The addition of sintilimab (Tyvt) to chemotherapy significantly improved progression-free survival (PFS) among patients with 

-mutated, nonsquamous non–small cell lung cancer (NSCLC) who disease progressed following EGFR TKI-targeted treatment. Sintilimab, a novel bevacizumab biosimilar injection (Byvasda), thus met the primary end point of the phase 3 ORIENT-31 trial (NCT03802240), leaving researchers optimistic about the future of nonsquamous NSCLC treatment. 

Data from the first interim analysis, which were reviewed by the independent data monitoring committee and were based on an assessment by the blinded independent radiographic review committee (BIRRC), showed a statistically significant and clinically meaningful PFS improvement with the combination vs pemetrexed/cisplatin alone in the intent-to-treat (ITT) population.

Moreover, sintilimab in combination with chemotherapy also demonstrated a trend toward a PFS benefit vs chemotherapy alone, although the data are not yet mature.

Additionally, the prespecified PFS futility analysis comparing sintilimab plus bevacizumab biosimilar injection and chemotherapy with sintilimab plus chemotherapy was not found to cross the futility stopping boundary. The addition of the biosimilar to sintilimab and chemotherapy has a numerical benefit.

No additional safety signals were reported with sintilimab and bevacizumab biosimilar injection.

Detailed findings from the trial will be shared at an upcoming medical conference.

“ORIENT-31 is the first prospective, double-blind, phase 3 study worldwide to demonstrate significant PFS benefit with an anti–PD-1 antibody combination therapy in this patient population,” Professor Shun Lu, Oncology Department of Shanghai Chest Hospital, and principal investigator of ORIENT-31, stated in a press release. “It has shown the clinical value of adding sintilimab plus bevacizumab biosimilar injection to platinum chemotherapy. This quadruple regimen has the potential to bring forth a new and more effective treatment option to patients with 

-mutated nonsquamous NSCLC following treatment with an EGFR TKI.”

ORIENT-31 enrolled patients with disease progression following a first- or second-generation EGFR TKI who had either confirmed 

-positive disease but progression on a third-generation EGFR TKI treatment. The trial also enrolled those who experienced progressive disease after first-line treatment with a third-generation EGFR TKI.

Study participants were randomized 1:1:1 to receive intravenous (IV) sintilimab at 200 mg every 3 weeks plus bevacizumab biosimilar injection at 15 mg/kg every 3 weeks and pemetrexed at 500 mg/m2 every 3 weeks and cisplatin at 75 mg/m2 every 3 weeks or sintilimab plus placebo 2 combined with pemetrexed/cisplatin or placebo 1 plus placebo 2 plus pemetrexed/cisplatin.2

Following a total of 4 cycles of combination therapy, participants will go on to receive maintenance treatment with sintilimab plus bevacizumab biosimilar injection and pemetrexed, sintilimab plus placebo 2 and pemetrexed, or placebo 1 plus placebo 2 and pemetrexed. Maintenance treatment will continue until radiographic disease progression, intolerable toxicity, or any other conditions that necessitate treatment discontinuation.

The trial seeks to enroll 480 participants, and the primary end point is PFS per BIRRC and based on RECIST v1.1 criteria. Key secondary end points comprise overall survival (OS), investigator-assessed PFS, objective response rate, and safety.

Previously, in May 2021, a biologics license application for the frontline use of sintilimab injection plus pemetrexed and platinum-based chemotherapy in patients with nonsquamous NSCLC was accepted by the FDA for review.3

The application was based on findings from the phase 3 ORIENT-11 trial (NCT03607539), which indicated that the combination resulted in a significant improvement in PFS compared with chemotherapy alone in this patient population.4 At a median follow-up of 8.9 months, the IRRC-assessed median PFS in the investigative and control arms was 8.9 months (95% CI, 7.1-11.3) and 5.0 months (95% CI, 4.8-6.2), respectively (HR, 0.482; 95% CI, 0.362-0.643; 

The Chinese, double-blind, randomized phase 3 ORIENT-11 study examined the safety and efficacy of sintilimab plus pemetrexed and platinum-based chemotherapy as a frontline treatment in 397 patients with nonsquamous NSCLC.

