Lurbinectedin (Zepzelca) has demonstrated impressive activity and tumor reduction in patients with small cell lung cancer (SCLC), and its addition to the treatment arsenal represents a promising development in a field with limited available options, according to Wade T. Iams, MD. However, questions pertaining to its clinical application remain.

“We finally have a new option for patients with relapsed SCLC,” Iams said. “We saw an [encouraging] overall response rate in these patients treated with lurbinectedin with a significant reduction in tumors, which compares favorably with previously available chemotherapy options.”

lurbinectedin for the treatment of patients with metastatic SCLC

 with disease progression after platinum-based chemotherapy. The regulatory decision was based on data from a phase 2 basket trial (NCT02454972), which showed that patients treated with the agent experienced an overall response rate (ORR) of 35.2%,1 and 65% of those enrolled in the study experienced a reduction in tumor size.2

Additionally, in July 2020, the agent was added to the 

Clinical Practice Guidelines in Oncology by the National Comprehensive Cancer Network (NCCN)

 for the second-line treatment of patients with SCLC.

® during an Institutional Perspective in Cancer webinar on Lung Cancer, Iams, and assistant professor of medicine for the Division of Hematology/Oncology at Vanderbilt-Ingram Cancer Center, discussed the efficacy and safety of lurbinectedin in patients with SCLC, the impact of its approval on the paradigm, and remaining questions regarding its use.

®: What was the significance of the accelerated FDA approval of lurbinectedin? How has it impacted clinical practice?

: Lurbinectedin was only the second FDA-approved agent for patients with relapsed SCLC. The only previous option was topotecan. As such, this has been a significant development for patients who haven't seen many developments for decades. We're excited about more options for these patients in the clinic. This was great progress for the field.

What is known about the mechanism of action of lurbinectedin? What makes it unique from other agents?

Lurbinectedin is a transcription factor inhibitor that acts by blocking RNA polymerase at the site of active transcription. In the sense that it is a broad cytotoxic agent, we would place it in a category of more traditional cytotoxic chemotherapy. However, [lurbinectedin] differs from other cytotoxic chemotherapy agents [because of its] administration schedule. We're hopeful that the transcription factor profiles that are inhibited by lurbinectedin can potentially be more specific for SCLC, although that's under investigation.

A really intriguing dynamic, to me, is [whether there is] specificity of this agent for subtypes of SCLC, which is where the preclinical science in [this disease] is moving. [We’re] defining for subtypes by transcription factor profiles and [determining] what relationship this new agent may have to each subtype is a really intriguing [area of focus].

What should be known about the safety profile of this agent when used as a monotherapy?

When used as monotherapy, which is the FDA-approved application, the most common adverse effect [AE] observed was fatigue in a slight majority of patients. The vast majority [of patients] were not hospitalized; it was not a severe AE.

The big toxicity to be aware of is neutropenia, but I took that all the way to rate of febrile neutropenia, which typically guides our use of primary prophylactic growth factor for these patients. In the COVID-19 era, we've had ASCO recommendations to lower the threshold to use of primary prophylaxis growth factor down to 10% rates. Now, when we look at the monotherapy lurbinectedin data, [we see a] less than 10% rate of febrile neutropenia. Although, there is a much higher rate of grade 3 neutropenia without febrile neutropenia [with the agent]. Distinguishing between those 2 is a big component of looking at these toxicities.

Patients did have more expected nausea, vomiting, and diarrhea. There was only 1 hospitalization, or grade 3 or higher toxicity, for a gastrointestinal event, and that was 1 episode of diarrhea. [Additionally], only 1 skin toxicity of grade 3 or higher [was observed], and less than 10% of patients had transaminase elevation of grade 3 or higher. No hospitalizations for acute kidney injury [occurred], although some creatinine elevation was observed. [However,] when we put that next to other chemotherapy toxicities [that we see], I would certainly describe it as very well tolerated.

How do you feel this agent fits into the treatment landscape? What are some questions that still need to be sorted out?

The big question when we look at the clinical application of lurbinectedin for patients with relapsed SCLC is, how do we feel about the time since they received their last platinum chemotherapy? The way that the study breaks down results is by 3 months since last platinum, or more than 3 months since last platinum.

The way that our NCCN guidelines break down that timeline is 6 months since last platinum chemotherapy vs 6 months after last platinum chemotherapy. The reason I harp on that point is because we know that reusing that platinum chemotherapy is more effective, particularly if patients have had 6 months since their last platinum. However, some folks also use that 3-month threshold clinically.

The application of lurbinectedin is a bit stronger compared with the other options [available] for patients who have relapsed in less than 3 months. When we get to the [patients who are] platinum sensitive, relapsed 3 months or even 6 months or later, I think there's more of a question about do you reinstitute that platinum that they had the first time around? That may be dependent on adverse effects and tolerance of that individual patient the first time they received it. Or do we use lurbinectedin? Lurbinectedin, again, is FDA approved for any of those scenarios, and it is an NCCN guidelines option for any of those scenarios, but it is a wrinkle, clinically, in the platinum-sensitive setting.

