreated ES-SCLC without CNS disease, which of the following results would you tell him/her was reported from the phase III IMforte trial of lurbinectedin + atezolizumab vs atezolizumab as first-line maintenance therapy after platinum etoposide plus atezolizumab?

Here we have a question. In consultation with a patient with previously untreated extensive stage small-cell lung cancer without CNS disease, which of the following results would you tell him or her was reported from the phase II IMforte trial of lurbinectedin plus atezolizumab vs atezo as first-line maintenance therapy after chemotherapy plus atezo?

1. It did not improve response, PFS, or OS;
2. It improved response, but not PFS or OS;
3. Improved response and PFS, but not OS;
4. Improved response, PFS, and OS.

You can vote in the polling section.

[00:18:35]

The answer here to the question is option D. The addition of lurbinectedin into atezolizumab improved response PFS and OS in the phase III IMforte trial, as discussed; objective response was increased from 10% to 19%. PFS from 2.1 months to 5.4 months, and overall survival from 10.6 months to 13.2 months.

NSCLC

[00:19:01]

Moving on to non-small-cell lung cancer.

[00:19:06]

ALNEO: Phase II Trial of Perioperative Alectinib in Potentially Resectable Stage III ALK-Positive NSCLC

Here, we had one of the studies presented was a phase II trial from Italy called the ALNEO trial. This addresses an emerging question in earlier-stage lung cancer, in terms of we now have an approval for adjuvant ALK inhibitor alectinib. However, what do we do for stage III locally advanced cancers? This was a singular in phase II trial enrolled patients with previously untreated ALK-positive stage III lung cancer, candidate for resection after multidisciplinary discussion, and 33 patients in the trial received alectinib 600 mg twice a day at the standard dose for 2 cycles and then went to surgery. Postoperatively could receive further adjuvant alectinib for up to 2 years, with the primary endpoint of major pathological response by blinded independent review.

[00:20:02]

ALNEO: MPR by BICR (Primary Endpoint) and Response Rates

Here we see the results. The major pathological response rate among those 33 patients was 42%. Pathologic complete response rate was 12%, and the radiographic response was also encouraging at 67%. At a median follow-up of 20 months, 91% of patients were alive, and only 18% had experienced disease recurrence.

[00:20:30]

ALNEO: Surgery and Downstaging

In terms of the surgery, a high proportion of 85% of patients underwent surgery, and most of these were zero resections. Less than 10% required pneumonectomy, and about 80% of patients were able to receive adjuvant alectinib postoperatively.

[00:20:51]

ALNEO: Safety Summary

In terms of safety, there were grade 3 and above treatment-related events were quite low, between 9% and 12% going from neoadjuvant to adjuvant settings. These were events that you would expect, as we have seen in the past, related to the use of alectinib.

A small study, but perhaps expanding our experience with perioperative alectinib to the neoadjuvant setting.

I will hand over to Dr Piotrowska to discuss the next abstract.

[00:21:35]

NeoADAURA: Neoadjuvant Osimertinib ± CT vs CT Alone in Resectable EGFRm NSCLC

Dr Zofia Piotrowska (Harvard Medical School): Awesome. Thank you so much. Thank you for the invitation to be here. It was a really exciting ASCO, and I think the early-stage session was really one of the highlights for the lung cancer program this year. The NeoADAURA study was an eagerly awaited study looking at neoadjuvant osimertinib with or without chemotherapy compared to chemotherapy alone and respectable EGFR-mutant lung cancer. This is a space where we really have not known what to do for patients when an EGFR mutation was found in patients being considered for neoadjuvant therapy.

This was a global randomized phase III study where patients with respectable stage II-IIIb non-small-cell lung cancers with classical EGFR mutations were randomized to 1 of 3 treatment arms.

These were either osimertinib monotherapy for 9 weeks, osimertinib combined with platinum pemetrexed chemotherapy for 3 cycles, so, chemo plus osimertinib, or a control arm of chemotherapy with placebo. They then went on to have surgery, and then could have adjuvant therapy at the investigator's discretion. The primary endpoint of the study was major pathologic response by blinded independent review.

