With immunotherapy options expanding for patients with a range of gastrointestinal cancers to include combination strategies with chemotherapy, their use in the treatment course should come sooner rather than later for those with high PD-L1 expression, explained Aravind R. Sanjeevaiah, MD.

“We should be looking at PD-L status upfront, just like we already knew, but we should also be looking at PD-L1, and if [the combined positive score is (CPS)] greater than 5, we should introduce immunotherapy sooner rather than later,” Sanjeevaiah said. “Previously we used to order the PD-L1 [testing] later because it was only approved in the third-line setting, but the paradigm has [since] shifted.”

In January 2021, nivolumab (Opdivo) was granted priority review status for use as an adjuvant treatment for patients with resected esophageal or gastroesophageal junction (GEJ) cancer following neoadjuvant chemoradiation. The FDA will make a decision on the supplemental biologics license application (sBLA) by May 20, 2021.

Also that month, the FDA granted a priority review to an sBLA for nivolumab (Opdivo) in combination with a fluoropyrimidine- and platinum-containing chemotherapy for use in patients with advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma.The agency is expected to make a decision by May 25, 2021.

® during a 2021 Institutional Perspectives in Cancer Webinar on gastrointestinal malignancies, Sanjeevaiah, an assistant professor in the Department of Internal Medicine at UT Southwestern Medical Center, discussed how immunotherapy has altered treatment for patients for gastrointestinal cancers, both as monotherapy and in combination with chemotherapy.

How has the addition of immunotherapy impacted the way you treat your patients with gastrointestinal cancers?

: Many immunotherapy agents have been studied in gastrointestinal cancers, not just nivolumab, but also pembrolizumab [Keytruda], durvalumab [Imfinzi], atezolizumab [Tecentriq], and others. The first major study was the phase 2 KEYNOTE-059 [NCT02335411] trial, in which there was clear evidence of benefit with immunotherapy in metastatic gastroesophageal cancers.

The benefit appeared to be mostly in PD-L1-positive cancers in the third-line setting, and that is where it was approved and has lived, so to speak, for the last 2 to 3 years. Now, we have phase 3 data from CheckMate-649 [NCT02872116], which shows that, in patients with a CPS of 5 or higher, the introduction of nivolumab plus 5-fluorouracil [5-FU], leucovorin, and oxaliplatin [FOLFOX] would result in significant clinical benefit in terms of overall survival [OS]. That has been practice changing. There are further studies that are looking to see if that space can be further elaborated on, but the best evidence we have right now is from CheckMate-649.

How do you explain the discordant results between the CheckMate-649 and KEYNOTE-062 [NCT02494583] trials?

Let’s look at the differences between these 2 studies. Of course, the immunotherapy agent being used was different. In KEYNOTE-062, we used pembrolizumab, while in CheckMate-649 we used nivolumab. There was also a difference in the chemotherapy regimens. CheckMate-649 used FOLFOX, whereas KEYNOTE-062 used 5-FU and cisplatin.

Additionally, the sample sizes were different. CheckMate-649 was a larger study with about 790 patients in each arm, [while] KEYNOTE-062 had about 240 patients. That might have been a factor. Also, we need to gather more data about how many of the patients who progressed after chemotherapy [crossed over to receive] immunotherapy. We still do not have data regarding the crossover that influenced the survival in those patients.

How would you describe the clinical implications of the phase 3 CheckMate-577 (NCT02743494577) trial?

This is probably the most important study in the gastrointestinal cancer space. What the study did was examine patients who received chemoradiation followed by surgery. For patients who had residual disease after chemoradiation therapy, they were given adjuvant nivolumab. [There were] approximately 532 patients in that arm [with nivolumab], which was a 2:1 randomization, and [patients received] nivolumab every 2 weeks for 16 weeks, followed by 418 mg every 4 weeks for 1 year, or placebo.

