Targeted Oncology Staff

 Case-Based Roundtable event, Kartik Konduri, MD, medical director, Chest Cancer Research and Treatment Center, Baylor Charles A. Sammons Cancer Center, Texas Oncology, discussed the case of a 58-year-old patients with small cell lung cancer.

: Would you offer prophylactic cranial irradiation (PCI) for this patient? Why or why not?

: [It is important to consider a patient’s] performance status and age. PCI in elderly patients [can be] problematic in this scenario. There’s also the question of whether there is a benefit from PCI in the [overall] setting. Discussion should [occur] with a radiation oncologist, especially if there is a straight off, very good response.

Based on the immunotherapy studies, why should treatment be stopped after 2 to 4 cycles if the patient is tolerating treatment well?

The response [often] comes in the first 2 cycles. The big drop in the volume of disease comes in the first 2 cycles. Then there is a little more [reduction over] the next few cycles. In the past, when there was no immunotherapy to talk about, this is how [we] used to approach patients; 4 cycles or 6 cycles was the consideration at that time. If the patient was having an ongoing significant response, I would take it up to 6 cycles. That’s what they allowed in the control arm of the CASPIAN study [NCT03043872].

The question is: “Why not do the same thing with immunotherapy?” No one knows [the correct answer]. There are not much data to tell us one way or the other, so after 4 cycles [of immunotherapy treatment], I generally stop. It’s a judgment call, I think, beyond 6 cycles. In most circumstances you’re now talking about adding toxicities and a lack of significant benefit.

How do you define platinum-sensitive versus platinum-resistant SCLC?

There’s [some] strange terminology in SCLC, and physicians play around with it based upon their ease of utilization. Refractory disease is a situation where the patient progresses while on treatment. These patients have a more difficult circumstance and more aggressive disease. Refractory disease [indicates] no response to treatment. There’s also relapsed [disease], and the cutoffs are 90 days [or less, and] more than 90 days, in general. Less than 90 days is considered a resistant relapse. Patients [with a resistant relapse] might not do as well as patients who [relapse after] 90 days, which are considered sensitive relapses. A late relapse occurs at [approximately] 6 months [180 days]. In circumstances like this, the [most common] cutoffs that we have been using in SCLC are [less than] 90 days and more than 90 days. If you look at the package insert [for topotecan (Hycamtin)], [it is] approved for [use in patients who have progression after] 60 days.

 For a patient who progresses a couple of months [eg, 2 months] after completion of platinum-based chemotherapy, that’s considered a resistant relapse. A patient who progresses after 90 days, which is about 3 months, would be considered to have a sensitive relapse.

What are your thoughts on the treatment options and the results of the poll?

Before we had any other pieces of data, topotecan was our main go-to. People were translated even into the resistant relapses even in the less-than-90-day settings. The data from the older topotecan studies suggest that the benefit is less, about 10%, but the response rates are not necessarily the whole story. Does it control the disease and so on and so forth is the issue.

Lurbinectedin seems to have caught favor with most of you, at 42%. About 21% would platinum rechallenge the patient. Twenty percent talk about clinical trial, which is never the wrong thing, and then topotecan.

What are the National Comprehensive Cancer Network (NCCN) recommendations for subsequent systemic therapy in patients with SCLC who experience disease progression?

[Current] NCCN guidelines [for patients with SCLC undergoing subsequent systemic therapy are divided by those who experience a relapse after] less than 6 months and those who have a [relapse after] more than 6 months.

 The [guidelines] do not parse out the recommendations for between 60 days or 90 days, etc. Any [patient] having [a relapse after] 6 months is considered as having a late relapse; therefore, a rechallenge with the original regimen is considered.

Lurbinectedin [(Zepzelca) is an option] for patients who have relapsed [after] 180 days. For patients [who have relapsed after] less than 6 months, you can consider topotecan, lurbinectedin, or a clinical trial. There are other recommended regimens, but the top 2 standard-of-care treatments are topotecan and lurbinectedin. Topotecan has been [available] for a long time, for progression after more than 60 days after initiation of front-line therapy. Lurbinectedin [received] accelerated approval for [patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy].

[It is important to consider] the patient’s tolerance, prior therapies, and the timing of the relapse. Patients who progress while on treatment fare the worst, and those who progress in a short period of time after treatment do not do well on a long-term basis.

Can you describe the basket trial of lurbinectedin in patients with SCLC who experienced progression after front-line platinum-containing chemotherapy? What were the key efficacy results?

There was a phase 1 trial [NCT01970540] that used lurbinectedin with doxorubicin.4 Essentially, the trial showed [that] there was activity, there was a different way of dosing the treatment, and [it was associated with] a significant benefit for patients who had combinations of treatment even in resistant relapses. That [trial focused on outcomes occurring in] less than 90 days.