[00:22:50]

NeoADAURA: MPR by Blinded Central Pathology Review (Primary Endpoint)

These were the results, the primary endpoint of the study. You can see this was a large study, looking at numbers over 100 patients in each of these treatment arms. The median major pathologic response rate was improved in both the osi plus chemotherapy and the osimertinib alone arms, 26% and 25%, respectively, compared to the control arm, where it was quite low at only 2%. This was statistically significant when comparing either of the experimental arms of osi plus chemotherapy or osi monotherapy to the control arm.

[00:23:23]

NeoADAURA: Interim EFS (15% Maturity)

Now, when we look at interim event-free survival, this is quite immature data, only 15% maturity, but you can see that there was also a trend towards improvement in EFS rates at 12 months in both of the experimental arms. Notably, there were lower rates of EFS events in the patients who achieved a major pathologic response vs those who did not, as we might expect. Again, these are early data, and we will wait for these to mature.

[00:23:49]

NeoADAURA: Safety Summary (Neoadjuvant Period)

In terms of safety, specifically focusing on the neoadjuvant period, I think overall we can say that there were no surprises here. You can see the toxicities listed for each of these regimens, and I think that overall, we did not see any major unexpected events; the treatment exposure was as expected. Importantly, we saw low rates of pneumonitis, wound complications, or cardiac effects, even in the experimental arms. We certainly can see hematologic toxicities with the osimertinib plus chemotherapy regimen, but we are used to using that now from the FLAURA2 regimen in the metastatic setting. Overall, I would say that osimertinib, whether alone or chemotherapy, was well tolerated as a neoadjuvant regimen.

Taking this data together, I think of course we will have to wait for approvals, but I was encouraged to see the major pathologic responses here and now. Notably, there were relatively few pathologic complete responses seen in any of these arms. That is discouraging to see, but certainly, I think the major pathologic responses here are important. For patients with EGFR-mutant lung cancer, where we know that immunotherapy-based regimens are less effective and may limit our opportunity to give them adjuvant osimertinib following surgery, I think that now, osimertinib monotherapy or osimertinib plus chemotherapy are going to be regimens that we are looking at for these patients.

With that, Patrick, I will hand it over to you to discuss the next abstract, because you are one of the presenting authors. Let us talk about CheckMate 816.

[00:25:26]

CheckMate 816: Neoadjuvant Nivolumab + Platinum-Based CT in Resectable NSCLC

Dr Forde: Sure. Thank you very much, Zofia, and I am very happy to present CheckMate 816. This was the final. You may have heard about this study in the past. We presented several years ago the initial event-free survival and pathologic complete response data. This is the final presentation of this study. This was a randomized phase III trial randomizing patients with confirmed respectable stage IB-IIIA non-small-cell lung cancer using the 11th edition.

These would be in the current 9th edition would be predominantly stage II and III disease. Patients with non-EGFR or ALK durations were excluded, and patients were randomized to up to 3 cycles of platinum doublet chemotherapy in the control arm, or 3 cycles of platinum doublet chemo plus nivolumab in the investigation arm. Surgery was planned within 6 weeks after the last dose of neoadjuvant treatment.

The big difference between this trial and the perioperative studies, such as KEYNOTE-189, AGN, and CheckMate 77T, is that there was no mandated postoperative immunotherapy in CheckMate 816. The primary endpoints, which we have previously reported, event-free survival and pathological complete response, were both positive. At ASCO this year, we presented the final overall survival analysis from the trial.

[00:26:52]

CheckMate 815: OS

This is the final overall survival curve. At 5-year follow-up, there was an approximate 10% improvement in overall survival, favoring nivolumab plus chemotherapy, with a hazard ratio of 0.72 and a significant P value. In general, overall survival was improved across all of the key clinical subgroups, including stage IB-III disease, squamous or non-squamous disease. There was an enhanced benefit for PD-L1-positive tumors, which we have seen with event-free survival in this study previously.