Patients had to have stage IIIB/C or IV disease and not be eligible to undergo surgery or receive local therapy. They also needed to have an ECOG performance status of 0 or 1 and have a tumor sample available for PD-L1 assessment. Patients were stratified by gender, type of platinum therapy (cisplatin vs carboplatin) and PD-L1 expression level (tumor proportion score [TPS] less than 1% vs 1% or higher).

Participants were randomized 2:1 to receive either sintilimab at 200 mg (n = 266) or placebo (n = 131) in combination with pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 or carboplatin at area under the curve (AUC) 5, every 3 weeks for 4 cycles.

Patients in the investigative arm received sintilimab at 200 mg every 3 weeks for up to 2 years; plus pemetrexed at 500 mg/m2 every 3 weeks; those in the control arm received placebo every 3 weeks for up to 24 months plus pemetrexed at the 500 mg/m2 every-3-week dosing schedule. Thereafter, patients on the control arm were permitted to cross over to receive sintilimab at 200 mg every 3 weeks for up to 24 months.

The primary objective of the trial was PFS per IRRC. Secondary end points included OS, response rate, duration of response (DOR), time to response, and safety. Efficacy was examined in the ITT population and safety data included all patients who received at least 1 dose of study treatment.

Additional data from the trial showed that PFS benefit correlated with PD-L1 expression level. The median PFS in patients with a TPS of less than 1% was 7.3 months (95% CI, 6.2–not reached [NR]) vs 5.1 months (95% CI, 4.6-7.8) with sintilimab and chemotherapy alone, respectively (HR, 0.664; 95% CI, 0.406-1.086). In those with a TPS of 1% to 49%, the median PFS was 7.1 months (95% CI, 6.2-9.2) and 4.8 months (95% CI, 2.5-8.0), respectively (HR, 0.503; 95% CI, 6.2-9.2). In those with the highest PD-L1 TPS of 50% or greater, the median PFS had not yet been reached (95% CI, 9.2–NR) with sintilimab vs 5.0 months (95% CI, 4.3-6.8) with chemotherapy alone (HR, 0.310; 95% CI, 0.197-0.489).

The addition of sintilimab was also found to result in an approximate 40% reduction in the risk of death vs chemotherapy alone, which was determined to be nominally significant (HR, 0.609; 95% CI, 0.400-0.926; 

= .01921). The 6-month OS rates in the investigative and control arms were 89.6% and 80.4%, respectively.

Moreover, the sintilimab combination induced an objective response rate (ORR) of 51.9% vs 29.8% with chemotherapy alone. The disease control rates achieved in the investigative and control arms were 86.8% and 75.6%, respectively. Time to response was shorter in the sintilimab arm vs the chemotherapy-alone arm, at 1.5 months and 2.6 months, respectively.

The most common toxicities included anemia, reduced neutrophil count, reduced white blood cell count, reduced platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, nausea, reduced appetite, asthenia, vomiting, constipation, and pyrexia.

Innovent announces ORIENT-31, a phase 3 study of sintilimab in patients with EGFR-mutated nonsquamous non-small cell lung cancer with prior EGFR-TKI treatment, has met primary endpoint. News release. Innovent Biologics, Inc. October 17, 2021. Accessed October 18, 2021. 

Sintilimab +/- IBI305 plus chemotherapy (pemetrexed + cisplatin) for EGFRm + locally advanced or metastasis non-squamous NSCLC patients after EGFR-TKI treatment failure. ClinicalTrials.gov. Updated April 9, 2020. Accessed October 18, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03802240

US FDA accepts regulatory submission for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of people with nonsquamous non-small cell lung cancer. News release. Innovent Biologics, Inc. May 18, 2021. Accessed October 18, 2021. 

Zhang Li, Yang Y, Wang Z, et al. ORIENT-11: sintilimab + pemetrexed + platinum as first-line therapy for locally advanced or metastatic non-squamous NSCLC. 

. 2020;15(10). doi:10.1016/j.jtho.2020.08.002

This article was originally published on OncLive as “Novel Sintilimab Combo Significantly Improves PFS in EGFR-Mutated Nonsquamous NSCLC”

Articles

Sintilimab, a bevacizumab biosimilar injection, met the primary end point of the phase 3 ORIENT-31 trial by significantly increasing progression-free survival in patients with EGFR-mutated, nonsquamous, non–small cell lung cancer. 