The phase 2 basket trial looked at 9 tumor types, and there were 105 patients with SCLC [NCT02454972].

 These patients’ disease had progressed on platinum-based therapy. The requirements for those entering the trial were [absence of] brain metastases, ECOG performance status score less than or equal to 2, and only 1 prior line of chemotherapy. Treatment was given as 3.2 mg/m

[intravenously] every 3 weeks. Primary prophylaxis with granulocyte-colony stimulating factor was not allowed and probably not needed. The primary outcome was overall response rate. Most patients had an ECOG performance status score of 1, and there was a small proportion of never smokers in the SCLC cohort. [A total of] 30% had limited-stage disease and relapsed quickly. [Excepting the lungs], as expected, the most common sites [of cancer] were the lymph nodes, liver, and adrenal gland. CNS [central nervous system] involvement was seen in 4% of patients, [although] the trial design did not allow for patients to have any baseline CNS metastases.

PCI was given to 58% of patients previously. [A total of] 93% had 1 line of therapy, and 7% had a second line. [Approximately] 67% and 76% of patients had good responses,[partial and complete, respectively] to platinum therapy in the past. [A total of] 43% of patients [had a relapse within] 90 days and 57% [had a relapse after] 90 days.

There was a decent response of 35.2% in the overall population. The median duration of response was 5.3 months. [Among] patients who were responding, 43% were responding at 6 months. There [were no] complete responses. Most [35%] had a partial response. One-third had stable disease.

Median progression-free survival for the patients who had [a relapse in] less than 90 days was 2.6 months. [For those with a relapse after] 90 days it was 4.6 months. Overall survival [OS] was 5 months in patients who had a chemotherapy-free interval less than 90 days [ie, resistant relapse] and 11.9 months for those who had an interval greater than 90 days.

What do we know about lurbinectedin in the second line for patients with SCLC who are candidates for a platinum rechallenge?

Results from a [prespecified] analysis [of patients with SCLC from the basket trial] were presented at the 2020 North America Conference on Lung Cancer by Vivek Subbiah, MD, from The University of MD Anderson Cancer Center and [recently published] in Lung Cancer.7 [Subbiah et al] looked at a small proportion of patients [from the] study who had a chemotherapy-free interval of more than 90 days [n = 20]. [This] scenario is considered a late relapse. What was outstanding was the median OS: 16.2 months. The overall response rate, [as determined by an] independent review committee, was 60.9%. The median number of cycles was 6.

Please discuss the adverse event (AE) profile for second-line lurbinectedin in the basket trial?

In the phase 2 study of lurbinectedin, there were many AEs,

 [but] they were not significant in general. Abnormalities in creatinine occurred. Hepatotoxicity is a well-known AE [with lurbinectedin] and drops in blood counts. Febrile neutropenia [of] grades 3 and 4 was experienced by approximately 5% [of patients] combined. One [case of] skin ulceration with extravasation occurred. Fatigue, nausea, and diarrhea are known AEs, [as well as] hematological toxicity, particularly neutropenia.

How do patients do on topotecan as a second-line therapy for SCLC?

Von Pawel et al [conducted a] study in 211 patients.8 [All patients] were considered sensitive to frontline therapy [but had] disease progression more than 60 days after its completion. 2 The trial compared topotecan and CAV [cyclophosphamide, doxorubicin, and vincristine].8 CAV was the standard of care. There were no differences in response rate, duration of response, time to progression, or OS.

OS was about 5.8 months [with topotecan] versus 5.7 months [with CAV] for patients with platinum-sensitive disease. Oral topotecan was found to be equal to IV [intravenous] topotecan.

US Oncology also participated in this network study. There was no significant difference in outcomes for patients based on oral versus IV. [Both] oral and IV [formulations] are approved for use.

There are other trials and other studies; these are the seminal kind of data that resulted in the approval [of topotecan].

What warnings and precautions are listed in the prescribing information for topotecan and lurbinectedin?

Interstitial lung disease and extravasation and tissue injury are the major issues with topotecan.2 There is an extravasation issue with lurbinectedin, but [it is listed as a warning] for topotecan. Myelosuppression, hepatotoxicity, and embryofetal toxicity are known problems with lurbinectedin.

 [The topotecan prescribing information also includes] the requirement that absolute neutrophil count is at least 1500 cells/ mm3 and platelet count [is at least] 100,000/mm

 [when] starting treatment. Reducing the dose or withholding the dose should be considered.

How do you modify dosing for lurbinectedin?