In the phase 3 ATLANTIS trial (NCT02566993), lurbinectedin was paired with doxorubicin; the trial failed to meet its primary end point of overall survival (OS). What should be taken away from these findings?

That is the key question in the field. I would reserve my comments until we see more comprehensive data from this trial. All we've seen is that the primary end point was OS, and it was not met. To reiterate the structure of the trial, [it was] a 1:1 randomization of lurbinectedin plus doxorubicin compared with dealer's choice of cyclophosphamide/doxorubicin/vincristine or topotecan. Lurbinectedin was given at a lower dose than [it had been] in the monotherapy trial. All we know is that [the study] did not meet its primary end point. I'd like to see the full data set before we can fully interpret [what these data mean for the field].

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

Paz-Ares LG, Perez JMT, Besse B, et al. Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial. 

 2019;37(suppl 15):8506. doi:10.1200/JCO.2019.37.15_suppl.8506

This article was originally published on OncLive as, "

Lurbinectedin Makes a Splash in Second-Line SCLC.

Articles

Wade T. Iams, MD, discusses the efficacy and safety of lurbinectedin in patients with small cell lung cancer, the impact of its approval on the paradigm, and remaining questions regarding its use.

Lurbinectedin Shows Promise in Small Cell Lung Cancer Treatment

First-line treatment with camrelizumab, an investigational PD-1 inhibitor, plus chemotherapy induced robust and durable clinical responses in patients with advanced squamous non–small cell lung cancer (NSCLC), according to findings from the phase 3 CameL-sq trial that were presented during the 2021 European Lung Cancer Virtual Congress.

The median progression-free survival (PFS) was 8.5 months (95% CI, 6.9-10.4) with camrelizumab plus chemotherapy compared with 4.9 months (95% CI, 4.2-5.5) with placebo plus chemotherapy per a blinded independent review committee (BIRC; HR, 0.37; 95% CI, 0.29-0.47; 

 < .0001), meeting the primary end point of the study.

Moreover, PFS by BIRC favored the camrelizumab-based regimen vs the placebo-based regimen irrespective of age, sex, ECOG performance status (PS), smoking history, disease stage, presence of liver or brain metastases at enrollment, and PD-L1 status by tumor proportion score (TPS).

“These findings support camrelizumab plus paclitaxel and carboplatin as standard first-line treatment for [patients with] advanced squamous non–small cell lung cancer,” said Caicun Zhou, MD, PhD, lead study author and director of the Department of Oncology at Shanghai Pulmonary Hospital, affiliated with Tongji University School of Medicine in Shanghai, China, in a virtual presentation of the data.

As monotherapy, camrelizumab has shown antitumor activity in patients with previously treated advanced NSCLC. Additionally, interim findings from the phase 3 CameL trial showed that at a median follow-up of 11.9 months, the median PFS was 11.3 months with camrelizumab plus chemotherapy vs 8.3 months with placebo plus chemotherapy in patients with chemotherapy-naïve advanced nonsquamous NSCLC (HR, 0.60; 95% CI, 0.45-0.79; 

The findings from the CameL trial established camrelizumab plus chemotherapy as a standard frontline option for Chinese patients with advanced nonsquamous NSCLC who do not harbor 

The CameL-sq study aimed to establish camrelizumab as a standard frontline option for patients with advanced squamous cell disease.

In the study, 390 patients were randomized 1:1 to the camrelizumab- or placebo-based regimens. Patients in the camrelizumab group (n = 193) received 200 mg of camrelizumab plus carboplatin at an area under the curve (AUC) of 5 and 175 mg/m2 of paclitaxel in 3-week cycles for 4 to 6 cycles followed by 200 mg of camrelizumab given every 3 weeks until progressive disease or unacceptable toxicity.

Patients treated in the placebo group (n = 196) received placebo plus carboplatin and paclitaxel at the same dose as the camrelizumab group, followed by placebo until disease progression or unacceptable toxicity. Patients receiving placebo were allowed to cross over to 200 mg of camrelizumab if they experienced progressive disease with placebo per BIRC.

Eligible patients had pathologically confirmed stage IIIB to IV squamous NSCLC, no prior systemic treatment, and an ECOG PS of 0 or 1.

Patients were stratified by sex, smoking history (≥400 cigarette-years vs <400 cigarette-years vs never-smokers), and the presence of liver or brain metastases at enrollment (both sites vs 1 site vs none).

PFS per BIRC served as the study’s primary end point, with overall survival (OS), overall response rate (ORR), duration of response (DOR), disease control rate (DCR), and safety as key secondary end points.

Of the patients in the camrelizumab group, 126 discontinued treatment because of disease progression (n = 77), adverse effects (AEs; n = 23), withdrawn consent (n = 14), death (n = 6), investigator decision (n = 4), and other reasons (n = 2); 67 patients are receiving ongoing treatment. In the placebo group, 186 patients discontinued treatment because of disease progression (n = 161), withdrawn consent (n = 11), AEs (n = 5), death (n = 5), lost to follow-up (n = 1), investigator decision (n = 1), new antitumor therapy (n = 1), and other reasons (n = 1); 10 patients are receiving ongoing treatment.

