Bradley Monk, MD, a professor on the Clinical Scholar Track at the University of Arizona College of Medicine, Phoenix and a gynecologic oncologist at Arizona Oncology (US Oncology Network), discusses the phase 1b/2 innovaTV 205 (ENGOT-cx8/GOG-3024; NCT03786081) trial in patients with recurrent or metastatic cervical cancer.

This study is looking at the combination of tisotumab vedotin plus bevacizumab (Avastin), pembrolizumab (Keytruda), or carboplatin (Paraplatin). Testing these combinations makes sense biologically and mechanistically, according to Monk. The patients on this trial, who progressed on their second-line of therapy or later, will be in 1 of the 3 dose-escalation arms. The investigators identified the appropriate doses of tisotumab plus each of the 3 other therapies.

Monk explains that in the same space where these agents are used in earlier lines of therapy, the investigators will see how they will affect patients by way of dose expansion. To find the recommended phase 2 dose, patients will receive therapy with 1 of the combinations every 3 weeks. Because the half-life is only 1.7 days, there will be a fourth arm in the phase 2 looking at weekly dosing.

There will be an interim analysis after 15 patients are enrolled in each arm. The primary end point is overall survival. Monk says the investigators are also interested in the adverse events associated with these combinations. One adverse event associated with tisotumab is epistaxis, an eye toxicity, which they have a mitigation strategy for of eye drops. Patients on this drug also can also experience fatigue and neuropathy.

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Bradley Monk, MD, discusses the phase 1b/2 innovaTV 205 trial in patients with recurrent or metastatic cervical cancer.

Investigating Combinations in Recurrent or Metastatic Cervical Cancer

A novel irreversible Bruton’s tyrosine kinase (BTK) inhibitor, TG-1701, demonstrated early activity in mantle cell lymphoma (MCL) cells, providing evidence for scientific rationale for the combination of TG-1701 with ublituximab and umbralisib in non-Hodgkin lymphoma. The agent appears particularly promising in MCL lines resistant to ibrutinib (Imbruvica) treatment.

In patients with relapsed or refractory MCL, the development of BTK 

 mutation or overactivation of the NF-kB pathway, can lead to resistance to BTK inhibitors. Only TG-1701, in comparison with other reversible and irreversible BTK inhibitors, showed inhibitory activity when tested in REC-1 BTK 

This agent has also demonstrated similar cytotoxic activity compared with other BTK inhibitors in ibrutinib-sensitive MCL cell lines.

, Gaël Roué, PhD, senior scientist at Vall d'Hebron Institute of Oncology and Idibaps research institute Hospital Clinic Barcelona, discussed the rationale for evaluating TG-1701 in combination with ublituximab and umbralisib in ibrutinib-resistant MCL.

Interest in this new BTK inhibitor comes from the fact that there is a large interest in BTK inhibitors for B-cell malignancies due to the fact that although there is no specific activity with this, it could affect other kinases and signaling within the tumor B-cells. We are interested in this molecule which is much more specific to BTK. When we compare this second-generation molecule with the first-in-class ibrutinib, we observed it retains some activity in cases of resistance to ibrutinib.

: Could you elaborate the mechanism of action associated with TG-1701 and its potential synergy with ublituximab.

There was some interest in the possibility of combining BTK inhibitors with an anti-CD20 antibody due to the fact that in some studies the addition of BTK could lead to degradation of CD20. This could antagonize the activity of the anti-CD20 antibody, so we focused on this point by testing whether ibrutinib with TG-1701 could either sensitize or decrease the response of MCL cell lines to the first-in-class antibody rituximab (Rituxan) with ublituximab and also with umbralisib, which is a second-generation CD20 antibody

The readout of the supplements was the ADCC antibody delivered cell cytotoxicity which is one of the main effects of these antibodies in tumor B-cells, and we observed this when there was an antagonistic activity between the ibrutinib and rituximab or ublituximab in the cell lines. When we use TG-1701 instead of ibrutinib, this antagonism was not observed. We are able to maintain the cytotoxic activity of the antibody in this setting.

: Were there any notable results that you wanted to emphasize?

The results were interesting in detecting the mechanism of action of this combination, but why with not only the use the anti-CD20 antibody but we used the U2 doublet, which is used in the clinical [setting]. This is a ublituximab and umbralisib, which is a new PI3K-delta inhibitor, so when we use this combination, there is very nice synergistic activity both in 

. We could observe that this was due to a modulation of the inflammatory microenvironment in a sense, and we pass from anti-inflammatory environments to pro-inflammatory environments. Surgical analyses allow the immune factors to enter to the tumors, and then this could explain why the anti-CD20 antibody is working well in these settings.

: What are the next steps following this research?

