Autologous and allogeneic BCMA-directed CAR T-cell therapies are leading to deep and durable responses in patients with heavily pretreated multiple myeloma, with a low incidence of severe cytokine release syndrome (CRS) and neurotoxicity, explained Yi Lin, MD, PhD, who added that with a pending biologics license application (BLA), the field should start to consider which patients, who don’t fit the typical clinical trial eligibility criteria, might be a candidate for the treatment in real-world practice.

On September 22, 2020, the FDA granted a priority review designation to a BLA for idecabtagene vicleucel (ide-cel; bb2121) for the treatment of adult patients with multiple myeloma who have received at least 3 previous therapies, based on data from the pivotal phase 2 KarMMa trial (NCT03361748).

“When [these approaches are] available in practice, we’ll have to look at the FDA label,” said Lin. “Putting that in context with the trial experience and also with what we’re learning in standard-of-care practice in lymphoma and leukemia, what we will need to understand beyond the approved indication [in a certain] line of therapy is really patient characteristics, such as comorbidities and so on, because we would likely not be restricted by trial criteria anymore. Understanding what a safe condition to use CAR T-cell therapy in while still preserving the efficacy of the product [is something we’ll have to determine].”

® during the 2020 Institutional Perspectives in Cancer webinar on multiple myeloma, Lin, consultant, Division of Hematology, Department of Internal Medicine, consultant, Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, assistant professor of medicine and oncology, Mayo Clinic, discussed promising data with CAR T-cell therapy in multiple myeloma.

: How do the CAR T-cell therapies under investigation compare? Are they all leading to deep and durable responses?

: Cilta-cel [ciltacabtagene autoleucel; JNJ-68284528] and ide-cel are already in pivotal trials. With ide-cel, the BLA has been submitted to the FDA, so we’re anticipating review in early 2021. Cilta-cel is also getting ready for BLA submission to the FDA as well. Potentially in 2021, we may have these BCMA-targeted CAR T-cell therapies available in standard-of-care practice.

In these trials of heavily pretreated patients with poor-risk cytogenetics and penta-refractory disease, a single infusion of the CAR T [cells is leading to] very high overall response rates. A high percentage of these patients are having deep responses and reaching complete remission [CR] or stringent CR. A good proportion of those patients are also experiencing MRD [minimal residual disease]–negative disease. In myeloma, those are relevant metrics in terms of having more durable responses, and we’re seeing that [that’s true with] CAR T-cell therapy as well.

The median PFS [progression-free survival] is around 8.8 months for ide-cel, and the 12-month PFS rate for cilta-cel is close to 77%. That’s very exciting for a patient who has had continuous treatment. We have heard anecdotal reports from these patients on the CAR T-cell therapy trials that when they’re in remission, when they’re recovering post CAR T-cell therapy, it’s the “best they have felt.” It’s almost like before they had myeloma. Some of these metrics are being formally measured as quality-of-life outcomes in the pivotal trial. We’ve seen some of that reported as well in poster format at the 2020 ASH Annual Meeting and Exposition. Those data are very important to consider.

bb21217 is very interesting, because it’s one of these next-generation approaches we’re looking at to improve upon CAR T-cell therapy. There are a lot of emerging data regarding the phenotype of CAR T cells in myeloma, including other hematologic malignancies, [in that] the T cell that has more of a naïve with memory potential phenotype may contribute to better persistence and more active T cells. That’s one of the ways that bb21217 is trying to approach that.

During manufacturing, they’re exposing the T cells to a PI3K inhibitor to drive the phenotype functions of B cells. We’re seeing that with the CAR T cell that’s generated from patients on the study, the profiles of the CAR T-cell product do have more presence of these cells [compared with other products]. It’s still a little too early to say how the long-term clinical response will look, but initial results, in terms of response rates, are very encouraging.

Autologous products were the first to be developed, but now we’re starting to see allogeneic products as well. With longer follow-up, could they overtake autologous products?

That’s certainly a possibility. We’ve seen the data with ALLO-715; it’s very early yet. That study only has about 3 months of follow-up, but what we’ve seen has been very encouraging. The potential advantage of allogeneic CAR T-cell therapy [is that because] you’re generating [the allogeneic product] from a healthy donor, the T-cell function or the T-cell health or fitness might be better [than that of an autologous product from a patient with myeloma].

You can also make [the product] ahead of time, so it would be more ready off-the-shelf, but that comes with challenges. You are infusing T cells from somebody else, so there could be a risk for graft-versus-host-disease [GVHD], which we have seen with allogeneic stem cell transplant. This particular product comes with a lot of additional gene editing approaches to try to address that, and so far of about 31 patients who have been dosed, we haven’t seen any alarming signals for GVHD. These CAR T cells persist and are measurable in patients, which is also very encouraging, and we’re seeing early signals for response. We’re not seeing any concerns yet for the high incidence of more severe CRS, neurotoxicity, or infections.

The FDA recently approved selinexor [Xpovio] after 1 prior line of therapy. Given that we’re seeing a number of new novel agents being evaluated in earlier settings, are you concerned that when CAR T-cell therapy is approved, it’s not going to be used in the same population that it was studied in?

It will be interesting to see how it is adopted in the market. I’ve certainly heard concerns from others in the field that we’re not quite seeing a plateau in terms of PFS as we have seen in lymphoma. We have to keep in mind that these are very heavily pretreated patients that are studied on trials. I suspect, based on how the trials are designed, that the potential position of where it would be with the final FDA-approved indication would be after 3 lines of prior therapy and exposure to a proteasome inhibitor, IMiD [immunomodulatory drug], and a monoclonal antibody. If it is truly adopted for patients who would be eligible and have access to treatment centers, it could potentially buy them at least a period of time where they don’t need any therapies.

Though, we still have patients on these studies that are 2 years out or more in continued remission. I suspect because of how BCMA CAR T-cell therapy works––it’s really targeting a surface antigen, it’s not targeting particular cell signaling pathways, and we are seeing responses across other cytogenetic risks––that it wouldn’t necessarily impact how well it could function in real-world practice, but that’s something that we’ll need to learn as it becomes available.

What have we learned about managing CRS and neurotoxicity?

It’s certainly very encouraging to see that, across the CAR T-cell therapy studies, we have not generally seen a very high signal in terms of grade 3 or more severe CRS or neurotoxicity that would require ICU level monitoring. [Such scenarios have] generally [occurred] in single-digit percentages in less than 10% of cases.

There may be some component of how these CARs are designed. There may be some elements of the nature of the myeloma disease that contributes to this, but we’re also evolving in our understanding of when interventions like tocilizumab (Actemra) and steroids could be safely used to walk that balance between not losing response but preventing more severe toxicities. Within each protocol, the threshold for using tocilizumab and steroids do vary. Generally, there is a move towards using these drugs earlier in the onset of those symptoms, so patients don’t have to suffer through the more severe late effects. There’s a variable percentage of patients who get [these interventions], but it’s a higher percentage than in the earlier studies.