[00:27:25]

CheckMate 816: OS in Key Subgroups

These are some of these subgroups you will see. We will see for stage IB-II disease a 5% improvement in survival at 5 years, with IIIA disease and a 5-year follow-up about a 12% improvement in overall survival. PD-L1-negative disease similar, so absolute survival at 5 years, but hazard ratio trending towards favoring nivolumab plus chemo. And PD-L1-positive disease at 5-year follow-up over a 20% improvement in overall survival.

[00:28:06]

Posttest 2: The phase III NeoADAURA study evaluated preoperative treatment with osimertinib (Osi) ± chemotherapy (CT) vs CT alone in patients with resectable stage II‑IIIB EGFR-mutant NSCLC. Which of the following results were shown for the osimertinib containing arms vs CT plus placebo arm regarding major pathologic response (MPR)?

Here is one of the posttest questions again from the phase III NeoADAURA study, which evaluated preoperative treatment with osimertinib plus chemotherapy vs chemo alone in patients with respectable stage II-IIIB EGFR-mutant non-small-cell lung cancer. Which of the following were the results for the osimertinib-containing arms vs chemotherapy plus placebo regarding major pathologic response or MPR?

1. Similar MPRs for Osi with or without CT vs CT;
2. Improved MPRs for Osi with chemotherapy vs chemotherapy alone;
3. Improved MPRs for Osi vs chemotherapy only; or
4. Improved MPRs for Osi with or without chemotherapy vs chemotherapy.

Give it a little bit of time for people to answer this question.

Dr Piotrowska: Patrick, while we are waiting, maybe I will ask you, were you surprised by these results about the lack of—

Dr Forde: Yes. It is interesting because historically, we have thought that EGFR-mutant lung cancer can be quite sensitive to chemotherapy as well, but it did not appear to add too much here. What were your thoughts on this?

Dr Piotrowska: Yes, I too was surprised by that. I think that I would have expected that it would be a little bit higher, especially since we see improved outcomes in FLAURA2 in the metastatic setting when chemo is added to osimertinib. I think it was important data, and I think it gives us some leeway in selecting regimens once we have approvals.

[00:29:50]

Dr Forde: We have the results here 59%, option D, which is the correct answer. And as mentioned, the preoperative treatment with osimertinib alone or with chemo delivered quite similar results in terms of major pathologic response compared to those patients receiving chemo alone.

[00:30:11]

REZILIENT1: Zipalertinib in EGFR ex20ins-Mutated NSCLC After Prior Plt-Based CT ± Amivantamab

Dr Forde: Dr Piotrowska will take over this one.

Dr Piotrowska: Yes. I will present the next few abstracts here. So moving now, I should say to the metastatic setting. A few different studies done in the space of EGFR-mutated non-small-cell lung cancer that I think maybe we are not yet practice-changing, but certainly encouraging in terms of novel drugs that we hope to see approved in the near future. First, focusing on patients with EGFR exon 20 insertions in non-small-cell lung cancer. Recall that these are mutations that are not generally sensitive to drugs like osimertinib, and where amivantamab is approved.

For patients with EGFR exon 20 insertions, right now, amivantamab plus chemotherapy is our preferred standard of care first-line regimen for patients based on the positive results of the PAPILLON study. While we briefly had mobocertinib as an approved oral TKI for these patients, that has been withdrawn from the marketplace based on negative phase III data. Currently, we have a dearth of oral options for our patients with EGFR exon 20 insertions, but a number of drugs in development that are eagerly awaited, and one of them is this zipalertinib. I was a co-author on this study. These are updated results from the REZILIENT1 study, which was an open-label phase I/II study of zipalertinib in patients with pretreated EGFR exon 20 insertion-mutated non-small-cell lung cancer.

In this analysis, we provided updated safety data for a larger cohort of patients treated at the recommended phase II dose of 100 mg BID, and also looked specifically at patients who had been previously treated either with platinum chemotherapy alone, or patients treated with platinum-based chemotherapy and amivantamab and other plus or minus other exon 20-targeted agents. This was not a randomized study. These were separate cohorts that enrolled patients, but again, looking at outcomes with zipalertinib based on these different treatment histories here.