We have to characterize the tumors we use, so we are only calculating the prediction of inflammatory cytokines. We have characterized the infiltration of mouse cells and mouse macrophages, and we now have to validate our original analysis. We also have to validate the expression of these cells within the tumors. We are trying to explain why the activity of TG-1701 is maintained in case of a mutation of BTK, but why this activity is lost when we have activation of the NF-kB pathway? We have some evidence that the older kindnesses can be inhibited by TG-1701, allowing the compound to work in case of tissue decay. However, in case of over expressed signaling, the activity of this molecule is broad. We are waiting for the proper technical analysis of the different cell lines to observe the PI3k inhibitor, which [might] explained how this molecule can work in case of BTK inhibition.

: Is there any other research in MCL that you are involved in that you would like to highlight?

We are also working with some new immunotherapy based on the inhibition of CD47. We know CD47 is really relevant to immune checkpoint in B-cell malignancies, so we are using this specific antibody from TG Therapeutics which is called TG-1801, to this antibody could block a CD47 immune checkpoint, specifically on tumor B-cells. We have evidence that this blockade can augment the infiltration of macrophages to give you all the immune effector activity against the tumor.

Articles

In an interview with Targeted Oncology, Gaël Roué, PhD, discussed the rationale for evaluating TG-1701 in combination with ublituximab and umbralisib in ibrutinib-resistant MCL.

Novel BTK Inhibitor Appears Promising in Mantle Cell Lymphoma and Other NHLs

Cemiplimab (Libtayo) received its approval from the FDA in September 2018 for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or radiation, and this therapy has now become the standard of care for this patient population.

approval of this PD-1 inhibitor for cutaneous squamous cell carcinoma

 was based on findings from the phase 2 EMPOWER-CSCC-1 study and 2 expansion cohorts from the phase 1 Study 1432 trial, but longer-term findings from the EMPOWER-CSCC-1 trial have showed continued responses in this patient population. 

 was recently presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting.

According to the 3-year follow-up, the trial demonstrated a clinically meaningful improvement with cemiplimab in patients with advanced cutaneous squamous cell carcinoma. The overall response rate (ORR) was 46.1%, which included a complete response (CR) rate of 16.1%. The median time to CR was 11.2 months, and the duration of response had not yet been reached, nor the overall survival (OS).

The Kaplan-Meier estimated probability of OS was 73.3% (95% CI, 66.1%-79.2%). The estimated median progression-free survival for all patients was 18.4 months (95% CI, 10.3-24.3), and the Kaplan-Meier estimated progression-free survival rate was 44.2% at 24 months (95% CI, 36.1%-52.1%).

 Danny Rischin, MD, director, Division of Cancer Medicine, head, Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, discussed the findings from the EMPOWER-CSCC-1 study of cemiplimab in advanced cutaneous squamous cell carcinoma that led to the drug’s FDA approval.

: What are what were the initial data seen with this agent that led to its approval?

 Cemiplimab is a monoclonal antibody directed against the PD-1 receptor, and it's been tested in this phase 2 trial in patients with advanced cutaneous squamous cell carcinoma. These are patients who no longer have metastatic disease and [are not eligible for] curative surgery or radiotherapy. In the data, the initial analyses from this study led to its registration approval in many jurisdictions around the world that have established this as the standard of care for patients advanced cutaneous squamous cell carcinoma. The report presented at ASCO this year represent longer follow up and updated data.

: Could you elaborate on the phase 2 trial, what it examined, who it is examining, and the methods of design?

 The phase 2 trial enrolled patients with advanced cutaneous squamous cell carcinoma, and there were 2 groups, including patients that had metastatic, including nodal, disease and patients who had advanced disease, so they were no longer suitable for surgical treatment or for radiotherapy. Among the eligibility criteria, it's important to emphasize these were immunocompetent patients, so patients who were immunosuppressed were not eligible for this study. There's been a number of groups enrolled, and the initial registration was based on the early groups. We presented the pooled analysis of groups 1-3; groups 1 and 3 enrolled patients with metastatic disease, and group 2 was advanced disease. Groups 1 and 2 received weight-based dosing of the cemiplimab, given every 2 weeks, and group 3 received a flat-dose of 350 mg every 3 weeks.

: What does the longer term follow up data look like?

 The key findings are this demonstrates the durability of responses. One of the impressive things over time with successive analysis is the increasing CR rate. If we look at what the ORR is, if you pull 193 patients, the ORR is 46%. If you look at group 1, where in the first analysis, the CR rate was 77%, and second analysis was 17%. It's now up to 20%, so patients were treated for a maximum 2 years, but we're seeing increasing durability of responses and even responses improving over time.

Now in terms of the duration of response, 88% of responses are ongoing in 12 months and 70% at 24 months, so most patients who responded with a CR or partial response have an ongoing response. If you look at the OS, 75% of patients alive at 2 years. Previously with available treatments, the average survival was no more than 15 months, so it's a marked improvement in outcomes for these patients who previously had incurable disease.

: How do you think this agent compares with others in this space?