What novel agents caught your eye at the 2020 ASH Annual Meeting and Exposition?

I was most excited to see Allogene’s allogeneic product. What’s reassuring is that generally we are seeing response signals, but it’s a little too early to tell whether that will translate into an advantage in clinical response compared with the current generation CAR T cells. There are lots of products to keep an eye on, but it’s hard to pick a lead yet.

With the bispecific antibodies, we’re now seeing some reports from non-BCMA approaches. With a number of BCMA-targeted CAR T-cell therapies and bispecific antibody-drug conjugates, we do need to move into the non-BCMA space fairly quickly. It’s very exciting to see pretty high early response rate signals from those approaches as well. CAR T-cell therapies targeting those same antigens are also starting [to be developed], so probably by the 2021 ASH Annual Meeting and Exposition, we’ll hear some results from those studies as well. Immunotherapy approaches are moving very quickly in myeloma, and it’s always exciting to have those options for our patients.

Is it too early to start thinking about how you might approach patient selection once CAR T-cell therapies are approved?

It’s never too early to think about patient selection. It’s quite common that patients with myeloma need to get bridging therapy or continue some type of therapy while their autologous CAR T cells are being made. How that may impact or potentially be used to optimize the response of CAR T-cell therapy is not formally studied in a trial. We’ll learn from real-world practice. In terms of patient access to this product, is there a potentially broader range of conditions and comorbidities where CAR T-cell therapy can still be safely given with a reasonable expectation of response?

Are other targets emerging aside from BCMA?

GPRC5D and FcRH are the ones that are currently [being developed for] bispecific approaches. CAR T-cell therapy trials will be starting or have recently started [with those targets] as well. Thus far, based on the expression of these targets, they seem to have very limited off-target toxicities. Fingers crossed. We’ll continue to truly see that profile in the clinical trial settings. Those are the [targets] to really watch out for.

The very first report of CAR T activity in myeloma was with a CD19-directed approach. There’s still some continued effort to see if a combination of CD19 and BCMA have a role in myeloma. To that end, there are some combinations of BCMA-directed CAR T-cell therapy approaches with and CD38 or CS1. Ultimately, the novel targets are the ones to watch out for and likely will have a role, if we do see a desirable response, very quickly after BCMA-directed approaches.

US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel; bb2121). News release. Bristol Myers Squibb and bluebird bio, Inc. September 22, 2020. Accessed February 8, 2021. 

This article was originally published on OncLive as, "

CAR T-Cell Therapy Carves Out a Role in Multiple Myeloma

Articles

CAR T-Cell Therapy Is Promising in Myeloma

Sapanisertib failed to show significant activity and a favorable toxicity profile in patients with refractory metastatic renal cell carcinoma (mRCC) regardless of mTOR or PTEN status, according to findings from a phase 2 study (NCT03097328) that were presented during the 2021 Genitourinary Cancers Symposium.

At a median follow-up of 10.4 months (range, 1.0-27.4), the objective response rate (ORR) was 5.3% (n = 2; 90% CI, 1.0%-15.6%). The median progression-free survival (PFS) was 2.5 months (95% CI, 1.8-3.7), and the median overall survival (OS) was 11.2 months (95% CI, 9.3-not reached).

“Sapanisertib had poor tolerability and minimal activity in patients with treatment refractory metastatic RCC, and there was no clear benefit among patients with mTOR or PTEN alterations,” Bradley McGregor, MD, lead study author, and clinical director of the Lank Center for Genitourinary Oncology, senior physician at Dana-Farber Cancer Institute, and instructor of medicine at Harvard Medical School, said in a virtual presentation of the data.

Treatment options following progression on a checkpoint inhibitor and VEGF TKI are limited for patients with mRCC. Approved rapalogs, which have modest activity in mRCC, inhibit only mTORC1, whereas sapanisertib inhibits the entire mTOR pathway by targeting mTORC1 and mTORC2.

The multicenter, single-arm study enrolled 38 patients with clear cell mRCC who had received at least 2 prior lines of therapy and non-clear cell mRCC who had received at least 1 prior line of therapy with an ECOG performance status of 0 to 2.

Patients underwent a mandatory baseline biopsy that evaluated PTEN status and over 477 genes, including TSC1, TSC2, mTOR, PIK3CA, and PTEN, prior to receiving 30 mg of oral sapanisertib weekly.

The primary end point was ORR. Secondary end points included PFS, OS, safety, and toxicity. ORR and PFS by PTEN immunohistochemistry status and oncopanel-identified mutations in the mTOR pathway served as correlative end points.

Regarding patient characteristics, the median age at the time of enrollment was 62 (range, 28-75). The majority of patients had clear cell histology (73.7%; n = 28), followed by non-clear cell RCC (26.3%; n = 10), which encompassed chromophobe RCC (n = 2), papillary RCC (n = 6), translocation RCC (n = 1), and unclassified RCC (n = 1). The majority of patients had intermediate-risk disease (76.3%; n = 29) per International Metastatic RCC Database Consortium risk assessment, followed by favorable- (13.2%; n = 5) and poor-risk disease (10.5%; n = 4).

The majority of patients were heavily pretreated, having received 4 or more prior lines of therapy (39.5%; n = 15). Though, patients who received 1 (13.2%; n = 5), 2 (21.1%; n = 8), and 3 (13.2%; n = 5) prior lines of therapy were also represented. A total of 5 patients (13.2%) had an unknown number of prior treatments.

The majority of patients had received a prior checkpoint inhibitor (75.8%; n = 25) but not an mTOR inhibitor (60.6%; n = 20).

Additional results showed that 2 patients experienced an unconfirmed partial response (PR; 5.3%), 15 patients experienced stable disease (SD; 39.4%), 17 patients experienced progressive disease (44.7%), and 2 patients were not evaluable (5.3%).

The median time on treatment was 1.6 months (range, 0.3-13.8). At the time of data cutoff, 2 patients remained on treatment (5.3%), 36 had discontinued treatment (94.7%), 29 had progressive disease (PD; 76.3%), 4 had unacceptable toxicity (10.5%), 1 withdrew (2.6%), 1 discontinued by patient decision (2.6%), and 1 discontinued by physician discretion (2.6%).

No clear benefit between mTOR and PTEN alterations and clinical benefit with sapanisertib was reported.

Among patients with intact PTEN (n = 12), 1 experienced a PR, 6 experienced SD, and 5 experienced PD. Among patients with diminished PTEN expression or PTEN loss (n = 7), 1 experienced an unconfirmed PR, 2 experienced SD, and 4 experienced PD.

Among patients with an mTOR pathway mutation (n = 6), 1 experienced an unconfirmed PR, 1 experienced SD, and 4 experienced PD. Among patients without an mTOR pathway mutation (n = 21), 2 experienced a PR, 1 experienced an unconfirmed PR, 8 experienced SD, and 9 experienced PD.