Baseline patient characteristics were well-balanced between arms. The median patient age was 64 years in the camrelizumab arm vs 62 years in the placebo arm, and the majority of patients were male in both arms. Most patients were smokers, had an ECOG PS of 1, and had stage IV disease.

Additionally, 13.0% of patients receiving camrelizumab had liver or brain metastases upon enrollment compared with 11.2% of patients receiving placebo.

In the camrelizumab arm, 47.2% of patients had less than 1% PD-L1 TPS expression, 30.1% had 1% to 49% expression, 19.2% had 50% or greater expression, and 3.6% were not evaluable. These rates were 49.5%, 25.0%, 22.4%, and 3.1%, respectively, in the placebo arm.

Secondary end point analyses revealed that the median OS was not reached (NR) with camrelizumab/chemotherapy (95% CI, 18.4-NR) compared with 14.5 months (95% CI, 13.2-16.6) with placebo/chemotherapy (HR, 0.55; 95% CI, 0.40-0.75; 

In all subgroups beside female patients (HR, 1.06; 95% CI, 0.21-5.26), median OS favored the camrelizumab regimen compared with the placebo regimen.

The ORR by BIRC was 64.8% (95% CI, 57.6%-71.5%) with camrelizumab/chemotherapy vs 36.7% (95% CI, 30.0%-43.9%) with placebo/chemotherapy. In the experimental arm, 7.8% of patients achieved a complete response (CR), 57.0% achieved a partial response (PR), 23.3% had stable disease (SD), 7.8% had progressive disease, and 4.1% were not evaluable. In the placebo arm, 1.5% of patients achieved a CR, 35.2% achieved a PR, 46.4% had SD, 14.8% had progressive disease, and 2.0% were not evaluable.

The DCR was 88.1% with the addition of camrelizumab (95% CI, 82.7%-92.3%) vs 83.2% with placebo (95% CI, 77.2%-88.1%). The median DOR was 13.1 months (95% CI, 9.3-15.7) vs 4.4 months (95% CI, 4.2-4.9), respectively.

Patients received camrelizumab for a median of 12 cycles (range, 1-32) and placebo for median of 7 cycles (range, 1-26). In both arms, patients received a median of 5 cycles (range, 1-6) of paclitaxel and carboplatin.

All patients (100%) on the camrelizumab regimen vs 99.5% of patients on the placebo regimen experienced any-grade treatment-emergent AEs (TEAEs); 80.3% vs 75.0% of patients reported grade 3 or 4 TEAEs, respectively.Additionally, 10.4% of patients in the camrelizumab group compared with 13.8% of patients in the placebo group died from TEAEs.

Similarly, all patients (100%) on the camrelizumab regimen vs 99.5% of patients on the placebo regimen experienced any-grade treatment-related AEs (TRAEs); 73.6% vs 71.4% of patients reported grade 3 or 4 TRAEs, respectively. Additionally, 3.1% of patients receiving camrelizumab compared with 1.5% of patients received placebo died from TRAEs.

Immune-related AEs (irAEs) were reported in 76.7% of patients on camrelizumab compared with 20.4% of patients on placebo.

Common TRAEs included hematologic events, such as decreased white blood cell, neutrophil, and platelet counts and anemia, and non-hematologic events, such as alopecia, hypoesthesia, asthenia, decreased appetite, nausea, increased alanine aminotransferase and aspartate aminotransferase, and extremity pain.

Common irAEs included reactive capillary endothelial proliferation, endocrinopathy, skin adverse reactions, pneumonitis, hepatitis, colitis, and hematologic toxicity.

Zhou C, Ren S, Chen J, et al. Camrelizumab or placebo plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC (CameL-sq): a randomized, double-blind, multicenter, phase 3 trial. Presented at: European Lung Cancer Congress; March 25-27, 2021; Virtual. Abstract 96O.

Zhou C, Chen G, Huang Y, et al. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. 

 2021;9(3):305-314. doi:10.1016/S2213-2600(20)30365-9

Camrelizumab Plus Chemo Prolongs PFS in Advanced Squamous NSCLC

First-line treatment with camrelizumab, an investigational PD-1 inhibitor, plus chemotherapy induced robust and durable clinical responses in patients with advanced squamous non–small cell lung cancer.

Investigational Combo Improves PFS in NSCLC Subset

Immunotherapy has yielded impressive survival benefits when used as a frontline treatment for patients with non–small cell lung cancer (NSCLC); however, with its increasing up-front use, the issue of resistance to checkpoint inhibition has become more pronounced, according to Edgardo Santos, MD, FACP.

“Immunotherapy is generally very effective, very well tolerated, and most importantly, it improves overall survival [OS],” Santos said. “For patients who fail immunotherapy up front, it is very difficult for them to switch to a regular cytotoxic drug. As such, we are focusing right now on trying to overcome resistance to immunotherapy.”

