I’d like to move on to our third and final section. We’re going to talk about some emerging approaches for the management of small cell lung cancer. Wade, I’m going to start with you. There have been a couple of interesting presentations regarding AMG 757 and then a second agent, BI 764532. If you don’t mind, briefly go over the data and try to put it into some context for us, please.

 This preceding discussion was a perfect segue for novel immunotherapy approaches and DLL3-targeted agents. I’ll discuss 2 different drugs in development. They’re both bispecific T-cell engagers. Within the broad field of oncology, the best analogy for drugs to these DLL3 agents is blinatumomab, a bispecific CD3/CD19 antibody, for patients with acute leukemia. In the context of small cell lung cancer, the data I’ll review have to do with novel drugs that are bispecific antibodies to DLL3—which is expressed in a majority of small cell lung cancer tumor cells, it doesn’t directly coincide to any of the subtyping we’ve discussed, it’s fairly independent of subtype—and CD3.

The goal of both of these drugs is to bring the host T cells to those small cell tumor cells. The first abstract that I’ll talk about is Amgen [Inc]’s AMG 757. This was a first-in-human dose-escalation study. Sixty-four patients were treated with the AMG 757 compound. It’s an IV [intravenous] infusion every 2 weeks. First, there are a couple of disclaimers before I tell you about the response and toxicity data. In relapsed small cell, we need to think about how much treatment these patients have received. The median number of lines of therapy was 2, so we’re generally talking about the third line of therapy or later. This is a difficult patient population with small cell lung cancer. These patients were in a dose-escalation cohort. That’s the caveat with the response data.

The response rate for partial responses was 13%. The disease control rate was about 43%. But as all of the panelists have touched on this evening, durable response is what we’re hoping for with these immunotherapy drugs. And among patients who responded, 71% had over 6 months of response. In a majority of patients who responded, it was very durable. That’s the high point of the DLL3 data, in my opinion.

Toxicity-wise, we’re always monitoring for cytokine release syndrome, which is essentially an acute inflammatory syndrome, in patients receiving these drugs, and 42% of them had any degree of cytokine release syndrome. In about a quarter of them, it was grade 3 or greater. We’re talking a need for observation and probably hospitalization in those patients. There was 1 participant who had a grade 5 pneumonitis event. There’s notable toxicity with this approach, but we’re going for that durability of benefit.

Were there any data regarding lines of therapy associated with toxicity in this patient population?

 Not that I’m aware of, but it’s a key question. In thoracic oncology in particular, when we’re looking at these phase 1 trial data, I’m always asking, “Is that a patient who had pneumonitis from a previous JAK1 inhibitor?” We’ve all seen that confound later lines of therapy, and it can be quite delayed. It’s a key question.

The second compound, also a bispecific T-cell engager, is from Boehringer Ingelheim [BI]. This abstract is just a plan for a first-in-human trial of that drug. Here are a couple key points on this upcoming trial. They’re looking to enroll 110 patients. A couple of interesting caveats for the BI trial: They are selecting for DLL3 tumor expression, and they’re including not just small cell lung cancer, but small cell of any type. In the broad oncology field, that’ll be well received, as we know there are different histologies that can transform to small cell. That’ll be very interesting to see.

Thank you so much for providing that update for us. Let’s go through the updates, and then we’ll have another discussion. Stephen, TIGIT is getting a lot of attention in both non–small cell and small cell. There’s an abstract involving small cell. I’m wondering if you can comment about that.

 Sure. There aren’t a whole lot of data to review here. TIGIT stands for T-cell immunoreceptor with Ig [immunoglobulin] and ITIM domains. It inhibits T cells and NK [natural killer] cells, another checkpoint. Tiragolumab is an anti-TIGIT IgG1 monoclonal, where we have a little data. The data are mostly from non–small cell lung cancer. Our colleague Delvys Rodriguez-Abreu, [MD,] presented the CITYSCAPE data. That’s a randomized phase 2 trial in non–small cell lung cancer. We saw that when you added an anti-TIGIT like tiragolumab to an anti–PD-L1 like atezolizumab, it significantly improved the response rate in PD-L1–high from 24% to 66%, improved PFS [progression-free survival], and the hazard ratio was a staggering 0.30, awarding that drug FDA breakthrough therapy designation.

We have multiple anti-TIGIT molecules in development now, and we’re looking at them in small cell lung cancer. SKYSCRAPER-02 is a randomized phase 3 trial. For full disclosure, I am on the steering committee of that trial. That’s looking at the IMpower133 regimen of carboplatin, etoposide, and atezolizumab with or without tiragolumab, or placebo. It’s a study of almost 500 patients and dual primary end points, PFS and OS [overall survival]. It’s no longer recruiting patients, so we’re eagerly awaiting the results from that trial.

Videos

Expert panelists weigh in on emerging data from recent presentations on small cell lung cancer, including novel immunotherapy approaches such as bispecific antibodies targeting DLL3 or therapies targeting TIGIT.