Treatment-related adverse effects consisted of nausea (50%; n = 19) fatigue (39%; n = 15, vomiting (34%; n = 13), mucositis (32%; n = 12), anorexia (21%; n = 8), diarrhea (18%; n = 7), rash (18%; n = 7), dyspnea (13%; n = 5), hyperglycemia (13%; n = 5), constipation (11%; n = 4), hyperkalemia (11%; n = 4), cough (8%; n = 3), dehydration (8%; n = 3), dry mouth (8%; n = 3), muscle weakness (8%; n = 3), pruritus (8%; n = 3), hyponatremia (5%; n = 2), elevated creatinine (3%; n = 1), myocardial infarction (3%; n = 1), syncope (3%; n = 1), and pneumonitis (3%; n = 1). No grade 4 or 5 toxicities occurred.

“Additional work is needed to find new targets for patients with advanced RCC,” concluded McGregor.


McGregor BA, Adib E, Xie W, et al. Biomarker-based phase II study of sapanisertib (TAK-228), an mTORC1/2 inhibitor in patients with refractory metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2021(suppl 6):306. doi:10.1200/JCO.2021.39.6_suppl.306

This article was originally published on OncLive as, "Sapanisertib Imparts Poor Activity and Toxicity Profile in Refractory mRCC."

Sapanisertib failed to show significant activity and a favorable toxicity profile in patients with refractory metastatic renal cell carcinoma (mRCC) regardless of mTOR or PTEN status. 

Sapanisertib: Poor Activity, More AEs in mRCC

Combinations of JAK inhibitors and novel agents, such as epigenetic regulators, could help prolong survival in patients with myeloproliferative neoplasms (MPNs), providing patients with more than a reduction in spleen size and symptomatic relief, explained Shella Saint Fleur-Lominy, MD, PhD, who added that for patients who have already progressed on ruxolitinib (Jakafi), fedratinib (Inrebic), momelotinib, and pacritinib could be potential second-line options.

“A lot of these agents will probably be used in combination with ruxolitinib for the most optimal response. It’s very promising to see all those different agents emerge that have an effect on disease outcome and modulation of the bone marrow,” said Saint Fleur-Lominy. “For every symptomatic patient who gets diagnosed with myelofibrosis, polycythemia vera [PV], or essential thrombocythemia [ET], we need to determine if they’re a candidate for a clinical trial, because that’s how we advance the treatment landscape.”

&#8239;during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Saint Fleur-Lominy, an assistant professor, Department of Medicine, at NYU Langone Health’s Perlmutter Cancer Center, discussed the current landscape of MPNs and the importance of addressing disease burden and progression. 

: What are some pathways apart from JAK that are involved in disease modulation that could become potential targets in MPNs? 

 Downstream of JAK, there are STAT dependent and independent pathways that are involved in disease modulation. A number of newer agents target those signals downstream of JAK. For example, there’s the oral kinase inhibitor alisertib, which is downstream of cNeT, which is downstream of JAK. It’s one of the molecules that is upregulated in this disease. The phase 1 study was very small, but when they analyzed bone marrow samples pre- and posttreatment, they saw that there was improvement in the degree of fibrosis, and preclinical data showed the same thing.

Other agents include epigenetic regulators. We have an ALS21 inhibitor. We have BT inhibitors. One was studied in combination with ruxolitinib in [JAK-inhibitor naïve patients] and patients who didn’t have a good response to ruxolitinib. One of the themes among these different agents is that that they modulate the disease. One of the key findings, particularly for the LSD1 inhibitor was that the bone marrow fibrosis and variant allele frequency was reduced significantly. Those diseases don’t just have the JAK mutation, they have a lot of other genes that could be mutated and that have [an effect on] survival, disease progression, and response to treatment. Having drugs that target those repeated clones is very significant. There’s also a telomerase inhibitor, and there is a phase 3 trial that is being planned.

What are some common complications of patients with MPNs that are being evaluated in studies?

Patients can have thrombotic events like clots, and we see that across the different subtypes of PV, ET, and myelofibrosis. Patients who have a low level of fibrosis can have those complications. It doesn’t matter how much fibrosis you have in the bone marrow. The risk is usually lower in younger people, but as you age, you see [patients at greater] risk. 

There is also a risk of bleeding events as well, especially in ET when people have a very high platelet count. There is also a risk of leukemic transformation because MPN is a disease that has mutations in hematopoietic stem cells, and those stem cells can transform [and] acquire new high-risk mutations and other chromosomal abnormalities and transform into acute leukemia. 

In terms of symptom burden, a very large study looked at the symptomatic manifestation of MPNs [and found that] the burden is really high. Approximately 80% of patients have a really high symptomatic burden, [ranging] from fatigue to other symptoms like reduced appetite, early satiety because of big spleen, or the big spleen causing abdominal discomfort. As high as 60% of patients have abdominal discomfort, or early satiety. Up to 80% of patients reported fatigue. 

Other symptoms like itching and night sweats [were also common]. Itching you see more with PV. Weight loss, fever, and bone pain [are additional symptoms that patients may experience]. The severity varies, so some patients have mild symptoms, and some patients have more severe symptoms. The main thing is that patients with MPNs have a very high symptomatic burden. That’s one of the reasons [a lot of studies] evaluating drugs in this disease usually use spleen reduction size and symptomatic relief as end points. 

What mutations are of the most interest in patients with PV, ET, and myelofibrosis?

One of the most common mutations is JAK2. These are diseases of abnormal JAK signaling. About 95% of patients with PV have the classic JAK2 V617F mutation, and the rest usually have [a JAK exon 12 or exon 14 mutation]. The JAK V617F mutation is found in up to 60% of patients with ET or myelofibrosis. MPL and CALR mutations are found in up to 30% [of patients]. 

How do the data with ruxolitinib and fedratinib stack up against each other?

Ruxolitinib was the first JAK inhibitor that was approved for the treatment of higher-risk myelofibrosis, and then later on was approved for the treatment of patients with PV who are intolerant to hydroxyurea or have not responded to hydroxyurea and are symptomatic. 

[The end point that was evaluated in the pivotal trial] in myelofibrosis was reduction of spleen volume and symptomatic relief. The COMFORT-I and COMFORT-II trials were both randomized controlled trials. The COMFORT-I trial had a placebo [control] and the COMFORT-II trial had best available therapy [as the control]. Both of these studies also had significant crossover. Once the investigators realized that ruxolitinib [led to a significant improvement in] patient outcomes and symptom relief, and that there was a signal for overall survival [OS], [patients were] allowed crossover [to receive ruxolitinib]. In COMFORT-II, there wasn’t really a significant [improvement in] OS, but the crossover [probably] affected that. 