[00:32:10]

Phase IIb REZILIENT1: Prior Therapies by Cohort

I think really the relevant question is here, how do patients do, particularly when they have had prior amivantamab exposure, acknowledging that for most patients now, if they get amivantamab chemotherapy frontline, this is the context in which we may be using some of these oral TKIs.

This is just a breakdown of the patients here, and again, this is just to really highlight. We had 143 patients who had had only prior chemotherapy. No amivantamab and no other exon 20 targeted agents on either on trial or approved. Then we had 101 patients who had prior chemotherapy and a prior exon 20-targeted therapy, which could include amivantamab, which was the case in 83% of these patients, as well as in some cases, 1 or more oral EGFR inhibitors, as you can see listed here. Then again, just to highlight that the safety cohort included all of these patients, 244 patients.

If we look at the confirmed ORR in these different subgroups, so in the overall efficacy population, including all 176 patients, the objective response rate here was 35%. If you look at the population of patients who had only had chemotherapy and no prior exon 20-targeted therapies, including amivantamab, the confirmed ORR was 40%. If you look at patients who had prior chemotherapy and a prior exon 20-targeted therapy, which again could include either ami or EGFR TKIs or both, the response rate fell a bit to 24%, and I will provide some more breakdown on the next slide.

A question of great interest, I think, is the CNS activity of many of these drugs in development. We did see systemic response rate in patients with baseline brain mets here was 31%. Importantly, the study was not looking specifically at intracranial response. This is the systemic response.

[00:34:00]

Phase IIb REZILIENT1: Efficacy per ICR With Prior ex20ins-Targeted Tx Subgroup

Now, if we break things down by patients who had had chemotherapy prior to amivantamab and no other exon 20 TKI, so I think this really represents the population we are most likely to use this agent, we saw a confirmed ORR of 30%, median duration of response of 14.7 months among these 30 patients. However, if you see that patients had amivantamab and other EGFR exon 20 TKIs, we see that response rate fall to 14%, duration of response 4.2 months, and I think this really highlights that there is probably some cross-resistance that many of these exon 20 TKIs in development are quite similar. And so, if you have previously been exposed to one which currently is only occurring in the context of clinical trials, your benefit here is less. However, for the clinically relevant question of patients with prior amivantamab, we saw, I think, an encouraging response rate of 30% and again median duration of response of nearly 15 months.

[00:34:56]

Phase IIb REZILIENT1: PFS (per ICR) and OS

This is the progression-free survival here. Again, looking at median PFS in the patients with only prior chemotherapy, 9.5 months. Those who had been exposed to prior amivantamab or other exon 20 drugs, it was 7.3 months.

[00:35:11]

Phase IIb REZILIENT1: Safety Summary

Just briefly touching on safety here, overall, you can see that there were some treatment-related, grade 3 or greater adverse events seen in about a third of patients, but only about 14% of patients needed dose reduction, and 8% discontinuation. Pneumonitis was seen in 6 patients, mostly with extensive prior treatment history. Overall, low rates of ILD seen here.

[00:35:38]

Phase IIb REZILIENT1: Treatment-Related AEs

Specifically looking at the breakdown of toxicities, this is an important question because many of these agents have had trouble with EGFR wild-type related toxicities, including skin and GI toxicities. We did see paronychia, rash of any grade in 40% and 30% of patients, respectively, as you can see here, as well as some acneiform dermatitis and dry skin. Encouragingly, the rates of grade 3 toxicities were overall low, and diarrhea was also relatively less common than we have seen with some of the other agents, including 20% any grade and only 2% grade 3 or more.

I think, this is an agent that continues to be in development and has an ongoing phase III study. There is also ongoing development of sunvozertinib and furmonertinib in this space, and we look forward to seeing more data with those.

[00:36:29]

Posttest 3: Which of the following patient subgroups with documented locally advanced or metastatic EGFR ex20ins-mutated NSCLC and prior treatment for recurrent/metastatic disease (including amivantamab) may potentially benefit from zipalertinib according to the primary results from the phase IIb REZILIENT1 trial results presented at ASCO 2025?