Emerging Treatments in SCLC: Bispecific Antibodies

 Is it fair to say that in this panel, we still think there’s a patient population, although rare, who might benefit from exposure to I/O [immunotherapy] post-progression? Anne, would you say that since we’re using chemotherapy-I/O up front, there isn’t much of a role for rechallenging with I/O at progression after lurbinectedin and paclitaxel? In your mind, is there a role for an I/O agent?

We can look to other cancer types for some guidance here. If you look at the melanoma or renal cell fields, there are some data that you can salvage patients who progress on I/O single agent with combination therapies.

But Anne, that’s not small cell [lung cancer]. That’s melanoma. Specifically in small cell, how do you feel about going back to a checkpoint inhibitor?

Learning from other tumor types can help us. But for small cell, it may be that we haven’t given up on combination therapy or even single-agent therapy later on. I don’t think we know enough. If you look at clinical trials, we have all sorts of combination approaches, where hopefully one of them will nab the golden ring. But there may be a signal, perhaps with an anti–CTLA-4 combination with anti–PD-L1. Even for going back to a single agent after chemotherapy, this is something that should be tested and may potentially have benefit, so I’m optimistic.

Sorry for interrupting you. I wanted you to say a little more about the rationale for your ipilimumab-nivolumab study. Is that specifically post–chemotherapy-I/O or is it post–other lines of therapy?

Our IIT [investigator-initiated trial] for ipilimumab-nivolumab is for relapsed small cell lung cancer, and it can be either on maintenance or further down the line. I don’t think we’re picky. If our patients have good performance status and they’re able to go on a trial so that we can look at what’s happening in a pretreatment and week-4 biopsy—we’ve gotten about a dozen of these paired biopsies to date that are really interesting—we can learn from that.

 You’ve got to hope that there’s some role for future immunotherapy. We tend to be optimists. In the lung cancer field, you have to be. When we look at immunotherapy vs other cytotoxic agents, we’ll see other drugs coming along, but the benefit is transient with cytotoxic agents. Immunotherapy as a class is so appealing to patients and oncologists because one of the tenets of immunotherapy is that long-term benefit and the potential for meaningful, durable long-term survival. It may be not going back to the exact same way you gave immunotherapy, but could there be some other synergy, attacking the microenvironment at the same time, or some way to unleash that immune response? We have to keep chasing that.

If I could add one more thing to that: immunotherapy is not a homogeneous class. If a PD-1 inhibitor doesn’t work, then maybe a Siglec-15 inhibitor, which is not expressed on the same cells, could be very useful. There are going to be a lot of tools we can use to harness our immune system.

I’m really interested in your ipilimumab-nivolumab idea. That’s something that should be explored in patients who have evidence of disease progression, so I’m glad somebody’s doing that study. I’m looking forward to it.

Anne Chiang, MD, PhD, renowned expert in thoracic oncology, guides a discussion on whether to rechallenge with chemotherapy + I/O after progression of small cell lung cancer.

SCLC: Rechallenging With Chemotherapy + I/O

 We’re going to move on to the second segment of the study, which has to do with relapsed/refractory small cell lung cancer. We’re going to discuss some treatment options for patients who have evidence of disease progression following what we just talked about: chemotherapy and immunotherapy. We’re also going to talk about a couple of approved drugs. Vivek, lurbinectedin has received a lot of attention lately. I’m wondering if you can cover some of the data and recent information that have been published and discussed at various meetings.

 Thank you so much, Hoss. As we all know, few options exist for patients with small cell lung cancer after failure of first-line therapy. Lurbinectedin was interesting as a selective inhibitor of oncogenic transcription. I mainly got involved in the trial because it was active in multiple small round blue cell tumors, including Ewing sarcoma. The phase 2 study that was designed was a basket study. Small cell was one of the arms of this basket study. They evaluated the safety and activity of lurbinectedin in patients with small cell lung cancer after failure of platinum-based chemotherapy. This was a simple single-arm, open-label, phase 2 basket study. They recruited patients from mainly Europe and the United States. Patients had to have an ECOG PS [performance status] of less than 2 in the absence of brain metastasis, and adequate organ function. Treatment consisted of lurbinectedin monotherapy at 3.2 mg/m2 as a 1-hour intravenous infusion every 3 weeks until disease progression.

Between October 2015 and January 2019, 105 patients were enrolled and treated on the lurbinectedin study. The median follow-up was 17.1 months. An overall response by investigator assessment was seen in 37 patients, for an objective response rate of 35.2%. The most common adverse events we saw were hematologic abnormalities, as this is chemotherapy; namely anemia in 9% of patients; low white blood cell count, leukopenia, in around 30% of patients; neutropenia in 46% of patients; and thrombocytopenia in 7% of patients. There were no treatment-related deaths reported. Lurbinectedin was active in the second line of therapy of small cell lung cancer in terms of overall response rate and had an acceptable and manageable safety profile.