In terms of PV, patients were higher risk and were not responding to hydroxyurea or were intolerant to hydroxyurea. These patients were phlebotomy dependent. A significant number of patients achieved phlebotomy independence and had a reduction in spleen volume and symptoms.

Fedratinib [Inrebic] is a selective JAK2 inhibitor compared with ruxolitinib, which is a JAK1/2 inhibitor. The thought is that [fedratinib] will be better tolerated than [ruxolitinib. When the investigators did the randomized placebo-controlled trial for fedratinib, they evaluated 2 different doses of fedratinib. At the higher dose, they saw a rare but serious complication of Wernicke encephalopathy. Because of that, we’re using the lower dose of 400 [mg].

In terms of the decrease in spleen size and symptoms, there didn’t seem to be a difference between the 400 [-mg] and the 500 [-mg] dose. Therefore, it makes sense that the 400 [-mg dose] is the one that we’re using. [Although fedratinib] results in less thrombocytopenia, ruxolitinib is the go-to drug for patients who can tolerate it. You can still use fedratinib post-ruxolitinib, but I don’t know about the reverse [sequence].

Do the data with momelotinib provide any insight into whether it should be used in the JAK inhibitor—naïve or post-ruxolitinib setting? 

We saw updated data [for momelotinib from the SIMPLIFY-1 and -2 studies] at the 2020 ASH Annual Meeting and Exposition. [Momelotinib] inhibits JAK1/2 and Activin receptor 1. One of the studies was a noninferiority study that randomized JAK-inhibitor naïve patients to ruxolitinib or momelotinib. The outcome was about the same. The other study was designed to be a superiority trial that was against best available therapy in patients who were post-ruxolitinib. The primary end point was clinical response rate, and it met the end point. [We also saw an improvement in] the total symptom scores and transfusion independence. The sustained responses and the survival benefit [for momelotinib] makes it a very promising [agent], especially for patients post-ruxolitinib compared with best available therapy.

A lot of those patients are older, and they may not be candidates for transplant. Therefore, having something that can prolong survival and make them feel better, post-ruxolitinib, is really important. When you withdraw ruxolitinib, patients can have symptoms rebound, which also seems to have an effect on survival, so if you have another JAK inhibitor that can keep them going, that’s very helpful. I’m hopeful for momelotinib and pacritinib.

MPN Efforts Set Sights on Improved Survival and Symptom Burden

New MPN Treatments Improve Survival and Symptom Burden

The radiographic and pathologic responses that have been seen with checkpoint inhibitors in lung cancer bodes well for the use of neoadjuvant therapy. However, the relationship between response and long-term outcomes, specifically with regard to overall survival, will have to be teased out before they become standard practice, explained David Spigel, MD.

“Patients and partners have asked me whether we can use [neoadjuvant immunotherapy] now, and the answer is no. It’s not a standard way to treat lung cancer at this point,” said Spigel. “[However,] at the pace and way end points read out [by way of] pathologic response rates and disease-free survival, we [won’t be] waiting 5 or 10 years for these long-term outcomes. I’m guessing we’ll see some readouts in the next 1 to 3 years.”

® during a 2020 Institutional Perspectives in Cancer webinar on lung cancer, Spigel, chief scientific officer and director of the Lung Cancer Research Program, and principal investigator at Sarah Cannon Research Institute, discussed ongoing research with immunotherapy in early-stage lung cancer.

 Does immunotherapy have potential to be brought into neoadjuvant and adjuvant settings in lung cancer? 

 A lot is happening in early-stage lung cancer, [which was a setting in which] we didn’t have any options. Even adjuvant platinum-based chemotherapy became something that was accepted only about 12 to 15 years ago.

There’s a lot of excitement, certainly about neoadjuvant approaches, but more pointedly [regarding the use of] immunotherapy in that space. Adjuvant immunotherapy is [also] going to find its way forward.

Even in limited-stage small cell lung cancer, a potentially curable setting, there are opportunities for developing other treatments like immunotherapy. 

How has immunotherapy helped to illustrate the value of neoadjuvant therapy? 

We’ve always had neoadjuvant therapy. [Even] when platinum-based adjuvant therapy became more standard, we were doing neoadjuvant therapy. Typically, it was: Could we find a role to downstage disease to make surgery possible or more successful? But neoadjuvant therapy kind of went away, because the pivotal, randomized, registrational trials were in the adjuvant setting. There were some pivotal neoadjuvant studies, but adjuvant therapy just became kind of the accepted way to go, and neoadjuvant therapy was something we kind of thought about on a case-by-case basis, usually for more locally advanced settings, like stage III and obviously in settings like pancoast tumors, which still is the case. 

With immunotherapy, I give a lot of credit to Patrick Forde, MBBCh, and his team at Johns Hopkins Medicine, but certainly [investigators] in New York as well, who started to show the value of neoadjuvant immunotherapy. For a couple of years now, we have seen impressive radiographic and pathologic responses with very brief exposures to checkpoint inhibitors. I’ve seen patients have amazing, even complete responses at the time of surgery. Now, we’re waiting on randomized trials to see if this [should be a] standard [approach].

Is there sufficient evidence to suggest that a patient who achieves a pathologic complete response to neoadjuvant therapy will have a favorable outcome? What research is being done to determine the relationship between response to neoadjuvant and adjuvant therapy and prognosis? 

Plasma-based assays [may be able to] help us understand what’s going on with a patient who was treated for cure in the adjuvant setting. Can we monitor patients’ disease in the blood and see if they’ve cleared a clone or [whether] clones reemerge? A good friend and colleague, Charlie Swanton, [FRCP, BSc, PhD, of Crick Institute], has helped open our eyes to this possibility. Studies are in progress to look at this question.

Particularly for neoadjuvant studies, unlike in breast cancer, the lung cancer field is not as advanced in terms of understanding the impact of a pathologic complete response rate. It’s probably the same—–that the less tumor that’s present at the time of resection bodes well for a good prognosis down the road. We don’t know that as well in lung cancer, although it’s probably true. We need a little bit more work to understand whether the early findings at the time of surgery are a good surrogate for how patients do long term. 

If you’re going to use drugs, like osimertinib [Tagrisso] or atezolizumab [Tecentriq] in early-stage disease, should you ever use those strategies again, if and when a patient has disease recurrence down the road? How, what, and when should you use it? Those are questions we don’t know, and we’ll have to figure out [the answers to].

Where is research headed in the early-stage setting?

We’re all waiting for the early-stage trials with immunotherapy to read out. We’re waiting for some additional work with osimertinib in the stage III unresectable setting. We are waiting for new drugs to prove that new targets are important, like KRAS G12C in the stage IV setting. As new therapies make it into stage IV disease, the obvious question is going to be the value of those therapies in earlier stages of disease.