Moving to our posttest question related to the study, so which of the following patient subgroups with documented locally advanced or metastatic EGFR exon 20-mutated non-small-cell lung cancer and prior treatment for recurrent or metastatic disease, including amivantamab, may potentially benefit from zipalertinib according to these phase IIb REZILIENT1 study results? Is it:

1. Patients with prior amivantamab only;
2. Patients without prior amivantamab only;
3. Patients with or without prior amivantamab; or
4. Patients without brain metastases.

Please vote.

[00:37:23]

Here are the correct answers. Patients with and without prior amivantamab. And again, we saw similar rates of benefit. I think this will be important when we think about how this drug is likely to be used in our clinical practice.

[00:37:37]

SAVANNAH: Savo ± Osi for Adv EFGRm NSCLC With MET Amplification or Overexpression After PD on Osi

Moving on, I think, to an important topic, which is patients who have been treated with first line with classical EGFR mutations, shifting gears away from those with EGFR exon 20, but moving to those with classical EGFR mutations and those who have progressed on initial EGFR TKI, so most commonly in our practice, patients who have progressed on osimertinib, we know that MET-mediated resistance is one of the most common targetable resistance mechanisms that can be identified. This can include either MET amplification, identified by FISH or NGS, or MET protein overexpression identified in IHC. We saw a couple of abstracts, which I will run through relatively briefly in the interest of time, which really look at the activity of combining a MET and EGFR inhibitor in these patients with MET overexpression or amplification after initial EGFR TKIs.

In the SAVANNAH study, which is a randomized phase II study which had a number of different cohorts, which have been presented in other abstracts as well, they had a subset of the study which really looked at the question of whether combining a MET an EGFR inhibitor is important, or whether you could just switch these patients to a MET inhibitor altogether and see similar outcomes.

Here is savolitinib is the MET inhibitor that was used together with osimertinib. In the small randomized cohort, we can see that patients with progression on first-line osimertinib who had high-level MET protein overexpression or amplification or randomized to either osimertinib plus savolitinib or savolitinib plus placebo.

[00:39:12]

SAVANNAH Randomized Subset: Response and PFS Summary

Really, the take-home here is clear, which is that the outcomes are significantly better if you continue the EGFR inhibitor and add a MET inhibitor, than if you switch altogether to a MET inhibitor. We have seen this in other contexts. We know that maintaining that EGFR inhibition is important, but you can see that the objective response rate, whether assessed by blinded review or investigator's assessment was 58%. I think, clinically meaningful with the combination of osi plus savo only 16% with savo and placebo. Median progression-free survival was 8.3 months vs 3.6 months.

I think the take-home here really is that if you do have patients who have MET amplification, combining a MET and EGFR inhibitor can be a good treatment option for these patients, leading to both high response rates and improvements in progression-free survival. Really, you have to think about the combination of a MET and EGFR inhibitor rather than a switch to a MET inhibitor alone.

[00:40:12]

SAVANNAH Randomized Subset: CNS Efficacy in Patients With Baseline CNS Metastases

In this particular study, they also were able to look at intracranial efficacy and showed that the outcomes were better when you combined osimertinib plus savolitinib, than savolitinib plus placebo. Whether you looked at the confirmed CNS response rate, which went from 25% to 43%, as well as in median duration of response, as you can see here.

[00:40:34]

SACHI: Savolitinib + Osimertinib vs CT in EGFR-Mutant, MET-Amplified Adv NSCLC After an EGFR TKI

I think, perhaps, a more interesting random question for a randomized trial is this one, which was addressed in the SACHI study. This was a phase III study conducted in China and this was asking a similar question in that what is the role of a MET and EGFR inhibitor? Once again, here, savolitinib plus osimertinib in patients with high-level MET amplification who had progressed on an initial EGFR TKI. Here, this was comparing osimertinib to savolitinib to our current standard of care for these patients, which is platinum-based chemotherapy.

In this study, which was performed exclusively in China, patients with high-level MET amplification. In this study the focus was MET amplification. The study did not include patients with MET protein overexpression, but patients with high-level MET amplification were randomized to either osimertinib + savolitinib, or platinum-based chemotherapy. The primary endpoint of the study was progression-free survival.