 I think it's important to remember that this is an elderly population. The median age was 72 years, and the oldest patient on study was 96, so it's a bit different than your average oncology study. For previous agents, we had chemotherapy and perhaps EGFR inhibitors. They weren't well tolerated by this population. The responses were generally a short duration, and many patients weren't treated because it wasn't thought to be in their interest to treat them. On the other hand with cemiplimab, the great majority of patients, despite age, can be treated. There's no suggestion that people who are elderly, respond any differently or have any experience different. This is a drug you can give this population, irrespective of age, expecting a high probability of response and benefit.

: Are there any other efforts being made evaluating the use of this agent further that you wanted to highlight?

 With the exciting results in the advanced setting, there's now intense interest about whether you could move this drug up into earliest stages of disease and improve outcomes. Particularly in the advanced setting where surgery and post-operative radiotherapy are the standard, we've identified from previous work that there are high-risk groups that still don't do that well with the standard treatment, and we are running an adjuvant study now which is looking at these high-risk patients after they've had surgery and radiotherapy, randomizing them between cemiplimab and placebo. This will be an important trial to establish whether giving it earlier in the disease can improve survival.

Along similar lines, there's been some preliminary data using adjuvant cemiplimab in the same group of patients showing a very high response rate in a preliminary study. Based on that, there are further studies being done exploring that approach as well.

: Were there any other data presented this year at ASCO in cutaneous squamous cell carcinoma that you want to highlight?

 There’s another abstract looking at the impact of cemiplimab in these patients on quality of life, showing improvement in quality of life and improvements in pain control. This suggests not just durable responses but ongoing tangible symptomatic benefit to patients.

: What would you say is your take home message to your colleagues regarding this work?

 Cemiplimab is a very effective treatment for advanced cutaneous squamous cell carcinoma; it’s the standard of care, and you can actually treat the great majority of patients. There are a few contraindications, but age is not a contraindication. You can treat expecting high probability of response, and the majority of the responses will be durable.

In an interview with Targeted Oncology, Danny Rischin, MD, director, discussed the findings from the EMPOWER-CSCC-1 study of cemiplimab in advanced cutaneous squamous cell carcinoma that led to the drug’s FDA approval.

Cemiplimab Upholds Efficacy in 3-Year Follow-up for Advanced Cutaneous Squamous Cell Carcinoma

A New Drug Application (NDA) was submitted to the FDA for pralsetinib (BLU-667) for approval consideration as treatment of patients with advanced or metastatic 

-mutant medullary thyroid cancer (MTC) and 

"Pralsetinib has broad potential to address the medical needs of patients with RET-altered cancers, who have not traditionally benefited from targeted therapy even though their tumors have a known disease driver," said Andy Boral, MD, PhD, chief medical officer at Blueprint Medicines, in a statement. "There are now pending marketing applications for pralsetinib in 

-altered non-small cell lung cancer and thyroid cancers, supporting our goal to advance treatment standards for these patients. We are working closely with the FDA and aim to bring this promising treatment to patients as expeditiously as possible."

Pralsetinib, an investigational inhibitor of 

 fusions and mutations, recently demonstrated promise in a cohort of 13 patients with 

 fusion–positive MTC in the phase 1/2 ARROW study (NCT03037385) of pralsetinib in patients with select 

The MTC cohort achieved an objective response rate (ORR) of 74% in the treatment-naïve patients and an ORR of 60% in patients who had previous treatment. The disease control rate (DCR) observed with pralsetinib in patients with 

 fusion–positive thyroid cancers was 100% (95% CI, 72%-100%). The best response was a partial response (PR), which was achieved in 91% of patients. Additionally, stable disease was observed in 9 patients and no patients had progressive disease.

During a presentation of the ARROW trial held during the 

2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program

 lead author Vivek Subbiah, MD, associate professor, Department of Investigational Cancer Therapeutics and Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, stated, “this shows that pralsetinib is active and the treatment benefit is prolonged in these patients with 

 fusion–positive thyroid cancer. The responses were rapid, within 2 to 3 months of initiating treatment and pralsetinib was active post radioactive iodine.”

Notably, one 66-year old male patient with differentiated thyroid cancer had a favorable outcome with pralsetinib treatment. He achieved a deep and durable PR that lasted 18 months, and also had a 94% shrinkage of target lesions.

The safety analysis for the thyroid population showed consistency with the overall study population for which data were presented separately during ASCO 2020. Most of the adverse events (AEs) were grade 1 or 2 in severity. Treatment-related AEs were observed in 15% of the population and of them, the most frequent were anemia (33%), increased aminotransferase (33%), decreased white blood cell count (33%), hypertension (30%), increased alanine aminotransferase (26%), hyperphosphatemia (19%), and neutropenia (19%). No patients discontinued treatment as a result of AEs.

Overall, pralsetinib showed antitumor activity in 

 fusion–positive thyroid cancer and across multiple solid tumors and was well tolerated in patients. The ARROW study is ongoing and is actively enrolling patients.