We have to get effective drugs in stage IV disease into earlier stages of cancer. However, we can’t assume it’s a one-size-fits-all approach, or that it’s going to work. Drugs that improve response rates don’t necessarily improve survival, so we have to solve that. 

Immunotherapy Could Restore the Value of Neoadjuvant Therapy in Lung Cancer.

Immunotherapy May Highlight Neoadjuvant Treatment's Use in Lung Cancer

Survival for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains poor, and although immunotherapy has been positioned as a holy grail, it would be preemptive to predict its future based on the number of small studies that have been performed to date, according to Amer Zeidan, MD, MHS.

Nonetheless, one of the first studies that showed the potential for checkpoint inhibition in hematologic malignances was a phase 1/1b study that evaluated ipilimumab (Yervoy) after allogeneic stem cell transplant. In the study, ipilimumab was administered at a dose of 3 mg/kg and 10 mg/kg every 3 weeks. The results demonstrated efficacy in patients who received the 10 mg/kg dose. Specifically, 5 of 13 patients with heavily pretreated AML achieved a complete response (CR).

Ipilimumab has also demonstrated activity in patients with relapsed/refractory MDS in a single-arm study of 29 patients. Although the marrow CR rate was only 3.4%, 7 patients experienced prolonged stable disease for 46 weeks or more, including 3 patients with stable disease surpassing 1 year. Moreover, the median survival was 9.8 months (295 days; 95% CI, 240-671+).

“In correlative analysis, we observed that patients who had increased expression of the costimulatory marker ICOS seemed to have better disease stabilization, so the direction is clearly headed toward trying to select patients using biomarker-driven strategies,” Zeidan, an associate professor of medicine in the Department of Internal Medicine and Section of Hematology at Yale University School of Medicine, Yale Cancer Center, said in a presentation during the 5th&#8239; Annual &#8239;International Congress on Immunotherapies in Cancer™. 

In another phase 2 study that evaluated the combination of nivolumab (Opdivo) and azacitidine vs ipilimumab and azacitidine in MDS, a higher response rate was observed with either combination compared with ipilimumab alone, at 70% and 62% vs 30%, respectively. However, the median overall survival (OS) was similar, at 11.8 months, not reached, and 8.5 months, respectively, said Zeiden.

Pembrolizumab (Keytruda) is also being subject to research in myeloid malignancies. Specifically, in a phase 1b study in combination with entinostat in MDS after failure on hypomethylating agents (HMAs). Data from the study have yet to read out, but are highly anticipated, said Zeiden.

Findings from a phase 2 study (NCT02775903) however stunted some of the excitement that had been generated with immunotherapy, putting into perspective the work that had been done to date. When the combination of a checkpoint inhibitor and an HMA, specifically durvalumab (Imfinzi) and azacitidine, was taken into a randomized trial vs azacitidine alone in patients with high-risk MDS and older AML, no difference was seen in progression-free survival (PFS) or OS.

Bispecific antibodies are another treatment class under investigation as a potential avenue forward for immunotherapy. One such antibody is sabatolimab, which targets IgG4 and TIM-3, and is the focus of several ongoing studies in MDS and AML. Specifically, the phase 2 STIMULUS-MDS1 (NCT03946670) and phase 3 STIMULUS-MDS2 (NCT04266301) trials in MDS and phase 2 STIMULUS-AML1 trial (NCT04150029) in AML.

Another path that will be explored is that of checkpoint inhibition plus chemotherapy, explained Zeiden. In a phase 2 study, the combination of pembrolizumab and 7+3 chemotherapy will be evaluated as frontline therapy in fit patients with AML.

The combination of azacitidine and venetoclax (Venclexta) has become the standard of care for older patients with AML, and preclinical evidence suggests that the BCL-2 inhibitor can augment the antitumor response of PD-L1 inhibitors.

As such, investigators have launched the phase 2 BLAST AML 2 study in which unfit patients with AML will be randomized to azacitidine plus venetoclax vs azacitidine/venetoclax plus pembrolizumab as frontline therapy.

Anti-CD47 antibodies are also under study and have shown promising, though early, activity in AML and MDS. For example, in combination with azacitidine, magrolimab has shown objective responses exceeding 60% in untreated AML and 90% in untreated MDS, with CR rates of 41% and 50%, respectively.

“Importantly, a lot of the responses seem to occur in patients who have TP53 mutations, which is one of the highest areas of unmet need in AML and MDS, because those patients do very poorly with conventional treatment,” said Zeidan.

Although magrolimab will move forward in development, Zeidan cautioned that the antitumor effects of anti-CD47 antibodies may not be class specific. For example, in a phase 1 study, CC-90002 failed to demonstrate any benefit in patients with relapsed/refractory AML and higher-risk MDS.

In conclusion, Zeidan stated, “Many of the studies that have been conducted are single-arm trials with small sample sizes. [However,] we are doing more and more randomized studies using novel inhibitors against TIM-3 and CD47. The field is definitely exciting for us, and we are hoping to see some clinical activity for our patients soon.”

Zeidan A. Immunotherapy for treatment of myeloid malignancies: will it fill the promise? Presented at: 5th&#8239;Annual&#8239;International Congress on Immunotherapies in Cancer™; December 12, 2020; virtual. gotoper.com/go/ICIC20Virtual

Immunotherapy Inches Forward in Development of Myeloid Malignancies

Immunotherapy Is Promising, Yet Understudied in Myeloid Malignancies

Germline predisposition variants associated with cancer susceptibility syndromes can underlie the genetic risk for rhabdomyosarcoma (RMS), indicating that germline testing should be performed in accordance with RMS subtypes and irrespective of age, according to findings from a study published in the 

Journal of the National Cancer Institute.

Germline cancer-predisposition variants were identified in 45 patients with RMS across 15 autosomal dominant genes (7.3%; all FOXO1 fusion—negative). The enrichment of germline cancer-predisposition variants in this population was statistically significant compared with controls (1.4%; P = 1.3 x 10-22). The majority of the predisposition variants (73.3%) were identified in predisposition genes that have been linked to pediatric RMS risk, such as TP53 (Li-Fraumeni syndrome), NF1 (neurofibromatosis type I), HRAS, and BRCA2.

“Currently, there are a limited number of genes considered to cause pediatric RMS,” said He (Hurley) Li, PhD, postdoctoral associate at the Human Genome Sequencing Center at Baylor College of Medicine and first author of the study. “But our study is pointing to new genes to consider. For example, we found that the BRCA2 gene, typically associated with adult breast and ovarian cancer, may also somehow influence the susceptibility of pediatric RMS.”

“Our study highlights the utility of sequencing large numbers of children diagnosed with cancer to identify these types of changes, termed pathogenic variants,” said Philip Lupo, PhD, associate professor of pediatrics, hematology and oncology at Baylor College of Medicine, and corresponding author of the study. “Understanding the frequency of these variants in children with RMS could influence strategies for genetic testing and future surveillance of patients with a pathogenic variant, as some of these variants may predispose children to multiple cancers later in life.”