Sintilimab Plus Chemotherapy Induces Superior Survival in EGFR-Mutated Nonsquamous NSCLC

The FDA has approved atezolizumab (Tecentriq) as an adjuvant therapy to treat adults with stage II to IIA non-small-cell lung cancer (NSCLC) whose tumors harbor PD-L1, as demonstrated by an FDA-approved test, following resection and platinum-based chemotherapy, according to a press release by Roche.

The regulatory decision was informed by findings from an interim analysis of the phase 3 Impower010 study. Results demonstrated that atezolizumab therapy following surgery and platinum-based chemotherapy decreased the risk of disease recurrence or death by 34% (HR, 0.66; 95% CI, 0.50-0.88) among patients with advanced NSCLC and tumors with PD-L1 expression.

"[Atezolizumab] is now the first and only cancer immunotherapy available for adjuvant treatment of NSCLC, introducing a new era where people diagnosed with early lung cancer may have the opportunity to receive immunotherapy to increase their chances for cure,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche, stated in a press release. “Today’s landmark approval gives physicians and patients a new way to treat early lung cancer that has the potential to significantly reduce risk of cancer recurrence, after more than a decade with limited treatment advances in this setting.”

No new safety signals were detected. Among patients receiving atezolizumab, 1.8% experienced fatal adverse events (AEs) and 18% reported serious grade AEs. The most common AEs included pneumonia (1.8%), pneumonitis (1.6%), and pyrexia (1.2%). However, other toxicities included increased aspartate aminotransferase, blood creatinine, and alanine aminotransferase, as well as hyperkalemia, rash, cough, hypothyroidism, pyrexia, fatigue/asthenia, musculoskeletal pain, peripheral neuropathy, arthralgia, and pruritus.

“Too many patients with early-stage lung cancer experience disease recurrence following surgery. Now, the availability of immunotherapy following surgery and chemotherapy offers many patients new hope and a powerful new tool to reduce their risk of cancer relapse,” said Bonnie Addario, GO2 Foundation for Lung Cancer, sin the press release. “With this approval, it is more important than ever to screen for lung cancer early and test for PD-L1 at diagnosis to help bring this advance to the people who can benefit.

Notably, atezolizumab is also approved for genitourinary, skin, breast, gastrointestinal, gynecologic, and head and neck cancers. It is currently being evaluated as a monotherapy and in combination with other medicines across multiple different settings in solid tumors.

US FDA approves Roche's Tecentriq as adjuvant treatment for certain people with early non-small cell lung cancer. News release. Roche. October 15, 2021. Accessed October 15, 2021. 

Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). 

. 2021;39(suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500

Atezolizumab is the first immunotherapy approved in the adjuvant setting to treat NSCLC.

FDA Approves Atezolizumab to Treat Select NSCLC in Adjuvant Setting

indicate that 6 months following the second dose of the Pfizer-BioNTech COVID-19 vaccine, patients with solid tumors and individuals without cancer displayed similar levels of COVID-19 antibodies in their blood.

Results from the study showed that 79% of those with solid tumors were seropositive for the antibodies compared with 84% of healthy controls at 6 months after their second dose of the vaccine. However, antibody levels in both groups decreased significantly from the time of vaccination.

“In our study we saw that in all outcomes, including immunogenicity, infectivity rate throughout the 6-month period, and safety, patients with solid tumors depicted a similar trend as the general population,” said lead study author Irit Ben-Aharon, MD, PhD, director of the oncology division at Rambam Health Care Campus in Israel.

Though the available COVID-19 vaccines have shown high efficacy in the general population, their long-term safety and efficacy among patients with cancer had been underrepresented. Moreover, patients with cancer receiving cytotoxic therapy or immune modifying agents were not able to participate in other vaccine studies, and as such, there remains an unmet need to examine the efficacy of the vaccines in this group.

Although it had been suggested that all patients with cancer were at increased risk for COVID-19 infection, recent studies have shown that outcomes and manifestations differ significantly depending on the malignancy type and treatment. Furthermore, data on vaccine efficacy in patients with cancer have shown similar short-term efficacy and safety among patients with when compared with healthy controls.