The NDA for pralsetinib will be reviewed under the Real-Time Oncology Review pilot program, which was designed by the FDA’s Oncology Center of Excellence to review approval applications more efficiently.

In addition to MTC, Blueprint Medicines, Inc, the developer of pralsetinib is also seeking approval for pralsetinib as treatment of locally advanced or metastatic 

 fusion–positive non–small cell lung cancer. The application for this indication was accepted by the FDA in May 2020 and was granted a priority review; an application is also being validated by the European Medicines Agency. The FDA target action date for the lung cancer indication is November 23, 2020.

Blueprint Medicines announces submission of New Drug Application to FDA for pralsetinib for the treatment of advanced ret mutant and ret fusion-positive thyroid cancers. News release. Blueprint Medicines, Inc. July 1, 2020. Accessed July 1, 2020. 

Subbiah V, Hu MH, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors. 

. 2020: 38 (suppl; abstr 109). doi: 10.1200/JCO.2020.38.15_suppl.109

"Pralsetinib has broad potential to address the medical needs of patients with RET-altered cancers, who have not traditionally benefited from targeted therapy even though their tumors have a known disease driver."

FDA Approval Sought for Pralsetinib in RET+ Medullary Thyroid Cancer

In the phase II VISION study, tepotinib demonstrated promising responses and tumor shrinkage in patients with non–small cell lung cancer (NSCLC) who harbor the 

 exon 14 skipping mutation in 99 evaluable patients, which included 66 patients who were entered into the study based on results from a liquid biopsy assay.

Tepotinib, an oral MET inhibitor, induced an objective response rate of 46.5% (95% CI, 36.4%-56.8%) in the VISION study. The median duration of response was 11.1 months (95% CI, 7.2-not evaluable), and the disease control rate was 65.7% (95% CI, 55.4%-74.9%).

exon 14 skipping mutation occurs in approximately 3% to 4% of patients with NSCLC and more frequently in older adults. The mutation is also mutually exclusive with other frequently occurring genomic alterations. These mutations are often determined by tissue biopsies, but 

this trial uniquely demonstrated that this mutation can also be detected with a liquid biopsy assay

 and will produce the same benefit among patients.

“For this older patient population, this is important because you don't want to repeat the [tissue] biopsy to do the testing,” said Xiuning Le, MD, PhD. “If it can be with a very convenient blood draw, then you can detect if the patient has 

 exon 14 and subsequently confer the benefit.”

In the liquid biopsy cohort of patients, the objective response rate was 48.5% (95% CI, 36.0%-61.1%) versus 50.0% with tissue biopsy (95% CI, 36.8%-63.2%). The median duration of response was 9.9 months in the liquid biopsy cohort (95% CI, 7.2-NE) versus 14.0 months in the tissue biopsy cohort (95% CI, 7.3-NE), and the disease control rate was 65.2% (95% CI, 52.4%-76.5%) versus 69.7% (95% CI, 57.1%-80.4%), respectively.

, Le, of The University of Texas MD Anderson Cancer Center, discussed the results of the phase II VISION study. She also highlighted the role of liquid biopsy in this space.

 In the last, I will say 2 decades, we know a subset of lung cancers have the oncogene driver. If we can target appropriately those patients who derive significant benefit. So met exon 14 is a newer target. It becomes very clear in the last 5 years or so that for those patients, their tumors are dependent on my 

 exon 14 is skipped out due to the mutation, the 

 signaling just keeps going to drive the cancer cells growth. That's how it turned into a lung cancer.

Tepotinib, the small molecule inhibitor, is a specially designed small molecule that's an oral drug, once a day, [which is] very convenient. The drug targets the intracellular part of the 

, even with the 14 skipped. Tepotinib still works because it is an optimized molecule for 

 amplification, and the molecule is very potent. In the cell culture system, you only need a nanomolar in order to achieve a complete suppression and in patients. We also know this is very efficacious with more than 99% of target engagement. That's the idea of why we have established this oncogene driver. We have a smart designed small molecule inhibitor, so we wanted to test if this molecule will work in this patient population.

 This trial is a single-arm trial. The hypothesis is very strong, and the biology is completely laid out by the scientific community. Using a single-arm [design] rather than having a chemotherapy comparison arm is ethical because we don't want to deprive half of the patients who have to go on to chemotherapy, so it's a single-arm design.

Nowadays, I think the field, including the FDA, accept targeted therapy, and we can use this type of trial design because 

 exon 14 is not a very common alteration in lung cancer. This trial is a single-arm [study] but multicenter. We have over 130 sites globally enrolling patients in order for us to have a good cohort of patients to know if our hypothesis holds true.

 The trial is massively positive. What we've seen is, in the first 99 patients we can report on, the response rate is 46%. When we talk about response rates, the tumor has to shrink by 30%, and we call that a real response. In the 99 patients, we have 90% of tumor shrinkage, really showing the hypothesis was correct. The small molecule inhibitor worked on those tumors and induced tumor shrinkage. Some patients are shrinking more, and some tumors are shrinking less, but this is a positive results showing tepotinib works for this patient population.