®, during an Institutional Perspectives in Cancer webinar on Lung Cancer, Santos, a founding member of the Florida Precision Oncology Care, medical director of research services, and associate professor at Florida Atlantic University, discussed advances made with immunotherapy regimens in the first-line treatment of patients with metastatic NSCLC and areas of active investigation.

®: The phase 3 KEYNOTE-189 (NCT02578680) trial is one of the most pivotal trials examining immunotherapy in patients with stage IV disease. How did this trial set the stage for future efforts?

: KEYNOTE-189 was a landmark [trial] in NSCLC. In a subsequent follow-up of more than 23 months, the study still demonstrated positive results, with clinical meaningful outcomes, including OS and progression-free survival [PFS]. The combination of pembrolizumab [Keytruda] plus chemotherapy of either cisplatin or carboplatin, followed by maintenance therapy [comprised of] pembrolizumab and pemetrexed, was very well tolerated. [Additionally,] all the primary end points [of the trial] were positive.

A dual-immunotherapy approach was examined in the phase 3 CheckMate-227 trial (NCT02477826). Could you speak to the significance of this research?

After KEYNOTE-189, which showed that the addition of immunotherapy to chemotherapy improves OS, several clinical trials have shown clinical meaningful outcomes for our patients with stage IV lung cancer. CheckMate-227 [examined] the combination of nivolumab [Opdivo], which is a checkpoint inhibitor, and ipilimumab [Yervoy], another checkpoint inhibitor that focuses on the CTLA-4 pathway. For the first time, we have a combination of checkpoint inhibitors with no chemotherapy involved and improved OS over chemotherapy. Now, we have this option for patients who do not want to receive any chemotherapy whatsoever; we can offer them just pure immunotherapy.

for use in the frontline treatment of patients with metastatic NSCLC and PD-L1 positivity. Could you expand on how this regulatory decision impacted the paradigm?

Prior to CheckMate-227, we could only use immunotherapy alone if a patient had PD-L1 expression above 50% in the tumor. When we see a patient with lung cancer, we do a biopsy to test for PD-L1. Depending on the expression, we have different indications by the National Comprehensive Cancer Network to decide what we can do [in terms of treatment]. For those patients who have an expression of PD-L1 above 50%, we can use immunotherapy alone. However, for patients with a PD-L1 expression below 50%, we would have to combine with chemotherapy. Now, [because of] CheckMate-227, we can use immunotherapy alone in patients with a PD-L1 expression below 50%.

Then, in the phase 3 CheckMate-9LA trial (NCT03215706), chemotherapy was added to nivolumab/ipilimumab. What was the objective of this research?

The idea here was to achieve better outcomes. In this study, the primary end point was OS, and the trial demonstrated positive results for OS and for PFS. Importantly, by adding chemotherapy to the nivolumab/ipilimumab combination, when you stratify all patients by PD-L1 [expression], which is the best biomarker that we have for immunotherapy, this combination was positive for all the subgroups [analyzed].

The other thing worth mentioning is that the chemotherapy given in this study was very short. Instead of the classic set of 4 to 6 cycles of a platinum-based doublet that we [generally] use for patients with stage IV disease, in this study, we use 2 cycles. As such, the patient receives nivolumab/ipilimumab plus 2 cycles of chemotherapy, and then after those 2 cycles [of chemotherapy] are done, the patient will continue with nivolumab/ipilimumab alone.

Also, during the study, if a patient had adenocarcinoma or squamous cell carcinoma, the appropriate chemotherapy was assigned based on their histology. We know that histology matters for the type of chemotherapy we use.

What should be known about the safety of the chemoimmunotherapy approach?

The cycles of chemotherapy [in CheckMate-9LA] were given once every 3 weeks, so there is 3 weeks off in between cycles 1 and 2. No red flags were reported, and no added toxicities were observed beyond what we already knew [to be common] from nivolumab and ipilimumab, which is important to emphasize.

What are some other ongoing trials of interest that are further examining novel approaches with checkpoint inhibitors?

Several studies are coming up. One phase 3 study is looking at another checkpoint inhibitor called sintilimab [Tyvyt], [which] seems to be effective. The caveat is that we are waiting for the OS data [with this approach]. This study was done in the first-line treatment of [patients with] stage IV lung cancer. Cemiplimab-rwlc [Libtayo] is another checkpoint inhibitor [of interest]. The agent showcased] strikingly positive results, with a long-term median OS [observed in] patients with a PD-L1 expression above 50%.

What are some future directions for research?

What is more important is what we are doing in this space when a patient [progresses] on up-front immunotherapy. What we are doing now is looking to use, perhaps, another checkpoint inhibitor in combination with another pathway to overcome the resistance of the tumor to immunotherapy.

This interview was conducted prior to the February 22, 2021 FDA approval of cemiplimab for use in the frontline treatment of patients with advanced NSCLC with a PD-L1 expression level of 50% or higher.

Santos Spotlights Success With Checkpoint Inhibition in Frontline Metastatic NSCLC

Edgardo Santos, MD, FACP, discusses advances made with immunotherapy regimens in the first-line treatment of patients with metastatic non–small cell lung cancer and areas of active investigation.