[00:41:31]

SACHI: PFS

We saw here that the investigator assessed PFS was improved from 4.5 months to 8.2 months in the ITT population, and also improved if you focused on the patients who had received a prior third-generation EGFR inhibitor. Hazard ratios here were 0.34 and 0.32. You might wonder why this also includes patients who have had prior first- or second-generation EGFR inhibitors, but recall that this study was done in China, where third-generation EGFR inhibitors are still not universally used as first-line therapy, and in some cases, patients may receive a first-generation TKI followed by third-gen. That is why there is this difference.

Overall, certainly I think encouraging to see that clearly, savolitinib plus Osimertinib seems to do better than chemotherapy for these patients if they are found to have MET amplification at the time of progression on their initial EGFR inhibitor.

[00:42:28]

SACHI: Response and OS

Response rate was also improved from 34% with chemotherapy. Reasonable for what we might expect to 58% with osimertinib plus savolitinib, and the median duration of response again here improved. Median overall survival improved. This data is only 40% mature, but from 17.7 to 22.9 months. This does not yet meet statistical significance.

I think this is certainly important and interesting data.

[00:42:55]

SACHI: Safety Summary

When we look at safety from this study, you can see here that treatment-related adverse events were seen in both arms of the study at relatively similar rates, I would say.

[00:43:05]

SACHI: Most Frequent TEAEs (in ≥20%)

The types of toxicities that we are seeing were a little bit different. With combination of osimertinib and savolitinib, we can see things like cumulative edema, peripheral edema, hypoalbuminemia, things that we know and can see with MET inhibitors, ALT, and AST increase. Whereas with chemotherapy, of course, we see typical chemotherapy-related side effects.

I think this data is very interesting, particularly as it relates to an ongoing global phase III study called SAFFRON, which is testing the same approach of osimertinib + savolitinib vs platinum-based chemotherapy in a global study in patients with high-level MET amplification or overexpression on a protein level. I think, that study will give us additional information, but overall, I think this also speaks to the role of biopsy in patients after progression on first-line therapy in EGFR disease, so that we can identify potential MET amplification and treat patients with these combinations when available.

[00:44:04]

HERTHENA-Lung02: Patritumab Deruxtecan (HER3-DXd) vs CT in EGFRm Adv NSCLC After a 3rd-Gen EGFR TKI

Just to briefly touch on a study that was eagerly awaited, but, ultimately, I think had somewhat disappointing results. This is a HERTHENA-Lung02, a study of patritumab deruxtecan, an antibody drug conjugate targeting HER3, vs chemotherapy, as a second-line therapy in EGFR-mutant disease after a third-generation EGFR TKI. Here, HER3-DXd or patritumab deruxtecan had been tested in prior single-arm studies and showed encouraging results in this TKI-resistant EGFR-mutant lung cancer space, leading to this randomized study, a second-line study, essentially of patritumab vs chemotherapy. Here, patients with metastatic EGFR-mutated, classical EGFR-mutated non-small-cell lung cancer who had prior EGFR inhibitors, but no prior chemotherapy were enrolled; 586 patients enrolled here randomized 1:1 to a single-agent patritumab or platinum-based chemotherapy. The primary endpoint of this study was progression-free survival by blinded review, and we had heard a press release that the study was positive.

[00:45:14]

HERTHENA-Lung02: Overall and Intracranial PFS, OS

This was the first full presentation of that data. While you can see here the median progression-free survival here was statistically improved in the patritumab arm with a hazard ratio of 0.77, unfortunately, this was only about a 2-week improvement in medium PFS from 5.4 to 5.8 months. I would say not clinically significant in terms of that improvement and importantly, overall survival, which was a key secondary endpoint of the study, was not improved and in fact quite similar across these 2 treatment arms.

I think this was while disappointing, I think this was the important finding here that was the lack of improvement in median overall survival led to a press released just around the time of ASCO that said that the application for approval of patritumab, which had been under review by FDA, was withdrawn based on the results of this study.

Unfortunately, patritumab is not moving forward in this patient population. There are a number of other antibody drug conjugates in development, including datopotamab deruxtecan as well as a number of others. So stay tuned for more ADCs in this space.