CheckMate-577 showed that survival was drastically different for patients who received adjuvant nivolumab, and the median disease-free survival was 22 months compared with 11 months [for placebo]. That is impressive. There are other studies being conducted right now to answer the same question—whether there is a role for immunotherapy in the perioperative setting. In particular, the phase 2/3 EA2174 [NCT03604991] study [is looking at this question with] nivolumab and ipilimumab. That will be another study to look out for in the next few years.

What emerging agents in this space are of interest?

There are all sorts of studies looking into the use of immunotherapy agents along with docetaxel, oxaliplatin, leucovorin, and 5-FU [FLOT], which is not a standard perioperative chemotherapy. Those recent studies should be looked at going forward and could show that we can improve upon the current success rate in curing patients with resectable gastroesophageal cancers.

This article was originally published on OncLive as, "

PD-1 Regimens Lead Charge Against Gastrointestinal Cancers

Articles

With immunotherapy options expanding for patients with a range of gastrointestinal cancers to include combination strategies with chemotherapy, their use in the treatment course should come sooner rather than later for those with high PD-L1 expression.

Immunotherapy Regimen Continues to Improve GI Treatment

Chronic immune-related adverse effects (irAE) arising from adjuvant anti–PD-1 therapy in patients with high-risk melanoma are more common than previously recognized, and often persisted with longer follow-up, according to findings from a multicenter cohort study published in 

Chronic irAEs, which are defined as those that persist after 12 weeks of anti–PD-1 discontinuation, occurred in 43.2% of patients enrolled to the trial (n = 167/387). Although the majority of these chronic irAEs were grades 1 or 2 (96.4%; n = 161/167), most of the effects persisted until last available follow-up (85.6%; n = 143/167).

“It is certainly important to recognize that anti–PD-1 therapy, regardless of this study and others, certainly does improve outcomes for patients with melanoma and is something that I will certainly still be offering my patients” lead study author Douglas Johnson, MD, MSCI, an associate professor of Medicine at Vanderbilt University Medical Center, and clinical director of Melanoma at Vanderbilt-Ingram Cancer Center, told 

. “There is a subset of patients with stage III melanoma who have a very low risk of recurrence, and for those patients, [these data] may make us reevaluate how to [treat] them, and perhaps [revisit] how [we] make risk/benefit determinations in those settings.”

Moreover, irAEs such as endocrinopathies (83.0%; n = 73/88), arthritis (48.9%; n = 22/45), xerostomia (52.9%; n = 9/17), neurotoxicities (73.3%; n = 11/15) and ocular effects (62.5%; n = 5/8), were the most likely to become chronic, while effects impacting visceral organs like the liver, colon, lungs, and kidneys, had much lower rates of becoming chronic.

“We tend to think of specific organs that are being affected by these toxicities,” Johnson said. “The big ones that come to mind are the colon, the lungs, and the liver, but the toxicities in those organs seem to really get better; it was toxicities in the smaller organs that seemed to more commonly develop into chronic [effects].”

Adjuvant therapy with anti–PD-1 agents has been found to result in improved relapse-free survival (RFS) in patients with resected, advanced-stage melanoma. However, the long-term effects of this treatment approach remain uncharacterized. To address this knowledge gap, investigators launched this retrospective, multicenter cohort study to determine the incidence, length, spectrum and associations of chronic irAEs that arise from adjuvant anti–PD-1 treatment in patients with stage III and IV melanoma. The study was conducted from 2015 to 2020 at 8 medical centers across the United States and Australia.

The median age for patients enrolled on the study was 63 years (range, 17-88) and the majority were male (60.7%; n = 235/387). Additionally, 74.9% (n = 290) had preexisting comorbidities, 85.8% (n = 332) had cutaneous primary sites, and 51.2% (n = 198) had 

 wild-type variants. Moreover, 33.1% (n = 128) of patients had resected stage IIIB melanoma, while 39.5% (n = 153) had resected stage IIIC disease. Around 84% (n = 326) of patients had received prior treatment with nivolumab (Opdivo), and 15.8% (n = 61) of patients received pembrolizumab (Keytruda), with a median treatment duration of 306 days (range, 1-1049).