Checkpoint Inhibitors in Lung Cancer: The Progress Continues

The role of comprehensive genomic testing in patients with cholangiocarcinoma has become more pronounced as more is learned about the biology of the disease and as more agents are being developed to target associated alterations, according to Daniel Lin, MD, MS.

“What we've seen in many gastrointestinal cancers, and biliary cancer is a good example, is the key role that comprehensive genomic testing can play for patients [in that it can be used] to guide their treatment [decisions] and to expand their options,” Lin said.

Fifteen to 20% of all patients with biliary tract cancers have tumors that harbor 

 mutations, while 10% to 15% of tumors harbor 

 In recent years, many options targeting these alterations have emerged in the pipeline and impacted the outcomes of these patients.

For example, ivosidenib (Tibsovo) resulted in improved progression-free survival (PFS; HR, 0.37; 95% CI, 0.25-0.54) and overall survival (OS) after adjustment for crossover (HR, 0.49; 95% CI, 0.34-0.70) in previously treated patients with 

-mutated cholangiocarcinoma, according to data from the pivotal phase 3 ClarIDHy trial (NCT02989857).

For previously treated patients with cholangiocarcinoma and 

 fusions or rearrangements, infigratinib elicited an overall response rate of 23.1%, with a median duration of response of 5.0 months and a median PFS of 7.3 months.

 “For patients who have been previously exposed to chemotherapy who harbor this alteration, this is another clinically meaningful therapy,” noted Lin. Other FGFR inhibitors under exploration includepemigatinib (Pemazyre) and futibatinib.

® during an Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Lin, a medical oncologist and assistant professor at the Sidney Kimmel Cancer Center of Jefferson Health, discussed pivotal trials examining important targeted agents for patients with cholangiocarcinoma and the importance of comprehensive genomic testing to guide treatment decisions.

®: How would you say findings from the phase 3 ClarIDHy trial have impacted clinical practice?

: With the ClarIDHy trial, and also with the infigratinib trial and all the FGFR inhibitor trials, is that comprehensive genomic testing can make a huge difference for patients [with biliary cancers] in terms of expanding options and finding meaningful therapies. ClarIDHy, [which examined] the IDH1 inhibitor ivosidenib, clearly demonstrated an improvement in both PFS as well as OS in patients with 

 mutations who were previously exposed to chemotherapy, after you accounted for all the crossover that occurred. [Ivosidenib] is certainly a clinically meaningful treatment option to offer for patients with cholangiocarcinoma with an 

With regard to the phase 2 trial with infigratinib, what stood out to you from those data?

The same theme in that patients with this specific alteration had very good disease control rate [DCR]. In this particular study, the ORR was approximately 25%, and the median PFS was about 7 months. As we've seen in most of the FGFR inhibitor trials, manageable toxicities [have been observed] with this [agent].

Infigratinib is not the only FGFR inhibitor under exploration; pemigatinib and futibatinib are also being examined in these patients. How do these agents compare with one another?

The key takeaways when you're comparing all those trials, is that the pemigatinib trial had a little bit more [patients who were in the] second line as opposed to third line, compared with the futibatinib and infigratinib trials. Really, when we look at cross-trial comparisons, which generally we are told not to do but we do it anyway, we found that the DCRs are fairly similar, so a little over 80% across these trials. The median PFS seems to always fall around 7 months, maybe slightly less in terms of the response rate for the infigratinib trial, but it stacked up pretty well, in comparison. With all the FGFR inhibitors, it's going to be interesting [to see] where they fall in terms of the treatment landscape.

Do you recommend comprehensive sequencing over single-gene testing for

mutations? What advantages does the former have over the latter?

Yes. With comprehensive sequencing, the advantages would be that we not only are looking for specific alterations, but what is especially relevant, is looking to see whether there are any other alterations of interest, particularly if they open access to other clinical trials for these patients.

For example, in some of my patients, I sometimes can come across CDK-related alterations. Another relevant [alteration] in terms of biliary cancers, for which we don't necessarily have large phase data but they will still be clinically meaningful, are 

 mutations. BRAF inhibition, as well as ErbB2 and HER2 alterations, can open possibilities for targeted anti-HER2 therapy.

1. Lowery MA, Ptashkin R, Jordan E, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. 

. 2018;24(17):4154-4161. doi:1158/1078-0432.CCR-18-0078

2. Zhu AX, Macarulla T, Javle MM, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (

. 2021;39(suppl 3):266. doi:10.1200/JCO.2021.39.3_suppl.266

3. Javle MM, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an 

. 2021;39(suppl 3):265. doi:10.1200/JCO.2021.39.3_suppl.265

Comprehensive Genomic Testing Alters the Rapidly Evolving Cholangiocarcinoma Treatment Landscape.

Daniel Lin, MD, MS, discusses pivotal trials examining important targeted agents for patients with cholangiocarcinoma and the importance of comprehensive genomic testing to guide treatment decisions.

Genomic Testing Leads Change in Cholangiocarcinoma Landscape

The FDA has granted a fast track designation to poziotinib for use in previously treated patients with HER2 exon 20 mutations, according to an announcement from Spectrum Pharmaceuticals.