Practical considerations for lurbinectedin [include infusion] over 60 minutes at 3.2 mg/m

 and dose reductions as [needed to] 2.6 mg/m

 for the first and second dose reductions, [respectively]. If a patient experiences grade 4 neutropenia, the drug [should be withheld] until neutropenia comes down to grade 1 [or less], then [resumed at a] reduced dose. If a patient has thrombocytopenia of grade 3 [or greater], withhold and then reduce the dose. If a patient has grade 2 hepatotoxicity, withhold until grade 1, but lurbinectedin can be resumed at the same dose. If a patient has\ grade 3 [hepatoxicity, withhold until grade 1 or less], and the dose should [be] reduced. These [AEs and necessary dose reductions] are not surprising.

What would you do if this patient had brain metastases?

[The basket] trial did not allow patients with CNS metastases [at baseline].5,6 But, there were up to 25% to 30% response rates with topotecan for patients with brain [metastases]. [In the trial, there was] a proportion of patients who did have brain metastases [at baseline], but they were treated and cleared of brain metastases. They were not active brain metastases. Patients might have had PCI. They might have had a few brain metastases that were treated.

There is a concern [about overusing lurbinectedin in patients with brain metastases]. I find it very hard to believe that [patients with refractory/relapsed SCLC] will have a significant benefit with second-line [topotecan]. In resistant relapsed SCLC, the data are about 10% to 12%. It becomes an issue of benefit with the approximately 22% response rate.

The basket trial [with lurbinectedin] was a small, single-arm study with 105 patients, and not randomized. [In patients who] are free of brain metastases, I will recommend lurbinectedin over topotecan. If the patient is not doing well and their performance status is around 2, I favor lurbinectedin. [With topotecan,] I use the 5-day regimen, which is standard. That regimen has shown benefit. In the 3-day regimen or the weekly regimen, there are less efficacy data and they show less beneficial outcomes even in other disease states. The problem is that the 5-day regimen is not easy to do, it causes cytopenias, and you need to have primary prophylaxis. If the patient has asymptomatic brain metastases, I generally recommend topotecan with the hope that it will cross the blood-brain barrier and have an impact. [With] extremely short relapses, I don’t know if there’s any particularly great drug.

Are there any emerging data in this setting? 

The phase 3 ATLANTIS trial [(NCT02566993) assessed] lurbinectedin plus doxorubicin versus [physician’s choice of] topotecan or CAV.

[was given] with a flat dose of doxorubicin 45 mg/m

 for 10 cycles, followed by lurbinectedin maintenance versus CAV or topotecan. [This design] was based upon a phase 1 study where they looked at the combination in this situation. In the past, they [observed] that when they combined a slightly different dosing, there was a response rate of 92% in 27 patients with a chemotherapy-free interval of greater than 90 days and a 5.8-month progression-free survival. For those with [an interval] less than 90 days, a response rate of 33% [was observed] with a progression-free survival of 3.5 months. [However, ATLANTIS was] a negative trial [according to a recent] press release.

 The primary end point of OS was not met. The secondary end points favored the [lurbinectedin combination]. [The ATLANTIS trial did not use the] 3.2 mg/m

[dose of lurbinectedin], which is the standard accelerated approval FDA regimen. If [the secondary results] mirror that of the basket study, [this combination may be beneficial].

1. Paz-Ares L, Dvorkin M, Chen Y, et al; CASPIAN investigators. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. 

. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6

2. Hycamtin (topotecan) for injection. Prescribing information. Novartis; 2018. Accessed March 10, 2021. https://bit.ly/3rAGX0F

3. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 2.2021. Accessed March 1, 2021. https://bit.ly/3t1ffdU

4. Calvo E, Moreno V, Flynn M, et al. Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study. 

l. 2017;28(10):2559-2566. doi:10.1093/annonc/mdx357

5. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. 

. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1

6. Perez JMT, Leary A, Besse B, et al. Efficacy and safety of lurbinectedin (PM1183) in small cell lung cancer (SCLC): results from a phase 2 study. 

2018;36(suppl 15):8570. doi:10.1200/JCO.2018.36.15_suppl.8570

7. Subbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment. Lung Cancer. 2020;150:90-96. doi:10.1016/j.lungcan.2020.10.003

8. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. 

. 1999;17(2):658-667. doi:10.1200/JCO.1999.17.2.658

9. Zepzelca (lurbinectedin). Prescribing information. Jazz Pharmaceuticals; 2020. Accessed March 10, 2021. https://bit.ly/3rDgQq1

10. Farago AF, Drapkin BJ, Lopez-Vilarino de Ramos JA, et al. ATLANTIS: a phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/ vincristine in patients with small-cell lung cancer who have failed one prior platinumcontaining line.