In this study, investigators sought to examine the long-term safety and efficacy of the COVID-19 vaccine in this population at 6 months after vaccination.

The study enrolled patients with solid tumors receiving active anti-cancer therapy and followed their progress for 6 months after the administration of the second dose of the vaccine. Patients must have been receiving their cancer therapy throughout 6-month duration, as well.

In the study cohort overall, investigators enrolled 154 patients with solid tumors, in addition to 135 age-matched healthy controls. Of the original cohort, 88 patients were enrolled; 64 who met the inclusion criteria were subsequently added.

In the solid tumor cohort, the median age was 66 years (range, 32-87), and more than half of patients were male (55%). In the control cohort, 56% of individuals were women and the median age was 63 years old (range, 50-87).

Most of the patients with cancer enrolled presented with metastatic disease (84%), and the most common cancer types were gastrointestinal (36%), lung (23%), breast (17%), and genitourinary cancers (11%). Moreover, the most common anti-cancer treatment among patients was chemotherapy (62%), followed by biological agents (36%) and immunotherapy (30%).

Additional data showed that chemotherapy was more highly associated with seronegative serologic status vs other treatment modalities (27% vs 10%; odds ratio [OR], 0.31; 

 = .02), and women were more likely to be seropositive than men (93% vs 75%; OR, 0.21; 

Furthermore, there was 1 documented case of severe COVID-19 infection that required hospitalization in the cohort of patients with cancer.

In terms of safety, elevation of liver enzyme levels was reported in 10% of patients with cancer up to 6 weeks after receiving the first dose of the vaccine. Moreover, newly documented regional lymphadenopathy was reported on 5% of CT/PET scans. However, all adverse effects were resolved in all patients throughout the course of the study period.

Additionally, the vaccination led to anti-cancer treatment delays for 6% of patients with cancer, all of whom were receiving chemotherapy. Delays were most commonly due to neutropenia, mild thrombocytopenia, and neutropenia with herpes labialis.

“Our study indicates that the pattern of immunogenicity and efficacy of the [Pfizer-BioNTech COVID-19 vaccine] in patients with solid tumors on active intravenous anti-cancer treatment 6-months post vaccination resemble the pattern of the general population,” the study authors concluded. “Former subtle differences which were evident between the 2 cohorts shortly after vaccination disappeared throughout time. Nonetheless, due to uncertainty of the extended efficacy of the vaccine in the general population and recent reports on rising infection rates among vaccinated individuals, adherence to health care risk reduction recommendations is cardinal.”

Waldhorn I, Holland R, Goshen-Lago T, et al. Six month efficacy and toxicity profile of BNT162b2 vaccine in cancer patients with solid tumors. 

. Published online September 2, 2021. doi:10.1158/2159-8290.CD-21-1072

Six-month efficacy of Pfizer/BioNTech COVID-19 vaccine in patients with solid tumors similar to general population. News release. American Association for Cancer Research. September 2, 2021. Accessed September 2, 2021.

The Pfizer-BioNTech COVID-19 vaccine induces similar levels of COVID-19 antibodies in patients with solid cancer compared with people without cancer.



COVID-19 Vaccine Elicits Similar 6-Month Antibody Response in Both Patients with Solid Tumors and the General Population

For this episode of “The Vitals,” we spoke with Martin Dietrich, MD, PhD, an assistant professor of internal medicine at the University of Central Florida, a fellow of the American College of Physicians, and a medical oncologist at Florida Cancer Specialists & Research Institute. Dietrich highlighted some recent advances and ongoing research in stage III non–small cell lung cancer (NSCLC) and discussed some of the ways immunotherapy and targeted therapy has evolved in recent years.

Podcasts

“I think the biggest [change] that we’ve seen is the addition of adjuvant or consolidated chemotherapy following the completion of concurrent chemotherapy and radiation. We have seen the 4-year overall survival data now and the 5-year update from the PACIFIC study in the adjuvant setting, obviously confirming the initial signal that patients who have initiation of immunotherapy early carry a significant risk reduction for progression and overall survival…”

Expert Discusses Biggest Updates in NSCLC Treatment 

The ongoing phase 3 CheckMate-73L trial (NCT04026412) will appraise the safety and efficacy of nivolumab plus chemoradiation followed by nivolumab and ipilimumab (Yervoy) in patients with stage III non–small cell lung cancer (NSCLC) that is unable or not planned to be removed by surgery.