The submission of a new drug application (NDA) for the agent is anticipated later this year, according to Spectrum Pharmaceuticals.

“There are currently no approved therapies to treat patients with HER2 exon 20 mutations and we are pleased that the FDA has granted fast track designation for poziotinib,” Joe Turgeon, president and chief executive officer of Spectrum Pharmaceuticals, stated in a press release. “Momentum is building to unlock the potential of poziotinib.”

Recent data from cohort 3 of the phase 2 ZENITH20 trial (NCT03318939) were presented at the 2021 ESMO TAT Virtual Congress and showed that when poziotinib was given at a daily dose of 16 mg, it elicited clinically meaningful activity in treatment-naïve patients with metastatic NSCLC with 

The objective response rate (ORR) achieved in this patient population was 27.8% (95% CI, 18.4%-39.1%) and the disease control rate (DCR) was 86.1%. At a median follow-up of 9.2 months, 12 of 79 patients continued to receive poziotinib. The median duration of response (DOR) with the agent in this cohort was 6.5 months. Notably, 91% of patients in the intent-to-treat (ITT) population experienced tumor shrinkage with poziotinib.

Moreover, preliminary findings from cohort 5 of the trial indicated that when the agent was delivered at a twice-daily dose in patients with metastatic NSCLC who harbored 

 exon 20 mutations, patients experienced a reduction in toxicity.

Specifically, the toxicity rate in those who received the agent at a daily dose of 16 mg was 31% vs 21% in those given at a twice-daily dose of 8 mg. In those who received a daily dose of 12 mg vs a twice daily dose of 6 mg, the toxicity rates were 27% and 16%, respectively. Findings from cycle 1 of treatment indicated that twice-daily dosing schedules of either 8 mg or 6 mg led to a relative reduction in dose interruptions by 38% and 52%, respectively.

In July 2020, the trial was reported to meet its prespecified primary end point for cohort 2, where poziotinib was evaluated in patients with previously treated NSCLC and HER2 exon 20 insertion mutations.

Data from the intent-to-treat analysis demonstrated that poziotinib resulted in a confirmed ORR of 27.8% (95% CI, 18.9%-38.2%). All responses experienced with the agent were confirmed by a central imaging laboratory per RECIST criteria. Moreover, the observed lower bound of 18.9% was noted to have surpassed the prespecified lower bound of 17% in this population.

The median DOR with poziotinib at a median follow-up of 8.3 months was 5.1 months in this cohort. Moreover, the DCR reported with the agent was 70%, and the median progression-free survival (PFS) was 5.5 months.

The trial is comprised of 7 independent cohorts of patients. Specifically, cohorts 1 through 4 are independently powered for a prespecified statistical hypothesis with a primary end point of ORR. Cohorts 5 to 7 are exploratory.

Earlier data from cohort 1 showed that poziotinib resulted in an ORR of 14.8% (95% CI, 8.9%-22.6%) and a DCR of 68.7% in pretreated patients with NSCLC and 

 exon 20 insertions.4 Of the 115 patients included in the ITT population, 79 experienced disease stability or better with poziotinib. The median DOR in these patients was 7.4 months and the median PFS was 4.2 months.

Notably, 65% of patients experienced tumor reduction with poziotinib. However, because only 17 of the 115 patients experienced a partial or complete response to treatment, the primary end point of ORR was not met.

“We are actively preparing the NDA and delighted with this fast track designation,” Francois Lebel, MD, chief medical officer of Spectrum Pharmaceuticals, added in the release. “…We are optimistic about the twice daily dosing strategy and we will provide a data update at AACR in April.”

FDA grants fast track designation to Spectrum Pharmaceuticals’ poziotinib. News release. Spectrum Pharmaceuticals. March 11, 2021. Accessed March 11, 2021. 

Sacher A, Le X, Cornelissen R, et al. Safety, tolerability and preliminary efficacy of poziotinib with twice daily strategy in EGFR/HER2 exon 20 mutant non-smell cell lung cancer. Presented at: ESMO TAT Virtual Congress; March 1-2, 2021; Virtual. Accessed March 11, 2021.

Spectrum Pharmaceuticals announces positive topline results in HER2 exon 20 insertion mutations from cohort 2 of the poziotinib ZENITH20 trial. News release. July 27, 2020. Accessed March 11, 2021. 

Xiuning L, Goldman J, Clarke J, et al. Phase 2 study of poziotinib in NSCLC with EGFR exon 20 insertions. Presented at: 2020 American Association for Cancer Research virtual Annual Meeting I; April 27-28, 2020. Abstract CT081. 

FDA Grants Fast Track Status to Poziotinib for HER2 Exon 20–Mutated NSCLC

The FDA has granted a fast track designation to poziotinib for use in previously treated patients with HER2 exon 20 mutations.

Poziotinib Gets Fast Track Status for HER2 Exon 20–Mutated NSCLC

The FDA has approved the VENTANA ALK (D5F3) CDx assay as a companion diagnostic to identify patients with 

-positive non–small cell lung cancer (NSCLC) who are eligible to receive treatment with lorlatinib (Lorbrena).