Reasons for treatment discontinuation included therapy completion for 50% (n = 193), irAEs for 25.3% (n = 98) of patients, and disease progression for 20.9% (n = 81) of patients. Moreover, median RFS and overall survival had not been reached. At a median follow-up of 529 days, the majority of patients (93%) were alive. Notably, patients with observed acute and chronic irAEs were found to have superior RFS compared with those who did not experience irAEs.

Of all 387 patients included on the trial, 69.0% (n = 279) experienced acute irAEs; 44.2% (n = 171) of these effects were grade 2 or higher, while 13.4% (n = 52) were grades 3 to 5 in severity. Two patients died from irAEs; 1 patient had myocarditis, while the other had Guillain-Barré–like syndrome.

The most common acute irAEs observed were dermatitis/pruritus (25.8%), thyroiditis/hypothyroid (16.3%), arthralgias (10.6%), colitis/diarrhea (9.8%), hepatitis (6.2%), pneumonitis (4.4%), and xerostomia (4.1%). About 28% of patients required treatment with glucocorticoids; 55.0% needed this for grade 2 irAEs, while 45.0% needed them for grade 3 to 5 effects.

In those who developed chronic irAEs, systemic glucocorticoids were needed in 32.9% (n = 55) of patients. The most common chronic irAEs observed were hypothyroidism (14.0%), arthralgias (5.7%), dermatitis/ pruritus (6.6%), adrenal insufficiency (3.1%), and xerostomia (2.3%).

Age and gender were not found to be linked with the development of chronic irAEs (63.0 years vs 63.0 years in those who did not develop chronic irAEs, 

 = .31, respectively). Moreover, the median time of onset of acute irAEs was not determined to be associated with chronicity (

 = .95). With the exception of endocrinopathies, those who were given glucocorticoids for acute effects did not go on to develop chronic effects more often than those who did not receive the agents (

The investigators concluded that the risks of chronic irAEs should be integrated into treatment decision-making for this patient population.

“In terms of future directions, we might potentially be able to intervene early and identify these effects before they established themselves to become chronic,” Johnson noted.

Patrinely JR, Johnson R, Lawless AR, et al. Chronic immune-related adverse events following adjuvant anti–PD-1 therapy for high-risk resected melanoma. 

. Published online March 25, 2021. doi:10.1001/jamaoncol.2021.0051

Chronic immune-related adverse effects arising from adjuvant anti–PD-1 therapy in patients with high-risk melanoma are more common than previously recognized, and often persisted with longer follow-up.

Chronic Immune-Related Adverse Events Are Common in Certain Melanoma Subgroups

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

Lurbinectedin Makes a Splash in Second-Line SCLC.

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

Data from the pivotal phase 3 KATHERINE (NCT01772472) has led to the addition of ado-trastuzumab emtansine (T-DM1; Kadcyla) to the HER2-positive breast cancer treatment arsenal, but the toxicities associated with the approach must be appropriately managed so that patients can continue to receive it, according to Jane L. Meisel, MD.

The phase 3 KATHERINE trial examined ado-trastuzumab emtansine (T-DM1; Kadcyla) vs trastuzumab (Herceptin) and showed that the former resulted in a 50% reduction in the risk of invasive disease recurrence or death (HR, 0.50; 95% CI, 0.39-0.64; 

 <.0001). These data led to the May 2019 FDA approval of T-DM1 for use as an adjuvant treatment in select patients with HER2-positive early breast cancer.

Notably, 25.7% of the patients in the T-DM1 arm experienced a grade 3 or higher adverse effect (AE) vs 15.4% in the trastuzumab arm. Additionally, 18% of patients in the T-DM1 arm experienced AEs that lead to discontinuation of treatment.1

“It's tricky because these patients have been through a lot,” Meisel said. “It's a diagnosis of breast cancer, first of all, and it is a relatively toxic, intense, up-front therapy. It’s not the easiest thing, but for many patients, particularly those with high-risk disease, it really does make a difference. We try to do all we can to support patients through that.”