RMS is an aggressive tumor and the most common soft tissue sarcoma in children. Despite its prevalence, the genetic susceptibility of the malignancy is not as well defined compared with other pediatric malignancies.

Germline DNA from 615 patients with newly diagnosed RMS, consented through the Children’s Oncology Group, underwent whole-exome sequencing. The prevalence of cancer-predisposition variants in 63 autosomal dominant cancer-predisposition genes in these patients was compared with population controls (n = 9963).

Additional findings showed that 5 patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) linked to Costello syndrome.

Differences in genetic etiology were reported based on histology. Specifically, germline variants were more common in patients with embryonal versus alveolar RMS (10.0% vs 3.0%, respectively; P = .02).

Furthermore, patients with a cancer-predisposition variant were found to be younger at diagnosis (P = 9.9 x 10-4), and approximately half of germline variants (40.0%) were identified in patients aged 3 years or older, contrasting current genetic testing guidelines in patients diagnosed at an early age.

“These results may change our current decisions about when to offer genetic testing for children with RMS, which right now is focused on very young patients,” concluded Sharon Plon, MD, PhD, medical geneticist on the study team and professor of pediatrics, oncology and molecular and human genetics at Baylor College of Medicine.

Li H, Sisoudiya SD, Martin-Giacalone BA, et al. Germline cancer-predisposition variants in pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group. JNCI. 2020. doi:10.1093/jnci/djaa204

Genomic assessment of cancer-predisposition landscape of pediatric rhabdomyosarcoma. News release. Baylor College of Medicine. December 30, 2020. Accessed January 4, 2021. https://bit.ly/358HHkO

TP53, NF1 Among Genetic Variants Identified as Precursors to Pediatric Rhabdomyosarcoma

“But our study is pointing to new genes to consider. For example, we found that the BRCA2 gene, typically associated with adult breast and ovarian cancer, may also somehow influence the susceptibility of pediatric RMS.”

Genetic Precursors to Pediatric Rhabdomyosarcoma Identified

The coronavirus disease 2019 (COVID-19) pandemic has become another potential complication for patients with lung cancer, said Mark G. Kris, MD, who added that although the pandemic has disrupted patient care, it has yet to stunt scientific collaboration. 

Such a claim is best evidenced by the transition from large in-person medical meetings to virtual platforms, including that of the 15th Annual New York Lung Cancers Symposium. 

“This year’s NY Lung meeting was different. I don’t think anybody would have expected we’d be in the place we are today,” said Kris, who served as the co-chair of the meeting. “[However,] we had broad representation of the entire community of practitioners treating [patients with] lung cancer. One thing you’ll find [at NY Lung], which you may not find in other meetings, is the opportunity to hear how New York doctors are treating patients with lung cancers today [with] case presentations from institutions in the metropolitan area. People are really open about what they did, what they learned, and [they were] anxious to share that.”

, Kris, a medical oncologist, William and Joy Ruane Chair in Thoracic Oncology, Memorial Sloan Kettering Cancer Center (MSK),&#8239;discussed the strengths of this year’s New York Lung Cancers Symposium, the advances that have been made over the past year, and potential routes forward in advancing the field of lung cancer.  

 What were you most excited to hear about at the 15th Annual New York Lung Cancers Symposium? 

 Although we have this overarching concern about COVID-19 and the impact it has had on the lives of our patients and families and all of us, one of the key messages was that COVID-19 is another complication of lung cancer. The culprit here is lung cancer. We had discussions and presentations about some of the most important issues in lung cancer. Of my patients who died from lung cancer this year, all but 1 or 2 died from lung cancer, not from COVID-19. Our problem is lung cancer and the horrible threat it poses to our patients and what we can do to lessen that threat. 

A lot of very good information has come forward this year regarding ways to move forward. We have had new drugs approved and new information about using targeted therapies in the adjuvant setting, which will change the whole process for how we treat patients in the adjuvant setting. [We’ve also seen] the use of newer technologies. We had a special session on how our practices have changed due to the COVID-19 crisis, and also the use of things like cell free DNA, not just for diagnostic purposes, but also to help us monitor care and to help us guide therapy. All of these things [were covered at the meeting]. We had some great international and national speakers, and it’s one of the best groups we’ve ever had. It’s a shame everyone couldn’t be there to meet them in person.

Of the key developments that have been made in 2020, what has the potential to make the greatest impact on the paradigm?

The first is the ADAURA trial, which evaluated osimertinib [Tagrisso] in patients with completely resected lung cancer that harbors an EGFR mutation. People were very impressed by the dramatic benefit in event-free survival for those patients. [Those data] were game changing, not only for those patients with EGFR mutations, but it’s also going to make people think about looking at targeted therapy for patients with earlier stages and not just in [the] surgical [setting].

The next step is going to be [looking at] using targeted therapy in patients with locally advanced disease that are getting concurrent chemotherapy and radiation. Targeted therapies are going to be important in those patients’ care. This discussion with osimertinib in the surgery setting is going to lead to those other discussions. 

What has it been like to be a part of a team that has contributed so much to the field of targeted therapy in lung cancer?

I’ve been very lucky to work at MSK where my colleagues, many of whom [spoke at the meeting] have been involved in the approval of new drugs, such as selpercatinib [Retevmo]. Having more targeted therapies for [patients with] RET or MET mutations is very exciting. It’s really a kind of a dream come true that these drugs are being approved. 

If you had to describe the impact of COVID-19 on the lung cancer space over these past few months, how would you do so?

It’s been a horrible complication. We spend all this time trying to mitigate nausea and neutropenia, and then suddenly, our patients and their families had this put upon them and tremendous stress, and disruption in their care plans. There’s been a struggle to try to maintain their care. [We spend] weeks and months to put these plans together [with patients and their families], and suddenly [their family members or care takers can’t accompany them to the hospital]. 

To hear what the doctors are saying, to go over a scan report and make sure you understand it [can be difficult alone]. Here in Manhattan, [family members] have no waiting room. They can’t go to Starbucks, they can’t go in the diner on the corner, it’s all gone. It’s just a horrible stress on our patients. Then, of course, there’s the change in our practices and a physician I work with led a session at the meeting about how our practices have changed and how the practice of oncology has changed. 

Where do you hope the field of lung cancer will be in the next few years?

My hope is that we will be able to come up with ways to use all of the different tools that we have now to treat each and every patient. For example, somebody with metastatic lung cancer 5 or 10 years ago [would receive] chemotherapy. Now, [we have to determine whether to give] an antiangiogenic drug with chemotherapy. We also now have the opportunity to give patients a checkpoint inhibitor with an antiangiogenic drug and chemotherapy. 