On March 3, 2021, the FDA gave the green light to expand the indication of lorlatinib to include use in the frontline treatment of patients with 

-positive NSCLC based on data from the phase 3 CROWN trial (NCT03052608), where the agent led to a 72% reduction in the risk of progression or death vs crizotinib (Xalkori) in treatment-naïve patients (HR, 0.28; 95% CI, 0.19-0.41; 

 <.0001) per blinded independent central review assessment.

Previously, in November 2018, the regulatory agency granted an accelerated approval to lorlatinib for use in patients with ALK-positive NSCLCwhose disease had progressed on crizotinib and at least 1 other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor treatment for metastatic disease. The decision was based on a subgroup of 215 patients with 

-positive metastatic NSCLC from Study B7461001 (NCT01970865), in which lorlatinib elicited an overall response rate of 48% (95% CI, 42%-55%).3

“The FDA approval is great news for [patients with] 

-positive [NSCLC],” Jill German, head of Roche Pathology Customer Segment, stated in a press release. “It is essential that we identify patients with this cancer biomarker quickly and accurately so they can be treated with effective targeted therapy. This label expansion advances Roche’s commitment to personalized healthcare by providing [patients with] lung cancer with access to more treatment options and a better chance for progression-free survival compared to standard of care.”

The VENTANA ALK (D5F3) CDx assay was developed to qualitatively identify the ALK protein in formalin-fixed, paraffin-embedded NSCLC tissue stained with a BenchMark ULTRA or BenchMark XT automated staining instrument.

The assay is now approved for use as a companion diagnostic for the following 4 targeted therapies: crizotinib, ceritinib (Zykadia), alectinib (Alecensa), and lorlatinib. Data from previous studies have demonstrated that the assay is able to identify more patients with NSCLC who may derive benefit from an ALK-targeted treatment compared with fluorescent in situ hybridization (FISH) testing.

In 1 study, investigators selected patients with stage IV NSCLC who received crizotinib. Investigators assessed their tumors to detect 

 rearrangements through the use of either FISH or the VENTANA ALK (D5F3) CDx assay.

-positive NSCLC diagnosed by FISH or the VENTANA assay on either small biopsies or fine-needle aspirations were given ALK inhibitors. All patients determined to have 

 aberrations via the VENTANA assay responded to crizotinib with the exception of 3 patients who had primary resistance. No response was observed in 13 patients who tested positive for 

 aberrations via FISH but were negative via the VENTANA assay; this was confirmed using an external cohort of 16 patients.

In another study, investigators evaluated the potential of combining immunohistochemistry (IHC) via the VENTANA assay and FISH to determine the affordability of the approach. Investigators evaluated 410 unselected lung adenocarcinomas through the use of both tests.

Cases were examined as IHC score 3+ (n = 26), score 2+ (n = 9), score 1+ (n = 51), and score 0 (n = 282). Twenty-three of the 26 IHC 3+ and 5 of the 9 IHC 2+ cases were FISH positive, whereas 3 of 26 IHC 3+, 4 of 9 IHC 2+, and all 333 IHC 1+/0 cases were FISH negative. If FISH was considered to be the standard approach, then the sensitivity and specificity of the VENTANA assay for 3+/2+ as 

 positive were 100% and 97.9%, respectively. Notably, 2 of the IHC 3+ cases that were reported to be negative via FISH, were actually positive for 

On the final classify, the sensitivity and specificity for ALK IHC 3+/2+ was 100% and 98.8%, respectively; FISH was 90.3% sensitive and 100% specific. The investigators concluded that the VENTANA assay was able to detect some 

-positive cases that might have been missed by FISH.

In another study, investigators conducted FISH and IHC analyses on 297 lung adenocarcinomas. The VENTANA assay and the real-time polymerase chain reaction (qRT-PCR) assay were applied to evaluate the 

 mutational status in the discordant cases of FISH and IHC.

Results indicated that there was 100% sensitivity with IHC, with a specificity of 81.8% for detecting 

-expressed cases were negative, 5 of which had the 

 aberration detected via qRT-PCR. Three of those 5 cases showed 

Roche receives FDA approval for VENTANA ALK (D5F3) CDx assay to identify lung cancer patients eligible for targeted treatment with LORBRENA (lorlatinib). News release. Roche. March 9, 2021. Accessed March 9, 2021. 

US FDA expands approval of Pfizer's Lorbrena as first-line treatment for ALK-positive metastatic lung cancer. News release. March 3, 2021. Accessed March 9, 2021. 

FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. News release. FDA. November 2, 2018. Accessed March 9, 2021. 

van der Wekken AJ, Pelgrim R, Hart N’t, et al. Dichotomous ALK-IHC is a better predictor for ALK inhibition outcome than traditional ALK-FISH in advanced non–small cell lung cancer. 

. 2017;233(15):4251-4258. doi:10.1158/1078-0432.CCR-16-1631

Zhou J, Zhao J, Sun K, et al. Accurate and economical detection of ALK positive lung adenocarcinoma with semiquantitative immunohistochemical screening. 