. 2019 Jan;15(3):231-239. doi:10.2217/fon-2018-0597

11. Jazz Pharmaceuticals and PharmaMar announce results of ATLANTIS phase 3 study evaluating Zepzelca in combination with doxorubicin for patients with small cell lung cancer following one prior platinum-containing line. News release. Jazz Pharmaceuticals. December 3, 2020. Accessed March 1, 2021. https://bit.ly/3v7Qhvo

Articles

During a virtual Targeted Oncology Case-Based Roundtable event, Kartik Konduri, MD, discussed the case of a 58-year-old patients with small cell lung cancer.










Lurbinectedin Demonstrates Efficacy in First- and Second-line Small Cell Lung Cancer

Thomas Hutson, DO, PharmD, director, Urologic Oncology Program and cochair, Urologic Cancer Research and Treatment Center, Baylor University Medical Center, discussed the case of a 66-year-old patient with bladder cancer during a virtual 

: How did data compare between chemotherapies used in bladder cancer prior to the checkpoint inhibitor era?

: There was a tail on the [Kaplan-Meier] curve for cisplatin that we don’t see with carboplatin.

In lung cancer, they’re used interchangeably. Even for some small cell lung cancers, physicians are using it interchangeably. But like with testicular cancer, platinum chemotherapy in genitourinary cancer and bladder cancer is not equivalent. There’s better activity with cisplatin than there is with carboplatin. Because of this [tail on the curve], there’s been a focus on [whether] we should be giving chemotherapy [in patients with bladder cancer] because there is a small group of patients that get chemotherapy that do well.

I think if you treat enough patients with bladder cancer, you see patients who end up having great results. The numbers are small, so you have to have a large number [of patients] to treat. You don’t get that [tail] with carboplatin or gemcitabine. There is also quite a difference in the overall survival [OS] in patients that can get the gemcitabine/cisplatin combination.

The overall response rates [ORRs] are quite different [between chemotherapy regimens]. Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC] produced the highest ORR and complete response [CR] rate [of 72% and 25%, respectively], and median OS was 15.1 months with this regimen.

There’s some debate as to if it’s worth the toxicity, but these types of data show us that if [a patient] can get cisplatin, they should. Because if we don’t do that, if we negate chemotherapy in general, we’re going to lose any chance for a CR in these patients. We should consider chemotherapy still as the front line, especially if someone’s able to get cisplatin.

We take these data and extrapolate them in the perioperative setting. Right now, we’ll use these data to support neoadjuvant therapy. In that setting, the neoadjuvant therapy should be cisplatin. There’s a big movement, an education movement by the American Society of Clinical Oncology, to remind us that carboplatin is inferior, and you shouldn’t consider carboplatin in the neoadjuvant setting.

At Baylor University Medical Center, urologists are aware of the data of chemotherapy, and they tell me, “If I can’t give cisplatin [as a neoadjuvant therapy], I want to take the person to surgery. I don’t want neoadjuvant carboplatin.”

It’s hard for a community oncologist to know that kind of thing. But really, physicians should consider not giving carboplatin/gemcitabine [as a neoadjuvant therapy], because it’s so inferior. That’s pretty much what our experts tell us: We should be using cisplatin, or you can use split-dose gemcitabine/cisplatin.

A phase 2 trial [investigated] split-dose gemcitabine/cisplatin, every 21 days, that’s supposed to be more renally safe. I’ve [treated with] cisplatin down to creatinine clearances in the 35 mL/min range using a split-dose. That’s pretty much what we’re doing at Baylor University Medical Center—trying to go with gemcitabine/cisplatin one way or the other.

For patients who can’t get cisplatin, or I start them on cisplatin [and they] don’t do well, we send them to surgery because I’m always reminding myself that the curative therapy is not neoadjuvant chemotherapy. That adds at best 10% to their cure rate. The cure is surgery or radiation chemotherapy. That’s the take-home point. If they’re not tolerating chemotherapy, there’s no advantage to pushing it.

The other reminder is that in order to do radiation and chemotherapy as an alternative to surgery, you want to have had maximal transurethral resection of the bladder tumor. Then you still need to consider neoadjuvant chemotherapy.

Which trial backs the use of avelumab (Bavencio) in this setting?

The trial that really changed the standard of care, presented by Thomas Powles, MD, MBBS, MRCP, was a late-breaker abstract, LBA1.

 JAVELIN Bladder 100 [NCT02603432] was a study that established avelumab maintenance as a standard of care. They took patients who had first-line chemotherapy with either cisplatin or carboplatin/gemcitabine for 4 to 6 cycles and scanned [them]. Their response was either stable disease [SD], partial response [PR], or CR.

[Patients] were randomized to avelumab, continued every 2 weeks until unacceptable toxicity or progression, or [patients received] best supportive care [BSC] alone. The stratification was based upon the type of chemotherapy and whether they had a CR, PR, or SD.