We also have to make sure we look for [potential] targets for targeted therapy. All this has to come together for that individual patient, and that’s our challenge right now. We have so many opportunities, but [we have to] make sure that each patient has these opportunities. [These considerations have to be made] at every decision point of their illness too; it’s really complicated now. I’m hopeful that some of the discussions that [happened] at the meeting [gave] people some direction. I don’t think we have all the answers, but we [did spark] a discussion about making sure all the options are on the table at all times.

What distinguishes the NY Lung meeting from other medical meetings?

We [have] a whole bunch of case presentations, and even individual cases by some members. We also had different points of view [weighing in on those cases]. [For example], the moderator [would act as the] treating physician and synthesize the presentations and make a decision for that patient and talk about how they came to that decision. That’s kind of a unique way of discussing a lot of issues; [the meeting is] not simply presentations of data from this and that clinical trial; a lot of the meeting is case based.

2020 Ushers in Newfound Adjustments, Applications in Lung Cancer.

The coronavirus disease 2019 (COVID-19) pandemic has become another potential complication for patients with lung cancer, said Mark G. Kris, MD, who added that although the pandemic has disrupted patient care, it has yet to stunt scientific collaboration. 
 

Lung Cancer Advancements Continue, Despite COVID-19

Cemiplimab (Libtayo) demonstrated clinically meaningful antitumor activity, including durable responses, and acceptable safety in patients with metastatic basal cell carcinoma (mBCC) after progression on or intolerance to hedgehog inhibitors, according to findings from the prespecified interim analysis of the mBCC cohort of a phase 2 trial (NCT03132636) that were presented ahead of the 2020 SITC Virtual Congress.

Among 28 patients, the objective response rate (ORR) per independent central review (ICR) was 21.4% (n = 6; 95% CI, 8.3%-41.0%), which consisted of all partial responses (PRs). The stable disease (SD) rate was 35.7% (n = 10), which translated to a disease control rate (DCR) of 67.9% (95% CI, 47.6%-84.1%).

“There have been case reports with cemiplimab, but this is the first prospective study in any meaningful number of patients. The activity and durability [of the agent] seem to be promising,” said Karl Lewis, MD, lead study author, and professor of medicine-medical oncology at the Colorado School of Medicine, in a virtual press briefing ahead of the 2020 SITC Virtual Congress.

BCC is the most common type of skin cancer and ultraviolet exposure is a significant risk factor. The majority of patients with advanced BCC undergo curative surgery. However, systemic therapy is also available for patients with advanced disease who are ineligible for curative surgery or radiation.

Vismodegib (Erivedge) is an oral hedgehog inhibitor that is currently approved for patients with mBCC. However, no FDA-approved treatment options are available to patients who progress on or are intolerant to hedgehog inhibitors.

Cemiplimab, a PD-1 inhibitor, is the first systemic therapy that has shown clinical benefit in patients with locally advanced and mBCC after treatment with hedgehog inhibitors. The first demonstration thereof was reported in findings from the locally advanced cohort of this phase 2 study, which were presented during the 2020 ESMO Virtual Congress.

The phase 2 study enrolled 2 cohorts. Group 1 consisted of patients with nodal and distant mBCC, and group 2 comprised patients with locally advanced BCC (n = 84).

The mBCC cohort included patients with the opportunity to be followed for approximately 57 weeks to provide an ORR with a 95% confidence interval (CI).

Patients received 350 mg of intravenous cemiplimab every 3 weeks for up to 93 weeks. Tumor assessments were performed on days 1 to 5 every 9 weeks and on days 6 to 9 every 12 weeks thereafter. Tumor response assessment was measured by ICR, using RECIST 1.1 criteria for visceral lesions or modified World Health Organization criteria for skin lesions.

ORR per ICR served as the primary end point of the study. Secondary end points included ORR by investigator review, progression-free survival (PFS), PFS by ICR and investigator review, overall survival, complete response (CR) rate by ICR, and safety and tolerability of cemiplimab.

Regarding prior therapy in the mBCC cohort, 100% of patients received vismodegib (n = 28), 10.7% (n = 3) received sonidegib (Odomzo), and 10.7% (n = 3) received vismodegib and sonidegib.

Reasons for discontinuation of prior therapy included disease progression on hedgehog inhibitor therapy (75.0%; n = 21), prior hedgehog inhibitor intolerance (n = 10; 35.7%)—–predominantly for vismodegib (n = 11; 39.3%) vs sonidegib (n = 2; 7.1%)––and SD as best response after 9 months on hedgehog inhibitor therapy (n = 5; 17.9%).

Additional findings from the mBCC cohort indicated that 10.7% of patients (n = 3) achieved non-CR and non-progressive disease, and 25.0% of patients (n = 7) experienced progressive disease. Less than 10% of patients (n = 2; 7.1%) were not evaluable.

The median duration of response (DOR) had not been reached at the time of data cutoff. The 6- and 12-month DOR estimates were 100% (95% CI, 68.3%-97.6%) and 66.7% (95% CI, 19.5%-90.4%), respectively.

All 6 responses were ongoing at 1 year of treatment and had observed duration of at least 8 months.

The safety profile of cemiplimab was found to be consistent with prior reports of the agent in other tumor types. The most common any-grade treatment-related adverse effects (TRAEs) occurred in 78.6% of patients (n = 22). Grade 3 or greater TRAEs were reported in 17.9% of patients (n = 5), and 1 death from staphylococcal pneumonia occurred, which was determined to be unrelated to study treatment.

In previously presented findings of the locally advanced BCC cohort, cemiplimab led to an ORR of 31.0% (95% CI, 21.3%-42.0%), which included a 6% CR rate (n = 5) and a 25.0% PR rate (n = 21). Additionally, just under half of patients (48.8%; n = 41) achieved SD, translating to a DCR of 87% (95% CI, 60%-98%) in PD-L1—positive patients (PD-L1 ≥1%) and 77% (95% CI, 60%-90%) in PD-L1–negative patients (PD-L1 <1%).

“In the locally advanced cohort, responses to [cemiplimab] seemed to be delayed. Unlike cutaneous squamous cell carcinoma, for which cemiplimab is approved, those patients that respond seem to respond quickly, whereas in patients with basal cell carcinoma, there seems to be a time lag. Hopefully, with longer follow-up, this [21.4%] response rate might improve,” said Lewis.

In the locally advanced cohort, the median DOR per ICR had not been reached at the time of data cutoff. The 6- and 12-month DOR estimates were 90.9% (95% CI, 68.3%-97.6%) and 85.2% (95% CI, 60.5%-95.0%), respectively.

With regard to safety, the most common TRAEs were fatigue (25%; n = 21), pruritus (14%; n = 12), and asthenia (14%; n = 12). The most common grade 3 or greater TRAEs were fatigue (n = 2), colitis (2%; n = 2), autoimmune colitis (2%; n = 2), and adrenal insufficiency (2%; n = 2).

Fourteen patients (17%) discontinued treatment due to any-grade treatment-emergent AEs.