® during an Institutional Perspectives in Cancer webinar on breast cancer, Meisel, an associate professor for the Departments of Hematology and Medical Oncology, and Gynecology & Obstetrics at Winship Cancer Institute, Emory University School of Medicine, discussed the use adjuvant T-DM1 and the management of associated toxicities and the benefit of the combination pertuzumab (Perjeta)/trastuzumab in HER2-positive breast cancer.

®: What were the implications of the phase 3 KATHERINE and FeDeriCa trials (NCT03493854) now that more mature data have read out?

: KATHERINE was a fascinating study because it not only allowed us to take a very high-risk group and randomize them to a potential intervention, but it also showed that they really did much better when, instead of being given just 1 year of trastuzumab after not achieving a pathologic complete response [pCR], they were switched over to adjuvant T-DM1. That 3-year progression free survival [PFS] difference of 11% is really statistically significant, as well as clinically significant, and this has changed the way we treat our patients. Routinely, we are switching [patients] over to T-DM1 as was done in KATHERINE, and I believe this will start to change outcomes, as we see more and more of these patients do better.

FeDeriCa was a study that looked at pertuzumab and trastuzumab given subcutaneously as opposed to intravenously, with the primary end point being pertuzumab concentration, so more of a pharmacologic/pharmacokinetic end point as opposed to a clinical end point. The authors also looked at PCR rates with the subcutaneous administration and found that both the trough concentrations as well as the PCR rates were the same with subcutaneous versus IV administration.

[This is an] intervention that changes convenience for the patient, and in terms of safety, particularly during the pandemic, [it can prevent] time spent in the infusion center. This is a preparation which, technically, could be given in one's home as opposed to even in the clinic. Certainly, for patients who want to have the port removed or don't want to receive IV treatment for longer than they have to, this offers an opportunity to do just a little injection as opposed to an infusion. In terms of quality of life for patients, which really is a huge [factor] after they've been through so much, this represents a major step forward.

Were there any prohibitive toxicities observed in KATHERINE?

In the study, approximately 18% of patients discontinued T-DM1 because of toxicity. Generally, the populations that we see in studies are inherently a motivated, relatively well population of patients, while those we see in clinic may have more comorbidities or may not be as motivated as those who choose to join trials. As such, more [efforts are needed] to monitor these patients and to encourage them to stay on the T-DM1 because it is a little more challenging than the pertuzumab/trastuzumab. However, the benefit is there, so when patients seem as though they're going to benefit and they fit the criteria for the trial, we do try to get them to stay on [the drug].

I find it works best if I tell patients about the possibility [of toxicity] in the beginning. When I describe the neoadjuvant, anti-HER2–directed regimen, I talk about the fact that we'll use their surgery as both a part of their treatment, but also as an information-gathering piece. The result of the surgery, whether they get to PCR or not, will inform the next step. If they get to PCR, [they] would [then receive] trastuzumab, likely plus pertuzumab, or switch to T-DM1 if they don't. Once I get closer to that time point after the surgery, and if the patient is going to receive T-DM1, then we talk about what that will look like.

Often, I do see the patients each visit with T-DM1, at least in the beginning, just to see whether they're experiencing [effects] like nosebleeds, gastrointestinal distress, or worsening neuropathy. These are some of the most common [effects] that we see with the T-DM1 regimens, so we prefer to get on top of these effects and manage them right away. [Then] patients can either make the decision to discontinue and go back to pertuzumab/trastuzumab if they need to or can feel empowered that we have ways to manage the AEs and get through as much of that year of T-DM1 as possible.

Could you elaborate on some of the strategies used to manage those toxicities?

With neuropathy, one of the main strategies that we have is gabapentin, which can be helpful. Additionally, there's solid clinical trial data that support that icing the fingers and toes during chemotherapy treatment helps prevent neuropathy from getting worse; that can also be empowering: to know that there's something they can do, or can try, to help with that. In terms of the nosebleeds, which can happen with T-DM1, it's important to keep the nostrils moist. Vaseline or nasal sprays [can be used] sparingly if the nosebleeds are particularly bothersome. If a patient is having recurrent nosebleeds, we will refer them to an ear, nose, and throat [specialist].