[00:46:24]

HERTHENA-Lung02: PFS by Subgroup

With that, because patritumab is not moving forward, and we have several additional studies to get through, I think I will skip over the safety data here.

[00:46:33]

HERTHENA-Lung02: TEAEs in ≥10% of Patients

But suffice it to say that what we saw was that with patritumab deruxtecan, we saw chemotherapy-based side effects similar to what we see with platinum-based chemotherapy.

[00:46:43]

HERTHENA-Lung02: Adjudicated ILD

The rates of ILD were relatively low with this ADC, although this ILD as you know, has been a challenge with other deruxtecan-based antibody drug conjugates such as trastuzumab deruxtecan. I hope we will have more encouraging data with other antibody drug conjugates in the future, but unfortunately, this was a disappointing outcome for patritumab deruxtecan, based on these slightly positive in terms of the primary endpoint of PFS, but negative overall survival results from HERTHENA-Lung02.

With that, I will turn it over to you, Patrick, to discuss the last couple abstracts, before Q&A.

[00:47:22]

TROPION-Lung02: 1L Datopotamab Deruxtecan + Pembrolizumab ± Platinum CT in Adv NSCLC

Dr Forde: We are nearly there. After talking about one antibody drug conjugate here, I am going to review another one, datopotamab deruxtecan. And the background here is that this drug was in a trial vs docetaxel in the second-line setting in non-small-cell lung cancer called TROPION-Lung01. Which the headline numbers were essentially negative, did not show a significant benefit, I would say. However, it is being pursued in EGFR-mutant lung cancer and is currently under review by the FDA in that population, and pretreated EGFR-mutant. At ASCO this year, they presented TROPION-Lung02 and focused on the first-line indication, so, looking at the combination of datopotamab deruxtecan plus pembrolizumab plus or minus platinum doublet chemotherapy in advanced non-small-cell lung cancer. This study actually excluded patients who had actionable genomic alterations, so, quite a different population to the one currently under review by the FDA. There were 2 main groups, either datopotamab deruxtecan plus pembrolizumab or Dato-DXd plus pembro plus carboplatin or cisplatin. The primary endpoints were safety and tolerability, with secondary endpoints looking at efficacy measures.

[00:48:43]

TROPION-Lung02: Select TRAEs in ≥ 20% of First-line Patients

First of all, to look at the toxicity, one of the side effects we have seen with datopotamab and several other ADCs, one of the potential side effects is interstitial lung disease. Obviously, we know pneumonitis can be a side effect which we see with immunotherapy. Thankfully, here, there does not appear to be at least synergistic toxicity.

From that viewpoint, you will see about the fifth or sixth row down, pneumonitis rates were quite similar. Really not more than you would expect individually with the drugs, I would say. Another toxicity which we know can happen with datopotamab is dermatitis, and the numbers here are similar to what we have seen, probably with a single agent, I would say grade 1, 2, maybe a little bit higher, 52%. Grade 3 events of about 5% with the doublet. 2% with the triplet. Toxicity not dramatically increased, I would say, with this combination compared to datopotamab as a single agent.

[00:49:48]

TROPION-Lung02: Safety Summary for First-line Patients

Looking at the overall correlation of all of these events grade 3 and above events, 40% with the doublet, that is Dato-DXd plus pembro, and 55% with the triplet of chemotherapy plus pembro plus datopotamab.

[00:50:10]

TROPION-Lung02: Efficacy Summary for First-line Patients

To get to the efficacy point, and interestingly enough here, we see similar efficacy really across double treatment vs triplet. Pembro, Dato-DXd objective response rate 55%. A very good duration of response, 20 months in the first-line setting, and encouraging median progression-free survival of 11.2 months. With the triplet, relatively similar results overall, slightly higher. Objective response rate 30%, median duration of response 13, subjective response rate of 55%, median duration of response of 13.7 months and PFS of 6.8 months.