In conclusion, Mario Sznol, MD, professor of medicine and co-director of Yale SPORE in Skin Cancer at Yale Cancer Center, and co-moderator of the press briefing, offered some perspective on the study, stating, “This is really an important advance for these patients. [As we know], any new therapeutic has substantial clinical significance.”

Lewis KD, Peris K, Sekulic A, et al. Interim analysis of phase 2 results for cemiplimab in patients with metastatic basal cell carcinoma (mBCC) who progressed on or are intolerant to hedgehog inhibitors (HHIs). Presented at: SITC Virtual Congress; November 9-14, 2020. Poster: 428.

Cemiplimab Elicits Antitumor Activity in Metastatic Basal Cell Carcinoma

Cemiplimab (Libtayo) demonstrated clinically meaningful antitumor activity, including durable responses, and acceptable safety in patients with metastatic basal cell carcinoma (mBCC) after progression on or intolerance to hedgehog inhibitors.

Cemiplimab Is Promising for Metastatic Basal Cell Carcinoma Treatment

Frontline chemoimmunotherapy trials represent a critical milestone in extensive-stage small cell lung cancer (ES-SCLC), but one that requires better understanding of the methods that can be used to broaden the patient population in whom durable benefit is currently concentrated, according to Charles M. Rudin, MD, PhD.

“In the past couple years, the big news has been immunotherapy,” said Rudin, medical oncologist and chief of the Thoracic Oncology Service, co-director of the Druckenmiller Center for Lung Cancer Research, and Sylvia Hassenfeld Chair in Lung Cancer Research, at Memorial Sloan Kettering Cancer Center, in a virtual presentation during the 15th Annual New York Lung Cancers Symposium.

The two high-impact trials that have led to the rise of immunotherapy in the frontline setting of ES-SCLC are the phase 3 IMpower133 and CASPIAN trials, said Rudin. In IMpower133, patients with untreated ES-SCLC were randomized to atezolizumab (Tecentriq) plus etoposide and platinum vs etoposide and platinum alone. The results indicated a 30% reduction in the risk of death with the addition of atezolizumab vs chemotherapy (HR, 0.70; 95% CI, 0.54-0.91; P = .007).

 Moreover, the 12- and 18-month landmark overall survival (OS) analyses favored the chemoimmunotherapy combination vs chemotherapy alone, respectively (51.9% vs 39.0%; 34.0% vs 21.0%).

Data from the IMpower133 trial served as the basis for the March 2019 FDA approval of the combination as frontline therapy in ES-SCLC.

In CASPIAN, patients with untreated ES-SCLC were randomized to durvalumab (Imfinzi) plus platinum and etoposide vs platinum and etoposide alone. The addition of durvalumab led to a 27% reduction in the risk of death vs chemotherapy alone (HR, 0.73; 95% CI, 0.591-0.909; P = .0047).

 Similarly, the 12- and 18-, as well as 24-month landmark OS analyses favored the chemoimmunotherapy combination vs chemotherapy alone , at 52.8% vs 39.3%; 32.0% vs 24.8%; and 22.2% vs 14.4%, respectively.

In March 2020, the FDA approved the combination of durvalumab plus platinum and etoposide for the frontline treatment of patients with ES-SCLC, according to the results from the CASPIAN trial.

Another phase 3 trial, KEYNOTE-604, randomized patients with untreated ES-SCLC to receive the addition of pembrolizumab (Keytruda) to platinum and etoposide or chemotherapy alone in the first-line setting.

At the time of data cutoff in December 2019, the median progression-free survival (PFS) was 4.8 months with pembrolizumab vs 4.3 months with chemotherapy alone, meeting the co-primary end point of the study (HR, 0.73; 95% CI, 0.60-0.88).

However, the addition of pembrolizumab did not lead to a statistically significant improvement in OS, with a median OS of 10.8 months and 9.7 months in the pembrolizumab and chemotherapy-alone arms, respectively (HR, 0.80; 95% CI, 0.64-0.98; P = .0164).

Across the IMpower133, CASPIAN, and KEYNOTE-406 trials, the 12-month median PFS rates in the experimental arms were 12.6%, 17.9%, and 15.9% vs 5.4%, 5.3%, and 5.0% in the control arms, respectively.

Immunotherapy has also shown activity in the recurrent setting, evidenced by findings from the phase 1/2 CheckMate-032 trial, which demonstrated a median PFS of 1.4 months with nivolumab (Opdivo; n = 147) and 1.5 months with the combination of nivolumab and ipilimumab (Yervoy; n = 96) in patients with SCLC and disease progression on 2 prior lines of chemotherapy.4 Although the median PFS was modest, the curves suggested that patients who responded to the combination experienced durable benefit, with 6-month PFS rates of 15.9% and 22.1%, respectively.

A similar trend was seen in a pooled analysis of the phase 1b KEYNOTE-028 and phase 2 KEYNOTE-158 trials, where patients who received pembrolizumab after 2 prior lines of therapy experienced a median PFS of 2.0 months but 12- and 24-month PFS rates of 16.9% and 13.1%, respectively.

“The hockey stick appearance of the curves [is clear] where the curves just drop like a rock. Most of the patients do not benefit from this therapy, but then there’s a subset that clearly does,” said Rudin.

Although findings from these 2 trials served as the basis for the accelerated approvals of nivolumab and pembrolizumab as third-line treatment for patients with metastatic SCLC, the data are more indicative of the potential effects of immunotherapy than they are applicable for practicing clinicians now that immunotherapy has entered the first-line setting.

“In the third-line setting, we have these accelerated approvals for nivolumab and pembrolizumab, but we really don’t know how to give those now because we’re using PD-L1 checkpoint inhibitors in the first-line setting,” said Rudin.

Although immunotherapy has been the focus of discussion in ES-SCLC, other agents are entering the paradigm, explained Rudin, who cited lurbinectedin (Zepzelca) as a prime example of the potential actionability of alternative targets in the field.

“Lurbinectedin is a DNA-binder and an alkylating agent that affects transcription,” said Rudin.

The agent was evaluated in an open-label, single-arm, phase 2 basket trial (NCT-2454972) in patients with SCLC who had progressed on platinum-containing therapy. The results demonstrated an overall response rate (ORR) of 35.2% and a stable disease rate of 33.3%, which translated to a disease control rate of 68.6% (95% CI, 58.8%-77.3%).

The median durations of response, PFS, and OS were 5.3 months (95% CI, 4.1-6.4), 3.5 months (95% CI, 2.6-4.3), and 9.3 months (95% CI, 6.3-11.8).

“The real advantage of this drug over topotecan is on the toxicity side as much or more than on the efficacy side, particularly in terms of the hematologic toxicities” said Rudin.

Chemoimmunotherapy regimens are showing promise in the treatment of SCLC.

Caroline Seymour