In terms of liver function abnormalities, we do encourage patients to not drink heavily while they're on treatment and to abstain from Tylenol or other medications that might interfere with liver function tests.

Also, [we see] fatigue, [which] is multifactorial. We certainly see that [when patients are] on breast cancer therapies of all kinds.

Turning to FeDeriCa, now that the subcutaneous administration is approved, do you believe that patients will be more likely to pursue that option if they experience a milder toxicity?

They might, because options are everything. Some patients may be sticklers for the data, who may say they want to wait a little longer and see more before they make the switch. For other patients, the pharmacokinetics, and the fact that it's FDA approved, may be enough for them. They may want to make the switch if they feel like it's palatable.

Insurance coverage may be another issue. I'm not sure that every insurance company is going to cover it to the same degree as they cover intravenous administration. Finances may play a role, but I do believe this is going to be something that has legs, for sure.

von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. 

. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017

Miesel on Managing Toxicities With T-DM1 in HER2+ Breast Cancer

Data from the pivotal phase 3 KATHERINE has led to the addition of ado-trastuzumab emtansine to the HER2-positive breast cancer treatment arsenal, but the toxicities associated with the approach must be appropriately managed so that patients can continue to receive it.

T-DM1 Toxicity Management in Breast Cancer

Tipifarnib showed promising clinical activity in patients with recurrent and/or metastatic, 

-mutant head and neck squamous cell carcinoma (HNSCC) whose disease had progressed after prior therapy, according to results from a phase 2, open-label, single-arm KO-TIP-001 trial (NCT02383927) published in the 

Among the 20 response-evaluable patients with a variant allele frequency (VAF) of 20% or higher (high VAF) treated on study, 11 met RECIST v1.1 criteria for confirmed partial response (PR), which translated to an objective response rate (ORR) of 55% (95% CI, 31.5%-76.9%). Tipifarnib resulted in a significant improvement in median progression-free survival (PFS) over last prior therapy received, at 5.6 months (95% CI, 3.6-16.4) and 3.6 months (95% CI, 1.3-5.2), respectively. Moreover, the median overall survival (OS) with tipifarnib was 15.4 months (95% CI, 7.0-29.7).

“We are encouraged by the compelling efficacy and safety profile of tipifarnib in patients with recurrent or metastatic 

-mutant HNSCC,” Alan Ho, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center and principal investigator of this trial, stated in a press release.

 “Importantly, these patients experienced limited benefit on prior therapies, including immunotherapies, which demonstrates the high unmet need for this disease. These data also reinforce the relevance of genomic testing for 

 mutations to identify patients who could potentially benefit from tipifarnib treatment.”

Despite recent advances in immunotherapy, the prognosis for patients with advanced HNSCC remains poor, and the development of biomarker-directed therapies in the recurrent and metastatic settings has been limited. Tipifarnib is a farnesyltransferase inhibitor that disrupts 

 function and has demonstrated durable anticancer activity in previous studies. In February 2021, the FDA granted a breakthrough therapy designation to tipifarnib for use in patients with recurrent or metastatic 

-mutated HNSCC with high VAF based on data from this trial that were presented during the 2020 ASCO Virtual Scientific Program.

This trial enrolled patients with incurable solid tumors that harbored missense 

 mutations; it was divided into 2 stages. The first stage was comprised of 3 cohorts, patients with thyroid cancer, those with non-thyroid solid tumors, and those with squamous cell carcinoma other than HNSCC. The second stage of the trial included those in cohort 2 who had HNSCC only; the cohort was expanded to further characterize safety and tolerability indications of interest.