. 2014;9(3):e92828. doi:10.1371/journal.pone.0092828

Shan L, Lian F, Guo L, et al. Combination of conventional immunohistochemistry and qRT-PCR to detect ALK rearrangement. 

FDA Approves Companion Diagnostic for Lorlatinib in ALK+ NSCLC

The FDA has approved the VENTANA ALK CDx assay as a companion diagnostic to identify patients with ALK-positive non–small cell lung cancer who are eligible to receive treatment with lorlatinib.

FDA Approves Companion Diagnostic for Lorlatinib in ALK-Positive Lung Cancer

Poziotinib, when given at a daily dose of 16 mg, was found to demonstrate clinically meaningful activity when used in treatment-naïve patients with metastatic non–small cell lung cancer (NSCLC) who harbor 

 exon 20 mutations, according to data from cohort 3 of the phase 2 ZENITH20 trial (NCT03318939) presented during the 2021 ESMO TAT Virtual Congress.

Of 79 patients, 12 remained on treatment with the agent, with a median follow-up of 9.2 months. Twenty-two patients achieved a response with poziotinib, equating to an overall response rate (ORR) of 27.8% (95% CI, 18.4%-39.1%). Moreover, the disease control rate (DCR) in these patients was 86.1%.

Additionally, preliminary data from cohort 5 of the trial showed that when the agent was delivered at a twice-daily dose in patients with metastatic NSCLC who harbored 

 exon 20 mutations, toxicity rates were reduced.

The treatment of this patient population represents a significant unmet need, according to lead study author Adrian Sacher, MD, of the Medical Oncology and Haematology Department at Princess Margaret Cancer Centre.

In the open-label, multicenter phase 2 trial, investigators set out to evaluate the safety and efficacy of poziotinib in 7 patient cohorts of up to 603 previously treated and treatment-naïve patients with NSCLC.

To be eligible for enrollment to cohort 3, patients had to be treatment naïve with locally advanced NSCLC; they were allowed to have adjuvant/neoadjuvant therapies as long as they completed treatment at least 15 days before entering the study.

 Patients in cohort 5 had to have received at least 1 previous systemic treatment for locally advanced or metastatic NSCLC.

A total of 79 treatment-naïve patients with metastatic NSCLC and 

 exon 20 mutations were enrolled to cohort 3, and they received poziotinib at a daily dose of 16 mg. Cohort 5 enrolled a total of 40 patients with NSCLC who harbored either 

 exon 20 mutations. These patients were randomized to different doses of poziotinib, including daily doses of either 10 mg, 12 mg, or 16 mg, as well as a twice-daily dose of 6 mg or 8 mg.

The primary end point of trial was ORR per RECIST v1.1 criteria, while secondary end points included DCR and DOR. Investigators also evaluated PFS in these patients.

Additional data from cohort 3 of the trial showed that the median DOR with poziotinib was 6.5 months. The majority, or 91%, of patients in the intent-to-treat population experienced tumor reduction with the treatment.

In this cohort, the safety profile of the agent proved to be comparable with second-generation EGFR TKIs, with 33% of patients experiencing rash that was grade 3 or higher in severity and 23% of patients reporting grade 3 or higher diarrhea.

Results from cohort 5 indicated that the toxicity rate in those who received a daily dose of poziotinib at 16 mg was 31% vs 21% with a twice-daily dose of 8 mg. Additionally, toxicity rates were 27% and 16% in those who received a daily dose of 12 mg vs a twice daily dose of 6 mg, respectively.

Moreover, data yielded from cycle 1 of treatment showed that twice daily dosing schedules of either 8 mg or 6 mg resulted in a relative reduction in dose interruptions by 38% and 52%, respectively.

1. Sacher A, Le X, Cornelissen R, et al. Safety, tolerability and preliminary efficacy of poziotinib with twice daily strategy in EGFR/HER2 exon 20 mutant non-smell cell lung cancer. Presented at: ESMO TAT Virtual Congress; March 1-2, 2021; Virtual. Accessed March 4, 2021

2. Poziotinib shows promise in EGFR and HER2 exon 20 mutated non-small cell lung cancer. News release. ESMO. March 2, 2021. Accessed March 4, 2021. 

3. Phase 2 study of poziotinib in patients with NSCLC having EGFR or HER2 exon 20 insertion mutation. ClinicalTrials.gov. Updated September 16, 2020. Accessed March 4, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03318939

Poziotinib, when given at a daily dose of 16 mg, was found to demonstrate clinically meaningful activity when used in treatment-naïve patients with metastatic non–small cell lung cancer who harbor EGFR exon 20 mutations.

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Poziotinib Gets Fast Track Status for HER2 Exon 20–Mutated NSCLC

FDA Approves Companion Diagnostic for Lorlatinib in ALK-Positive Lung Cancer

Poziotinib Is Promising in EGFR Exon 20–Mutant NSCLC Treatment

FDA Expands Lorlatinib Approval for Frontline ALK+ NSCLC

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