: What did the safety profile look like for this agent?

 For tepotinib, we see the same signal of safety with the phase 1 portion of the trial. It is very well tolerated, even for the older patient population. The toxicities are the class effect meaning that for most of the inhibitors, because of how it inhibits oncogenic 

We see peripheral edema. We see patients have some nausea or upset gastrointestinal. We saw occasionally patient shave impaired liver function, but those are manageable and occur in a relatively small subset of patients.

: What population of patients with NSCLC have the

 The median age for MET exon 14 skipping mutations is 74 years old. In comparison, if we think about 

-mutant NSCLC or ALK-rearranged NSCLC, the patient population is much older because 

mutant patients are more around 50 to 60 years old; ALK patients are even younger, around 40 to 50 years old. For this patient population, it's so important to have a chemotherapy pill rather than trying to convince, say, a 78-year old to go through the very harsh traditional chemotherapy.

: What are the implications of the data from this study?

 Tepotinib has been approved in Japan for clinical use that happened in March 2020. The FDA gave us the Breakthrough [Therapy designation] for evaluation to see if tepotinib will be applicable for 

 exon 14-positive patients. We're hopeful that we can push tepotinib to the patient front sometime later this year.

: Are there any next steps planned for this trial?

 We're not planning on phase 3 because we think for a targeted therapy showing this much definitive efficacy, it is enough to convince the FDA to allow us to use this in the patient population in the near future. However, I think the field is constantly moving on. We show in this trial that the duration of response is 11 months, meaning if you're a patient and you get on to the study, I can tell you [there should be] 90% tumor shrinkage. Then if that happened, I will tell you, you can be on the drug for about a year, but what after that 1 year of benefit. When the tumor progresses, do we have combinations? Do we have newer agents to tackle the resistance? I think that will be the big question for the field coming up.

: What else would you like to highlight from this study?

 I think 1 particular point to stress from this trial is we also allowed the patients to be enrolled based on their liquid biopsy and based on their bladder tumor marker, so we had 66 patients [from this]. They had 

 exon 14 detected in the blood. When we compare the liquid cohort versus the tumor biopsy cohort, we see completely the same response.

For this older patient population, this is important because you don't want to repeat the [tissue] biopsy to do the testing. If it can be with a very convenient blood draw, then you can detect if the patient has 

 exon 14 and subsequently confer the benefit. I think that's very important information coming out from this study.

Furthermore, for this 66-patient cohort, we started to see that we can truly use the circulating tumor DNA to monitor the disease. In this paper, we show that in a subset of patients, the 

 exon 14 disappeared in their blood, and that coincides with the CT scan showing the significant tumor shrinkage.

Another note is this way to monitor the disease. Now we're waiting to see when the data is more mature to see if that will coincide with the disease progression. Can we help to predict when we need something else? What's the resistant mechanism? I think that's a very interesting part of we're looking forward to in the data.

: Do you see the role of liquid biopsy becoming more prevalent in lung cancer?

 I will say yes because I think liquid biopsy and tissue biopsy are complementary to each other. Liquid biopsy is very convenient and very non-invasive to the patient, and it can be done at multiple time points. Over the course of treatment, however, there are information we cannot learn from the liquid biopsy. For example, certain immunotherapy-related markers, like PD-L1, cannot be done because the sequencing fragments are much smaller than the real tissue DNA sequencing.

Certain research cannot be done just by liquid biopsy, but I think liquid biopsy will become more and more important, both in the clinical practice and also in the translational research.

In an interview with Targeted Oncology, Xiuning Le, MD, PhD, discussed the results of the phase II VISION study, which evaluated tepotinib in patients with advanced non-small cell lung cancer and harbor the MET exon 14 skipping mutation. She also highlighted the role of liquid biopsy in this space.

Positive Tepotinib Data Underscore Value of Liquid Biopsies in Non-Small Cell Lung Cancer

The FDA has granted approval to avelumab (Bavencio) as a frontline maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma who have not progressed with frontline platinum-based chemotherapy.

This is the first and only immunotherapeutic option approved by the FDA that has demonstrated significant overall survival (OS) benefit in the frontline setting in a phase 3 trial. In the JAVELIN Bladder 100 study, avelumab maintenance extended OS by 50% compared with the standard of care.