Lurbinectedin could represent a potential new treatment option for patients who have very few options when they relapse. This is being investigated both as monotherapy and in combination. What is the value of this monotherapy arm of this basket study? It provided the first clinical evidence of an agent with antitumor activity as a single drug in patients with relapsed small cell lung cancer, with durable responses. The results detected by the investigator assessment were robust and confirmed by independent central review as well. Lurbinectedin appeared to be a valuable treatment option. The benefits from the lurbinectedin study appear to be favorable compared with what we historically see with topotecan, which is the standard of care, in terms of both antitumor activity and safety.

This drug profile is relevant for patients with small cell lung cancer who have a very dismal prognosis. The NCCN [National Comprehensive Cancer Network] recommends a rechallenge with first-line treatment for relapsed small cell lung cancer with a chemotherapy-free interval of greater than 180 days. From this phase 2 basket study, activity was shown in this setting as well for lurbinectedin. We recently reported a preplanned analysis from this subtype. Interestingly, the investigator-assessed objective response rate in this cohort was 60%, with a median duration of 5.5 months and disease control rate of 95%. Interestingly, with the censoring of 53%, the median overall survival was 16.2 months. Of note, 60.9% and 27.1% of patients were alive at 1 and 2 years, respectively.

The most common treatment-related adverse events were hematologic disorders. Neutropenia was seen in 55% of patients, anemia in 10% of patients, and thrombocytopenia in 10% of patients. Increases in AST [aspartate aminotransferase] and AFP [alpha-fetoprotein] were noted in around 5% to 10% of patients. Interestingly, no cases of febrile neutropenia were reported.

What did it show? Lurbinectedin is an effective treatment for platinum-sensitive relapsed small cell lung cancer, especially in patients with a chemotherapy-free interval of greater than 180 days, with an acceptable safety profile. These encouraging results suggest that lurbinectedin can be another valuable tool in our arsenal and a therapeutic option rather than platinum rechallenge in these patients.

 We’re going to come back to a couple of discussion points.

Vivek Subbiah, MD, reviews the safety and efficacy of treatment with lurbinectedin in patients who have platinum-sensitive relapsed small cell lung cancer.

Treatment After Progression of SCLC: Lurbinectedin

Vivek, we’re going to give you something a little more difficult: KEYNOTE-604, the only 1 of the big, randomized phase 3 studies that didn’t hit its predefined statistical end points. I’m wondering if you can comment on the study and give your impression of the data.

 Thank you for the opportunity. As we all know, pembrolizumab, PD-1 inhibitor monotherapy, has shown anti-tumor activity in patients with small cell lung cancer. This was shown in the data from the KEYNOTE-028 and KEYNOTE-158 studies. The randomized double-blind phase 3 KEYNOTE-604 study compared placebo plus cisplatin and etoposide vs pembrolizumab plus etoposide and platinum in patients with previously untreated extensive-stage small cell lung cancer. Eligible patients were randomized 1:1 to pembrolizumab, 200 mg once daily every 3 weeks, or a saline-based placebo for up to 33 cycles plus 4 cycles of etoposide-platinum. The primary end points were PFS [progression-free survival] and OS [overall survival] in the intent-to-treat population. They enrolled around 453 participants; 228 were randomly assigned to pembrolizumab plus etoposide-platinum, and 225 patients to placebo plus etoposide-platinum.

Pembrolizumab plus platinum-etoposide significantly improved PFS. The hazard ratio was 0.75. The 12-month PFS estimate was 13.6% with pembrolizumab plus etoposide-platinum and 3.1% with placebo plus etoposide-platinum. Although pembrolizumab plus etoposide-platinum prolonged the overall survival, the overall survival estimates were 22.5 months and 12.2 months. The significant threshold for the overall survival was not met.

What’s the conclusion from this study? Pembrolizumab plus platinum-etoposide significantly improved the PFS compared with placebo plus etoposide-platinum as first-line therapy for patients with extensive-stage small cell lung cancer. They didn’t see any unexpected toxicities as seen with pembrolizumab plus etoposide-platinum. What did we gain from this? Although the addition of pembrolizumab to platinum-etoposide didn’t significantly improve the overall survival, it significantly prolonged the time patients lived without disease progression. The adverse-event profile of pembrolizumab plus etoposide-platinum was as expected and generally manageable.

What’s the clinical relevance of the study? We thank all the motivated patients, investigators, and the entire staff for enrolling in this study. They showed that pembrolizumab has clinical activity in extensive-stage small cell lung cancer as well as an adverse-event profile that allows it to be combined with other therapies. There’s value in exploring pembrolizumab in combination with other therapies in patients with small cell lung cancer to hopefully identify a future regimen that significantly prolongs the overall survival.

Key opinion leader in lung cancer, Vivek Subbiah, MD, examines the phase 3 KEYNOTE-604 trial of platinum-based chemotherapy + pembrolizumab and considers whether the data support findings from other trials of chemotherapy + IO combination approaches. 

Hossein Borghaei, DO, Fox Chase Cancer Center

Articles

Emerging Treatments in SCLC: Bispecific Antibodies

SCLC: Rechallenging With Chemotherapy + I/O

Treatment After Progression of SCLC: Lurbinectedin

First-Line Therapy in ES SCLS: KEYNOTE-604