[Investigators] looked at metastatic sites, visceral versus nonvisceral, and PD-L1 status. The primary end point was OS. They looked at all randomized patients and the PD-L1–positive population. The secondary end points were progression-free survival [PFS], safety, and patient-reported outcomes. There was no crossover allowed. There were 700 patients.

What were the efficacy data in the JAVELIN Bladder 100 trial?

When we look at the Kaplan-Meier curve of OS, the separation [of the curves] was maintained throughout.

The median OS was 21.4 months [with avelumab] versus BSC alone, at 14.3 months. The hazard ratio was 0.69 [95% CI, 0.56-0.86], so that’s a pretty attractive hazard ratio for a cancer trial, and it had a statistically significant P value [

It appears that patients who have at least SD with chemotherapy have a survival benefit by starting the checkpoint inhibitor right away and trying to maintain the benefit they got from chemotherapy. The median follow-up was 19.6 months with avelumab and 19.2 months with BSC.

The curves come back together [at a certain point], and there are a lot of theories as to why. One theory is that the patients who were [in the] BSC arm, when they progress, get a checkpoint inhibitor, so the checkpoint inhibitor is rescuing them. That’s why the curves come back together some. We know checkpoint inhibitors affect survival, and it’s the second-line agent of choice. Even though they get rescued with checkpoint inhibitors, it doesn’t catch up. There’s still benefit to early use of checkpoint inhibitors.

Across the board, all subgroups favored avelumab maintenance therapy. A couple of groups crossed the line. Age and performance status favored avelumab. The group with CR or PR seemed to have the greatest benefit [with avelumab], but it’s pretty similar to the SD group. Remember, the numbers are much smaller in the SD group. That may explain why it [crosses] 1.00. Then [with a] PD-L1 status of positive, negative, or unknown, there was still potential benefit or perceived benefit irrespective of PD-L1 status. However, PD-L1 positive status definitely increased likelihood of response.

Does PD-L1 status matter when using switch maintenance?

The OS [data in JAVELIN Bladder 100 looked at] the overall intention-to-treat population, which includes the PD-L1– positive or PD-L1–negative [population] versus the PD-L1–positive population alone. The OS was similar but [the PD-L1–positive group saw a] more enriched curve. They don’t have an OS median in that patient population [yet]. The BSC arm was at 17.1 months median OS. Further updates on these data are going to be useful.

How did patients do with the secondary end points?

PFS doesn’t really tell the story in this situation. For ORR in the PD-L1–positive population, [avelumab] does better than what we see in the overall population.

There were patients [who received prior] chemotherapy. They may not have had a CR [with chemotherapy], then they go on a checkpoint inhibitor and a few developed CRs. There are some people that had chemotherapy and had at least SD. You [may] put them on a checkpoint inhibitor, and they have progression.

Checkpoint inhibitors don’t work for everyone. The reason you’re choosing to [use them] is because of the entire patient population. You don’t know how your patient’s disease is going to behave. The checkpoint inhibitors have these benefit [data], and it will just have to play out on that individual patient. Unfortunately, there’s going to be about a third of your patients that don’t respond to a checkpoint inhibitor.

What were the adverse events (AEs) observed in this study?

When we look at AEs, the high level is what you would expect to see with a checkpoint inhibitor in this population [98.0%]. The AEs at grade 3 or more with the checkpoint inhibitor are low [47.4%]; the bulk of the AEs are going to be grade 1 or 2.

Remember, these patients are coming off chemotherapy and going on a checkpoint inhibitor, so they may already come into the checkpoint inhibitor with fatigue or cytopenias.

What’s interesting is the BSC arm gives you background [on how these patients would do normally]. That gives you the level of AEs that patients have that represents the disease itself and represents the AEs of the chemotherapy arm. Patients finish chemotherapy with some degree of AEs.

The treatment-emergent AEs led to discontinuation in about 12% of patients, which is low. That’s similar to what I’m familiar with avelumab when we’ve used it in kidney cancer. Death was attributed by investigator to study toxicity in 2 patients. One was sepsis, and the other was ischemic stroke.

If we look at immune-related AEs, the grade 3 level is quite low: 7% in total. Grade 1 or 2 was most predominant, and the most common [immune-related AE] was hypothyroidism. We saw skin rash and pneumonitis also.

High-dose corticosteroids, which they defined as greater than 40 mg of total daily prednisone or equivalent, were [used] in just 9% of avelumab-treated patients. That’s lower than what we’ve seen in other things like pembrolizumab [Keytruda] and nivolumab [Opdivo], where there’s a higher percentage [of patients] who need steroids.

Based upon these data—this is the first time we’ve ever had anything that’s shown survival benefit in patients after chemotherapy—the FDA approved [avelumab] for urothelial carcinoma maintenance treatment.