A total of 31 patients were split into 2 subsets: those with 

 VAF of 20% or greater and serum albumin level of 3.5 g/dL or greater or 

 of 35% or greater (n = 22), and those with a 

 VAF of 20% or less or 20% to 35% with a serum albumin of 3.5 g/dL or less (n = 9).

To be eligible for enrollment on the trial, patients had to have 

-mutant disease with a VAF greater than 20%, measurable disease per RECIST v1.1 criteria that was relapsed/refractory to prior therapy, as well as an ECOG performance status of 0 or 1. Patients who had previously been treated with a farnesyltransferase inhibitor, who had a history of coronary heart disease, or who had uncontrolled brain, leptomeningeal, or epidural metastases were excluded.

Initially, oral tipifarnib was given to patients with HNSCC at a twice-daily dose of 900 mg on days 1 through 7 and 15 through 21 of 28-day cycles, based on data from 2 prior trials that established the safety of this schedule. However, of the first 15 patients dosed, 9 needed a dose reduction to manage adverse effects (AEs). As such, the median dose of tipifarnib by cycle 2 day 1 was 600 mg, given twice daily. The trial protocol was then amended to begin the agent at 600 mg twice daily to improve tolerability of tipifarnib and allow patients to continue on treatment for a longer period of time.

The primary end point of the trial was investigator-assessed ORR, while secondary end points included safety and tolerability. PFS, duration of response (DOR), overall survival, and feasibility of molecular analyses using next-generation sequencing were also evaluated as exploratory end points.

Among the 22 patients with high-VAF HNSCC, the median age was 63 years (range, 20-89), and the majority were male (68.2%). The primary location of the tumor was the oral cavity in 45.5% of patients (n = 10), and patients received a median of 2 prior treatments, which included platinum-based chemotherapy (90.9%), immunotherapy (63.9%), and cetuximab (Erbitux; 50%).

Additional results revealed that the ORR for the intent-to-treat population (n = 22) was 50% (95% CI, 30.7%-69.3%). Among the 20 evaluable high-VAF patients, those with a VAF of greater than 35% had an ORR of 58.3% vs 50% of t hose with a VAF that was less than 35%. Three of 12 patients with a VAF greater than 35% had an albumin of less than 3.5 g/dL with 1 (33.3%) experiencing response to the agent. Notably, responses were rapid, with 8 of 11 patients who met PR criteria experiencing response at the time of their first tumor assessment.

Moreover, 7 of 11 patients who achieved PRs ended up discontinuing treatment because of disease progression. Of the 9 patients who did not respond to tipifarnib, all achieved a best response of stable disease and 6 experienced minor tumor regression. Three of 9 patients who had disease stability received treatment for about 7 months, while 7 patients with PR continued treatment for at least 6 months.

Of the 11 patients who received immunotherapy as their last prior line of treatment, 7 experienced a PR and 4 achieved disease stability with tipifarnib. In the 8 patients who had a prior line of treatment that was not immunotherapy, 3 experienced PRs and 4 had stable disease.

The PFS benefit with tipifarnib proved to be greater in the patients who experienced a PR vs those who achieved stable disease, at 9.5 months (95% CI, 5.5-NA) vs 4.0 months (95% CI, 1.9-NA), respectively.

Safety was evaluated in 30 patients who were treated with tipifarnib. The most commonly reported treatment-emergent AEs (TEAEs) of any grade, irrespective of VAF or albumin cutoff, were hematologic, and included anemia, neutropenia, leukopenia, and lymphopenia. Gastrointestinal effects, such as nausea, were also reported.

Three patients reported TEAEs that led to discontinuation of tipifarnib: 2 patients had laryngeal obstruction and 1 had respiratory failure; however, these effects were not determined to be related to the study treatment. No treatment-related deaths were reported, and at data cutoff, no high-VAF participants had discontinued treatment due to AEs.