“As the first immunotherapy to demonstrate a statistically significant improvement in OS in the first-line setting in locally advanced or metastatic urothelial carcinoma, the FDA approval of avelumab is 1 of the most significant advances in the treatment paradigm in this setting in 30 years,” said Petros Grivas, MD, PhD, 1 of the principal investigators in the JAVELIN Bladder 100 trial, in a statement. Grivas is director of the Genitourinary Cancers Program at UW Medicine. “With median overall survival of more than 21 months measured from randomization, the longest overall survival in a phase 3 trial in advanced urothelial carcinoma, the JAVELIN Bladder 100 regimen with avelumab as a first-line switch maintenance treatment has the potential to become a new standard of care based on its proven ability to reinforce the benefit (response or stable disease) of induction chemotherapy and extend the lives of patients with this devastating disease.”

these positive findings from the phase 3 JAVELIN Bladder 100 study

, which were recently presented during the 2020 American Society of Clinical Oncology Virtual Scientific Program. The trial demonstrated a 7.1-month improvement in the median OS with frontline avelumab maintenance combined with best supportive care (BSC) compared with BSC alone.

The median OS was 21.4 months with avelumab (95% CI, 19.9-26.1) versus 14.3 months with BSC alone (95% CI, 12.9-17.9), and this was a statistically significant improvement, demonstrating a 31% reduction in the risk of death in the overall population (HR, 0.69; 95% CI, 0.56-0.86; 2-sided 

In the multicenter, international, open-label, parallel-arm JAVELIN Bladder 100 study, 700 patients with unresectable locally advanced or metastatic urothelial cancer were randomized to receive either avelumab plus BSC (n = 350) or BSC alone (n = 350). Patients had to have received 4 to 6 cycles prior cycles of standard gemcitabine with either cisplatin or carboplatin and achieve a complete response, partial response, or stable disease. Patients received their treatment between 4 and 10 weeks after induction chemotherapy. Overall, 51% (n = 358) of the patients had tumors that were PD-L1 positive.

The median follow-up was 19.6 months in the avelumab arm and 19.2 months in the control arm. Among patients with PD-L1–positive tumors, the median OS had not yet been reached in the avelumab arm compared with 17.1 months in the control arm (HR, 0.56; 95% CI, 0.40-0.79; 

The median progression-free survival (PFS) per blinded independent central review in the overall population was 3.7 months with avelumab versus 2 months without (HR, 0.62; 95% CI, 0.52-0.75; 

 <.001). The HR for PFS also favored the avelumab arm in the PD-L1–positive group (HR, 0.56; 95% CI, 0.43-0.73).

All-grade “any-cause” adverse events (AEs) occurred in 98% of patients in the avelumab arm versus 77.7% in the control, and grade 3/4 AEs occurred in 47.4% versus 25.2%, respectively. The most common grade 3 or greater AEs in the avelumab versus control arms included urinary tract infection (4.4% vs 2.6%), anemia (3.8% vs 2.9%), hematuria (1.7% vs 1.4%), fatigue (1.7% vs 0.6%), and back pain (1.2% vs 2.3%), respectively.

Avelumab was administered to patients intravenously at 10 mg/kg every 2 weeks in 4-week cycles. BSC could include antibiotics, nutritional supportive, correction of metabolic disorders, and symptom control and pain management.

The current standard of care in the frontline setting for this patient population is platinum-based chemotherapy. However, most patients will progress within 9 months of initiation of treatment, and only 5% with metastatic disease will live longer than 5 years. For patients who do not progress following treatment with platinum-based chemotherapy, avelumab is administered as a frontline maintenance therapy until either disease progression or unacceptable toxicity occur.

Avelumab is also FDA approved for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The JAVELIN Bladder 100 trial served as confirmation for the continued approval of avelumab in this setting. The FDA has therefore converted the accelerated approval to a full approval.

FDA approves Bavencio as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma. News Release. Pfizer. June 30, 2020. Accessed July 1, 2020.

Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract LBA1.

The FDA approved avelumab as a frontline maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma who have not progressed with frontline platinum-based chemotherapy.

Avelumab Approved by FDA for the Treatment of Locally Advanced Urothelial Carcinoma

Survival rates were significantly improved with the addition of trastuzumab (Herceptin) to chemotherapy in patients with uterine serous carcinoma (USC), a rare and aggressive form of endometrial cancer. The findings are from a phase 2 trial (NCT01367002) published in 

“The randomized, multi-institutional phase 2 trial studied 58 women with USC whose tumors expressed high levels of the HER2 protein, which is known to drive several forms of cancer in women,” said Alessandro Santin, MD, professor of gynecology, obstetrics & reproductive sciences, leader of the Disease Aligned Research Team of the Gynecologic Oncology Program at Smilow Cancer Hospital and Yale Cancer Center, and senior study author, in a statement.

The study explored the use of carboplatin and paclitaxel chemotherapy with or without trastuzumab in patients with advanced or recurrent uterine serous papillary carcinoma who had overexpressed HER2 by immunohistochemistry or fluorescence in situ hybridization.

In the experimental arm, patients received 6 cycles of carboplatin/paclitaxel plus trastuzumab followed by maintenance trastuzumab until disease progression or unacceptable toxicity. The study looked at progression-free survival (PFS) as the primary end point and secondary end points included overall survival (OS) and toxicity.