Because of that, it’s been incorporated into the NCCN criteria as a preferred treatment after gemcitabine/cisplatin and the dose-dense MVAC.

 For cisplatin ineligibility, the preferred regimens…give you other choices, recognizing that there may be a reason to [treat with] atezolizumab [Tecentriq] or pembrolizumab in that setting too. What they’re looking at is PD-L1 expression. If the patient had high PD-L1 expression, then they were not eligible for platinum chemotherapy. Atezolizumab or pembrolizumab would [then be used] because that was the criteria for those trials, and they checked PD-L1 status.

Avelumab maintenance has really been incorporated into the standard of care and is now considered for all patients who are eligible for chemotherapy.

How do you sequence the therapies in this setting?

What sequence yields the longest median OS? The best OS is with switch maintenance.1 The greatest estimated median OS was 25 months with maintenance when you add up [the different therapies]. There was a phase 2 trial [NCT02500121] of [switch maintenance] with pembrolizumab. Avelumab and pembrolizumab had similar outcomes in the maintenance setting.

1. Plimack E. Discussion of LBA1. Presented at: 2020 American Society of Clinical Oncology Virtual Scientific Program; May 29-31, 2020; virtual.

2. Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. 

. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1

3. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. June 30, 2020. Accessed March 9, 2021. https://bit.ly/3jaforD

4. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 1.2021. Accessed March 9, 2021. https://bit.ly/39PQGtI

Thomas Hutson, DO, PharmD, discussed the case of a 66-year-old patient with bladder cancer during a virtual Targeted Oncology Case-Based Roundtable event.

Hutson Compares Avelumab for PD-L1 Positive Versus PD-L1 Negative Bladder Cancer

Vivek Subbiah, MD, associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, and medical director, Clinical Center for Targeted Therapy, Cancer Medicine Division The University of Texas MD Anderson Cancer Center, explored the treatment of 

-fusion positive non–small cell lung cancer during a virtual 

: What is the frequency of distribution of RET fusions and mutations in lung cancer?

: Lung cancer has become a poster child for precision oncology, beyond EGFR mutations, 

 fusions in non–small cell lung cancer [NSCLC] with a frequency of 1% to 2%.1 In major cancer centers, the more we test, the more we find. As long as we do broad-based panel NGS testing in these patients, we are able to identify these [mutations]. It’s seen in 10% to 20% of papillary thyroid cancers. In medullary thyroid cancer [MTC], almost 100% of the patients with a hereditary form of thyroid cancer have a 

 mutation, and anywhere from 60% to 90% of patients with MTC have a 

 mutation in MTC is M918, and in lung cancer, the most common fusion partner is the 

How do the National Comprehensive Cancer Network (NCCN) guidelines suggest treating patients with NSCLC and 

 rearrangement discovered prior to first-line systemic therapy, the preferred first-line therapy is selpercatinib [Retevmo] or pralsetinib [Gavreto].

Vandetanib [Caprelsa] and cabozantinib [Cabometyx] are category 2B and useful under certain circumstances. [For] the second line on progression from frontline [treatment], either selpercatinib or pralsetinib is recommended. [The NCCN guidelines] suggest initiating systemic therapy for NSCLC based on adenocarcinoma guidelines.

 rearrangement is discovered during the first line of chemotherapy, [the guidelines] suggest completing planned systemic therapy, including maintenance therapy, or interrupting therapy followed by selpercatinib or pralsetinib and, in some rare cases, cabozantinib or vandetanib. Again, cabozantinib and vandetanib are category 2B.

Which studies have looked at selpercatinib as treatment in this setting?

LIBRETTO-001 [NCT03157128] is an ongoing, global, multicenter clinical trial.3 As of the latest update, there have been 702 patients enrolled in other cohorts—that includes 

 We are focusing on NSCLC. There were 39 treatment-na.ve patients, and 105 [were] previously treated with platinum chemotherapy.

At that time, there were 531 patients on the study, and among those patients there were 253 with 

 fusion–positive NSCLC enrolled on the study. Per agreement with the FDA, the primary analysis set for defined criteria consisted of the first 105 consecutively treated 

 fusion–positive platinum chemotherapy refractory patients with NSCLC, and the first 55 patients with 

-mutant MTC previously treated with vandetanib or cabozantinib.

For lung cancer, we are going to focus on the first 105 previously treated patients and then the 39 

 fusion–positive treatment-naive patients [from a study] published in the 

[For the 105 previously treated patients], the median age was the same, 61 years. The male to female ratio was 62 female and 43 male patients. Seventy-one percent of the patients were never smokers. Similar to 

 and other fusion-driven tumors, these patients tend to be light smokers or never smokers, and a few patients were current smokers.