Tipifarnib will continue to be evaluated in the phase 2 AIM-HN/SEQ-HN trial (NCT03719690) in patients with 

"We are pleased to see our data from the phase 2 RUN-HN trial of tipifarnib published in the Journal of Clinical Oncology for review by the broader clinical community,” Troy Wilson, PhD, JD, president and chief executive officer of Kura Oncology, added in the release. "The highlighted data from the RUN-HN trial comes on the heels of our breakthrough therapy designation from the FDA and we continue to advance the ongoing AIM-HN registration-directed trial in patients with 

-mutant HNSCC, for whom there is an urgent unmet need.”

Ho AL, Brana I, Haddad R, et al. Tipifarnib in head and neck squamous cell carcinoma with 

. Published online March 22, 2021. doi:10.1200/JCO.20.02903

Kura Oncology announces publication of tipifarnib phase 2 data in Journal of Clinical Oncology. News release. Kura Oncology, Inc. March 22, 2021. Accessed March 24, 2021. 

Phase II study of tipifarnib in squamous head and neck cancer with HRAS mutations. ClinicalTrials.gov. Updated June 23, 2020. Accessed March 24, 2021. 

https://www.clinicaltrials.gov/ct2/show/NCT02383927

Tipifarnib Showcases Encouraging Efficacy in Relapsed or Metastatic HRAS-Mutant HNSCC

Tipifarnib showed promising clinical activity in patients with recurrent and/or metastatic, HRAS-mutant head and neck squamous cell carcinoma whose disease had progressed after prior therapy.

Tipifarnib Promising in Relapsed/Metastatic HRAS-Mutant HNSCC

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 priority review to the new drug application (NDA) for the novel compound pafolacianine sodium injection (formerly OTL38) for use in the identification of ovarian cancer during surgery, according to an announcement from On Target Laboratories, Inc.

Pafolacianine sodium injection has demonstrated the ability to bind to folate receptors and illuminate intraoperatively under near-infrared light; it can be administered intravenously prior to treatment-related surgeries. Utilizing the injection in ovarian cancer surgery could help to provide greater certainty of complete disease resection, as approximately 97% of patients with ovarian cancer express clear alpha-folate receptor proteins.

The use of pafolacianine sodium injection in ovarian cancer was investigated in phase 2 (NCT02317705) and phase 3 (NCT03180307) trials and was under Special Protocol Agreement from the FDA. Additionally, the agent has received both fast track and orphan designations from the regulatory agency.

“Our NDA is supported by our positive phase 2 and phase 3 clinical trials,” Christopher Barys, president and CEO of On Target Laboratories, stated in a press release. “As we move closer to FDA approval for ovarian cancer, we are realizing our mission to intraoperatively visualize more cancer and extend the benefits of a complete resection to patients.”

The phase 2 study enrolled 29 patients who were 18 years of age or older with a primary diagnosis, or high clinical suspicion, of ovarian cancer. Participants received pafolacianine sodium injection prior to planned debulking surgery.

Results showed that when controlling for correlation of detection among multiple lesions within a single patient, pafolacianine sodium injection had a sensitivity of 97.97% (95% lower boundary CI = 87.75) and a positive predictive value of 94.93% (95% lower boundary CI = 86.13). Additionally, 48.3% (n = 14/29; 95% CI, 0.29–0.67) of patients had at least 1 additional lesion detected by pafolacianine sodium injection.

In terms of safety, 8 patients experienced mild drug-related adverse effects (AEs). The most common AEs reported included infusion reaction, nausea, vomiting, and abdominal pain.

Data from the phase 2 trial led to the ongoing phase 3 trial, which is further evaluating the agent in that patient population.

Additionally, pafolacianine sodium injection is currently being investigated in the phase 3 ELUCIDATE trial (NCT04241315) for use in the intraoperative detection of lung cancer lesions. This multicenter trial will evaluate the safety, efficacy, and tolerability of pafolacianine sodium in patients with lung cancer and is expected to enroll up to 130 patients. The first patient was enrolled in the study in July 2020, and preliminary data is expected in 2021.

The FDA has granted priority review to the new drug application for the novel compound pafolacianine sodium injection for use in the identification of ovarian cancer during surgery.

Courtney Marabella