A total of 61 patients were followed for a median of 25.9 months. According to the updated survival results, the median PFS achieved with trastuzumab plus chemotherapy was 12.9 months compared with 8.0 months in the control arm (HR, 0.46; 90% CI, 0.28-0.76; 

 = .005). In the subset of 41 patients with stage III to IV disease who were treatment-naïve, the median PFS was 17.7 months with the trastuzumab combination versus 9.3 months with the control treatment (HR, 0.44; 90% CI, 0.23-0.83; 

 = .015). Finally, in the recurrent disease subgroup, the median PFS was 9.2 with the addition of trastuzumab to chemotherapy versus 9.2 months with the control (HR, 0.12; 90% CI, 0.03-0.48; 

Overall survival also favored the trastuzumab/chemotherapy arm. The median OS was 29.6 months with trastuzumab and chemotherapy versus 24.4 months with the control (HR,0.58; 90% CI, 0.34-0.99; 

 = .046). Among treatment-naïve patients with stage III to IV disease, the benefit of trastuzumab/chemotherapy was most evident as the median OS was not yet reached versus 24.4 months (HR, 0.49; 90% CI, 0.25-0.97; 

The safety analysis showed that trastuzumab was well tolerated in patients, said Santin. Also, both treatment arms demonstrated similar toxicity.

Preclinical research around the combination of trastuzumab and chemotherapy ultimately led tochanges in the National Comprehensive Cancer Network (NCCN) guidelines in 2018. The NCCN now recommend this combination for the treatment of patients with HER2-positive USC.

“With the revision of the NCCN guidelines, everybody started using it,” Santin said. Now that the final results for the trial are published, he expects much broader worldwide adoption of the combination.

1. Yale cancer center study validates combination therapy for aggressive endometrial cancer. News release. Yale cancer center. June 29, 2020. Accessed June 30, 2020. 

2. Fader AN, Roque DM, Siegel E, et al. Randomized phase ii trial of carboplatin–paclitaxel compared with carboplatin–paclitaxel–trastuzumab in advanced (stage iii–iv) or recurrent uterine serous carcinomas that overexpress her2/neu (nct01367002): updated overall survival analysis. 

. Published online June 29, 2020. doi:10.1158/1078-0432.ccr-20-0953

The addition of trastuzumab to chemotherapy in patients with uterine serous carcinoma had superior outcome compared with chemotherapy alone.

Trastuzumab Added to Chemotherapy Improves Survival in Uterine Serous Carcinoma

Nancy U. Lin, MD, associate professor of medicine at Harvard Medical School; associate chief of the Division of Breast Oncology at the Susan F. Smith Center for Women's Cancers; and director of the Metastatic Breast Cancer Program at the Dana-Farber Cancer Institute, discusses the latest findings from the HER2CLIMB study (NCT02614794) of either tucatinib (Tukysa) or placebo, added to trastuzumab (Herceptin) and capecitabine (Xeloda), for patients with previously treated HER2-positive metastatic breast cancer who have brain metastases.

The HER2CLIMB trial enrolled about 600 patients, of which 291 patients had brain metastases at baseline, which Lin says is a unique feature of this clinical trial. Of the 291 patients, 60% had new or active brain metastases when entering the study. She and the other investigators were looking at outcomes of patients with brain metastases enrolled on HER2CLIMB.

With the tucatinib regimen, the investigators found the intracranial response rate was higher. About half of patients on the triplet achieved a central nervous system (CNS) partial response or better compared with about 20% who received the placebo regimen. Lin says that more importantly, there was a prolongation of the CNS progression-free survival, which was defined as time from randomization to CNS progression or death. CNS progression was reduced by about two-thirds for patients receiving tucatinib, and there was a 5-month absolute improvement in median time to CNS progression or death.

There was a significant improvement in overall survival for the brain metastasis population receiving the triplet regimen. The hazard ratio for survival was 0.58, and there was an absolute improvement of about 6 months for the median overall survival with tucatinib in this difficult-to-treat patient population, according to Lin.

<< View more resources and information for HER2-positive breast cancer

Nancy U. Lin, MD, discusses the latest findings from the HER2CLIMB study of either tucatinib or placebo, added to trastuzumab and capecitabine, for patients with previously treated HER2-positive metastatic breast cancer who have brain metastases.

HER2CLIMB Study Shows Efficacy in HER2 Breast Cancer With Brain Metastases

Challenges Associated with GIST Management

Mutations in Gastrointestinal Stromal Tumors

GIST Mutations: Are Some Worse Than Others?

GIST Mutations: Treatment Decision Factors

Key opinion leaders discuss the evolving treatment paradigm for relapsed/refractory gastrointestinal stromal tumors, and provide an overview of supplemental data presented at the ASCO (American Society of Clinical Oncology) 2020 Annual Meeting.