Most of the patients had an ECOG performance status of 1, and almost 90% of the patients that were enrolled on both the arms had adenocarcinoma. The previous platinum chemotherapy treated cohort range of therapy was 3 lines of therapy. Apparently in Japan there was a patient treated with 15 lines of therapy. I don’t know what 15 lines of therapy you would have in cancer, but we have a patient on the study who went through 15 lines of therapy for NSCLC.

All 105 previously treated patients received platinum therapy. There were 55% who received anti–PD-L1 or anti–PD-1 therapy. Almost 50% of patients received another multitargeted tyrosine kinase inhibitor [TKI] for the 

 fusion. There were 36% in the 105 data set [of patients who were not treatment naive] who had brain metastasis at enrollment. There were 18% who were treatment naive who had brain metastasis.

 in 56% [of patients with previous chemotherapy treatment] and 67% in the untreated cohort.

The objective response rate [ORR] in the previously treated chemotherapy cohort, based on investigative assessment—that means the local site investigative assessment—was 70%. By independent blinded central review, the ORR was 64%. In the previously untreated patients, the investigative assessed cohort ORR was 90%, and the independent review ORR was 85%. There were 2 complete responses [CRs] in both the independent review and investigator assessment in the previously treated population.

The median duration of response [DOR] was 17.5 months by independent review and 20.3 months by investigator assessment [for patients who were previously treated]. In the previously untreated cohort, the median DOR was not estimable because the patients were still on study at the time of publication.

The median time to response was 1.8 months [overall]. We did scans every 2 months. I think this was the first time they did scans, so the median time to response was 1.8 months. When we treated these patients, and especially if they were clinically symptomatic, they became better within the first couple of weeks once we started treatment.

Responses were observed regardless of prior therapy with anti–PD-L1 or a multitargeted TKI, and regardless of the 

Most importantly, 1 of our [end] points is central nervous system [CNS] data. There were 38 of 105 patients who had a CNS metastasis at baseline. Among those 38 patients, 11 patients had measurable disease, [meaning it] could be measured by a central radiologist. Ten of those 11 patients with measurable lesions responded for a total of 91% objective intracranial response rate, a CR rate of 27%, and a partial response rate of 7%. The median intracranial DOR was 10.1 months in the data set that was published.

Have there been any updates to these data?

There was an updated poster that we presented at the 2020 American Society of Clinical Oncology [ASCO] annual meeting.

 Of the 253 patients, 80 patients had CNS disease at baseline. Among those 80 patients, 22 patients were deemed measurable by central evaluation. The number of patients with nonmeasurable disease was 58, and most of them were heavily pretreated before enrolling on this study.

Among the 22 patients with measurable CNS disease at baseline, the CNS ORR was 81.8%. There was an 85.7% ORR in the patients who [did not receive prior] radiation. There was 75% ORR in patients with prior CNS radiotherapy. Almost all patients in this data set with measurable disease had an intracranial response. The CNS DOR in the data set was 9.4 months, and the median follow-up in the patients without prior CNS radiotherapy was 15.7 months.

Can you discuss the progression-free survival (PFS) and safety data from LIBRETTO-001?

In the previously treated therapy cohort, the 1-year PFS rate was 66% by independent review. The 1-year PFS rate was 75% in the previously untreated cohort.

Adverse events [AEs] included hypertension—grade 3 hypertension was seen in 20 patients, which is 14%. We also saw grade 3 increased aspartate transaminase [AST] and alanine transaminase [ALT] levels in these patients. Eight percent of patients had an increased AST level, and 10% of patients had an increased ALT level.

In the entire data set, among all tumor types of 702 patients, 5% of the patients had a permanent discontinuation due to an AE, including ALT elevation, sepsis, increased AST, and drug hypersensitivity action in 0.3 to 0.4% of patients.6 Interruptions due to AEs were seen in 42% of patients, and dose reductions due to an AE were reported in 31% of patients.

On May 8, 2020, the FDA approved selpercatinib for [patients with] lung and thyroid cancer with 

What other studies looked at therapies for 

The ARROW study [NCT03037385] for pralsetinib was in advanced 

The study has not been published, but the drug is FDA approved.

 This was presented at the ASCO meeting, so we have that data set.

This was a phase 2 study of 400 mg once-daily dosing of pralsetinib, and the phase 2 dose expansion is still ongoing. The primary end point was ORR. The key secondary end points were DOR and disease control rate. 

In this study, 87 patients [had] received prior platinum therapy, and 27 patients…were treatment naive. Almost all of the patients had metastatic disease. Even in this study, the 

 fusions were 75% of the previously treated cohort and 70% of the treatment naive cohort. All of them were heavily pretreated before enrolling on the study in the prior platinum cohort.