[00:50:55]

TROPION-Lung02: Efficacy Outcomes by PD-L1 Status for First-line Patients

However, it is important to break this down by PD-L1 status because these are first-line patients. Here, particularly for the doublet, we see activity both in PD-L1-high disease 50% and above and also in PD-L1-low disease. Response rate in PD-L1-high disease, 100%, however, a very small number of patients. Response rate in the less than 50% population, 53%. With the triplet, we see similar response rates in both PD-L1-high and PD-L1-low disease, and again encouraging PFS and OS not yet reached.

[00:51:37]

TROPION-Lung02: TROP2 NMR* for First-line Biomarker Evaluable Subset Measured by QCS

There is a biomarker being developed for TROP2. This is an artificial intelligence-type biomarker looking at membrane and cytosolic expression of TROP2 and coming up with a predictive marker based on this. Here we see patients who are positive for this biomarker vs those who are negative. The breakdown, first of all, on the left of the screen relatively similar demographics. It does not appear to vary too much by PD-L1 expression levels. However, it does appear to differentiate also in terms of efficacy. We see here PFS is longer for those patients who are positive for the biomarker, 12 months vs 8 months, hazard ratio 0.62. Breaking it down by double vs triple, again we see a particular difference for the doublet, 10 months of median PFS in those who are negative for the biomarker and over 20 months of median PFS for those who are positive for this biomarker with a hazard ratio of 0.5. OS is not yet reached in either group, but hazard ratio 0.35. Small numbers, but I think worthy of further study in this setting.

[00:52:51]

Beamion LUNG-1: PROs With Zongertinib for Previously Treated Advanced HER2-Mutant NSCLC

Now moving on to a different setting, I think the final abstract we will discuss. This is Beamion LUNG-1, and looking specifically at patient reported outcomes with a novel TKI for HER2-mutant lung cancer. The background here is that some of the TKIs in this setting in the past have been quite toxic. In some cases, the toxicities have probably limited the ability to use them. I think it is useful here to have patient-reported outcomes be available. Here we looked specifically at patients who have pretreated lung cancer, who received zongertinib.

[00:53:25]

Beamion LING-1: PRO Measures and Timing of Assessment

Overall, the analysis was well-conducted, looked up as far as cycle 9 and compared to published data in this setting.

[00:53:38]

Beamion LUNG-1: Disease-Related Symptoms

In terms of disease-related symptoms in general, there was improvement or stabilization noted throughout the analysis period.

[00:53:48]

Beamion LUNG-1: Physical Functioning

Physical function improved or stabilized in 67% of patients throughout the analysis.

[00:53:55]

Beamion LUNG-1: Cough and Shortness of Breath

In general, reports of shortness of breath or cough also improved. Encouraging that this agent has tolerability and as well as efficacy.

[00:54:07]

Beamion LUNG-1: Overall Impact of AEs

In general, no new toxicities noted.

[00:54:10]

Q&A

I think those who were in the Q&A, I do not know if we have any questions in the chat.

Jeff Costanzo: Thank you both for going through all those studies. We do have a couple of questions, and I think Dr Forde, you have answered offline. I wanted to hear from Dr Piotrowska about these 2 topics listed here. One of the questions was about lurbinectedin. If lurbinectedin has been used as maintenance therapy, what would be your choice as a second line? Would you go for tarlatamab?

Dr Piotrowska: Combining the results from both IMforte and the DeLLphi studies that we saw, I do think that the lurbinectedin data is very encouraging, but I think it is going to be used for the right patient. Those patients who do not have disease progression, who have good functional status, and most importantly, I think who can tolerate the fact that there is going to be increased toxicities if you add lurbinectedin compared to immunotherapy just alone in maintenance. If you do use that combination that lurbinectedin + atezo maintenance, I think then this sets you up very nicely for tarlatamab as a second-line option for these patients.

I would say even more broadly, I think that DeLLphi data are very encouraging. That was a numerically very strong improvement in overall survival. I think no matter what the maintenance therapy, it would make me encouraged to use tarlatamab as a second-line therapy for really the majority of my patients with extensive-stage small cell. It is nice to have these 2 come together because I think prior to this, tarlatamab and lurbinectedin were both good options. If we use lurbi in maintenance, we would have maybe been less sure of what to do. However, the DeLLphi data, I think, really supports the use of second-line tarlatamab.