Expanding Options for Relapsed/Refractory Gastrointestinal Stromal Tumors

In June 2020, the FDA approved 6 drugs across multiple malignancies, a few of which were ahead of the Prescription Drug User Fee Act target action date. The FDA also granted Priority Review to 1 agent in advanced prostate cancer and granted Orphan Drug and Fast Track designations to a slew of oncologic drugs.

June FDA actions also revealed plans to review approval applications, with and without convening the Oncologic Drug Advisory Committee.

Here is a look back at the FDA happenings from the month of June 2020:

BLA for Ropeginterferon Alfa-2b as PV Treatment Accepted by the FDA

On June 4, 2020, the FDA accepted a Biologics License Application (BLA) for ropeginterferon alfa-2b, which is intended for the treatment of patients with polycythemia vera in the absence of splenomegaly. A decision on this BLA is expected in early 2021.

Margetuximab Gains FDA Orphan Drug Designation in Gastric/GEJ Cancer

The FDA granted margetuximab an Orphan Drug designation on June 5, 2020, for the treatment of patients with gastric and gastroesophageal junction cancer.

FDA Approves Nivolumab for Unresectable Esophageal Squamous Cell Carcinoma

On June 11, 2020, the FDA granted approval to nivolumab (Opdivo) for the treatment of patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma after receiving prior fluoropyrimidine- and platinum-based chemotherapy.

A Pegfilgrastim Biosimilar Has Received Approval from the FDA

The FDA granted approval to pegfilgrastim-apgf (Nyvepria), a biosimilar of pegfilgrastim (Neulasta), on June 11, 2020, which is indicated to decrease the incidence of infection due to febrile neutropenia in patients with non-myeloid malignancies who are receiving myelosuppressive anti-cancer agents associated with a clinically significant incidence of febrile neutropenia.

Berubicin Granted Orphan Drug Designation for Treatment of Malignant Gliomas

On June 12, 2020, the FDA granted Orphan Drug designation to berubicin an anthracycline anticancer drug intended for the treatment of malignant gliomas.

FDA Grants Orphan Drug Designation to DKN-01 for Gastric/GEJ Cancer

The FDA granted an Orphan Drug designation to DKN-01 on June 12, 2020, for the treatment of patients with gastric and gastroesophageal junction cancer.

FDA Grants Breakthrough Therapy Designation to Vorasidenib CDx in 

On June 15, 2020, the Oncomine Precision Assay was granted a Breakthrough Therapy designation by the FDA to detect isocitrate dehydrogenase 1 and 2 mutations in patients with low-grade glioma who may be eligible for treatment with vorasidenib (AG-881), a first-in-class IDH1/IDH2 inhibitor.

FDA Expanded Approval for Preventative Vaccine of HPV-Associated Oropharyngeal and Other Head and Neck Cancers

The FDA approved an expanded indication for GARDASIL 9 on June 15, 2020, for the prevention of oropharyngeal cancers, as well as other head and neck cancers, caused by human papillomavirus types 16, 18, 31, 33, 45, 52, and 58.

Gemtuzumab Ozogamicin FDA Approval Extended to Pediatric CD33-Positive Acute Myeloid Leukemia

On June 16, 2020, The FDA expanded the approval of gemtuzumab ozogamicin (Mylotarg) to include an indication for the treatment of newly diagnosed pediatric patients with CD33-positive acute myeloid leukemia, which includes patients as young as 1 month old.

Liposomal Irinotecan Combo Granted FDA Fast Track Designation for Advanced PDAC

A liposomal irinotecan (Onivyde) combination was granted FDA Fast Track designation on June 17, 2020, for the treatment of untreated and unresectable, locally advanced or metastatic pancreatic ductal adenocarcinoma.

Rolling NDA Submitted to FDA for Umbralisib as Treatment of Marginal Zone, FollicularLymphomas

On June 17, 2020, a rolling submission of a New Drug Application (NDA) was completed, requesting accelerated approval of umbralisib as treatment of patients with previously treated marginal zone lymphoma and follicular lymphoma.

FoundationOne CDx Approved for Detecting TMB-H Solid Tumors Eligible for Pembrolizumab

The FDA approved the use of FoundationOne CDx on July 17, 2020, as a companion diagnostic for pembrolizumab (Keytruda) to identify patients with tumor mutational burden–high solid tumors who would benefit from treatment with the immunotherapy.

Fruquitinib Receives FDA Fast Track Designation for Metastatic Colorectal Cancer

On June 18, 2020, fruquitinib (Frutiga) was granted Fast Track designation for the treatment of patients with metastatic colorectal cancer who have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and anti-VEGF therapy, as well as anti-EGFR therapy for 

FDA’s ODAC to Review Belantamab Mafodotin BLA for R/R Multiple Myeloma

On June 22, 2020, the FDA announced plans to convene a meeting of the Oncologic Drugs Advisory Committee to review the BLA for belantamab mafodotin as treated of patients with relapsed or refractory multiple myeloma

Here is a look back at the FDA happenings from the month of June 2020.