There were 43% of patients with CNS disease in the prior platinum cohort, and 37% of the patients had CNS metastasis in the treatment-naive cohort.

The ORR in this study in the treatment-naive cohort was 70%, and the overall response rate was 57% in the closed platinum treated cohort.

The data show 96% of the evaluable patients had tumor reduction, and 100% of the patients who were treatment naive responded. Interestingly, 6% of the evaluable patients had a CR, and 12% of CRs were in treatment-naive patients. Patients responded to pralsetinib regardless of prior treatment and regardless of the fusion partner.

Among the 87 patients with RET fusion–positive NSCLC, 8 had measurable CNS metastasis.10 This drug also has CNS activity. Half of the patients, 4 out of the 8 patients, had responses in the intracranial lesions, 2 patients had a CNS CR in this data set, and 75% of those responders had a DOR of greater than 6 months.

AEs seen in greater than 15% of patients with pralsetinib included grade 3 fatigue in 2.3% of patients and grade 3 hypertension in 14% of patients. An interesting AE is pneumonitis. Pneumonitis was reported in 10% at any grade, and 2.7% at grade 3/4, and 1.8% of patients discontinued permanently due to pneumonitis, pneumonia, or sepsis. Interruptions due to an AE were reported in 60% and dose reduction due to an AE was reported in 36% of the data set.

In terms of hematology parameters, there was a decrease in neutrophils reported, and 10% had grade 3/4 toxicity.

Based on these data, the FDA on September 4, 2020, approved pralsetinib for lung cancer with 

Interestingly, they also approved an Oncomine [Dx Target] Test as a companion diagnostic for pralsetinib.

How do you feel about the evolution of this landscape over the course of 2020?

We had not 1 but 2 drugs approved in 2020. [It was] a tough and challenging year for all of us, with the COVID-19 [coronavirus disease 2019] pandemic and so many different stressors in the world and practice. But for precision oncology, we have 2 selective RET inhibitors approved in NSCLC.

The phase 1 studies [of these drugs] were started in 2017; 3 years from the start of a phase 1 study to an FDA approval attests to the fact that both these agents are highly active in a high area of unmet need.

Would immunotherapy, despite a PD-L1 expression of 80%, work in a patient such as this?

I think that’s a great question. We published the data; I can talk about my own experience. [At The University of Texas] MD Anderson Cancer Center, we published the data showing lack of responsiveness of patients with NSCLC who harbored 

 fusions to immunotherapy. [Memorial] Sloan Kettering Cancer Center also published similar data.

We don’t know why these patients are PD-L1 positive. I would think PD-L1 positivity here is a red herring, and most of these patients with 

 fusions have a very low tumor mutation burden. And, in fact, when we sequence these patients, they are devoid of immune-infiltrating T cells.

[As with] other oncogenic driver lung cancers, such as 

 fusions also do not respond well to immunotherapy. If possible, if we have a patient with 

-altered NSCLC, I think we would prioritize a selective TKI as a preferred option over immunotherapy. The NCCN guidelines do not say anything about PD-L1; as long as it’s 

 fusion–positive disease, the preferred first line is a TKI.

We are still learning [about] immune responsiveness and oncogene drivers because, regarding immunotherapy and oncogenic responses, most of the immunotherapy trials excluded patients with 

 fusions. We don’t know how the patients responded with 

 fusions, even NTRK fusions on immunotherapy studies.

Only recently, with broad-based commercial planners, we’ve started testing for 

 fusions. It remains to be seen if patients post RET inhibitor respond to an immunotherapy or a chemoimmunotherapy. If an RET TKI wasn’t available for a patient for financial reasons, or a patient does not tolerate it, or if you want to administer immunotherapy, I think we would go with a chemoimmunotherapy option rather than just immunotherapy alone.

But there are no absolutes in medicine. There might be a handful of patients with 

 fusion lung cancer who might respond to immunotherapy, but we’ll wait [and see].

 fusion positive, I would offer one of the selective TKIs, if possible.

1. Subbiah V, Cote GJ. Advances in targeting RET-dependent cancers. 

. 2020;10(4):498-505. doi:10.1158/2159-8290.CD-19-1116

Vivek Subbiah, MD, explored the treatment options for RET-fusion positive non–small cell lung cancer during a virtual Targeted Oncology Case-Based Roundtable event. 

Targeted Oncology Staff | Authors

Articles

Lurbinectedin Demonstrates Efficacy in First- and Second-line Small Cell Lung Cancer

Hutson Compares Avelumab for PD-L1 Positive Versus PD-L1 Negative Bladder Cancer

Subbiah Explores Treatment of Non–Small Cell Lung Cancer With a KIF5B-RET Fusion

Roundtable Discussion: Choueiri Leads Debate on Second-line Therapy in Patients with RCC