Oncology Nursing News® recently met with Sandra Duncan, RN, BSN, to discuss the potential ramifications of this trial for both nursing professionals and patients alike. Duncan is a clinical oncology research nurse who supports patients with cancer being screened or enrolled in clinical trials at the Georgia Cancer Center at Augusta University.

Although Duncan has worked as a nurse for 21 years at Augusta University, it wasn’t until recently that she made the transition to participating in clinical trial research. In this interview she also discussed how empowering and rewarding that career switch has been, as well as what her specific responsibilities have been in supporting the CheckMate-73L trial.

“I love it,” she began, at the beginning of the discussion. “I love what I'm doing. I feel like I am a connector for our potential subjects, working with our principal investigators and some other multi-specialty areas here at Augusta University with this particular study and, of course, the sponsor as well”.

 What has been your experience with the Checkmate 73L trial?

We had our site initiation visit in May of this year. We have yet to enroll the first patient, but our goal accrual here will be 4 patients over the next life of the clinical trial. I know we will meet that goal.

We have clinics on every Tuesday & Thursday. We also screen the patients that our other multidisciplinary physicians have, such as CT surgery, our radiation oncologist, and other medical oncologists. We actually screen their listing of patients. Since we have access to electronic health records (EHR), and since we can't meet all the patients, we screen based upon the eligibility and prescreen to see if they are potential patients at that time. … So, what we do is prescreen those clinics, and then we will, at that time, come up with any potential subjects before we actually have clinical or bring them in for clinic. So, we have an idea if that patient will meet eligibility requirements before being even approached at all.

We had 1 potential patient, unfortunately. I say unfortunately because when we got the referral, the patient already had received cardiothoracic surgery and was opted unresectable.

We use that as an educational piece to other multidisciplinaries and our tumor board to say, “This is the kind of patient that would have benefited from this type of clinical trial.” So, as we move forward, it's going to be continuing education, particularly because we have weekly tumor board meetings, where we talk about potential patients and re-education.

What are some of the unmet needs in NSCLC treatment right now?

I think what this particular clinical trial is simply going to do is give our patients more options. [If a patient says,] “I know I don't want surgery, then what else is out there for me?” That’s when we start discussing immunotherapy. I think that's one of the things that's needed for patients who do not opt to have surgery, many of them don't want to be in the hospital setting. This simply gives patients more options to have immunotherapy while doing radiation therapy than the 1-year maintenance treatment. That’s what is not available right now.

What are some of the challenges as that role of connecting the PI and all those moving components for a trial like this?

It is a communication challenge to make sure everybody receives the same message. So, I think for the efficiency and effectiveness, the challenge is ensuring that everybody hears the same message at the same time­­­–it is important to relay information to all parties at the same time. And that's not always possible. So therefore, as a study coordinator, you are constantly either emailing or calling and trying to make sure everybody knows who is on board: Did you check your emails? Did you do this? Where are we?

You are constantly trying to make sure all parties are on board. Because what you don't want is to have patients wait and delay their care. Being proactive and making sure that all parties are up-to-date is imperative, including the patients in the middle. We have to make sure in the middle of the circle that they have what they need because sometimes we have challenging cases. For example, one [case] we had recently, not for this clinical trial, a patient was in the waiting room for over an hour. [It is] just frustrating. So, our goal is to be as efficient as possible, and, therefore, improve the patient’s overall survival.

Do you think the results of Checkmate 73L trial could change how we approach this disease, particularly from a supportive care standpoint?

I do believe that. I think once the numbers or the data come back, it will reflect that this may become the overall standard of care for patients.

And what, in your opinion, will be the grand takeaway for nurses who are following this trial or are interested in this research?

For nurses that are [lung specialists], I think they they can become mouthpieces for family members or for the community, just to say, “Did you know this study exists?” - especially for the [patients] who do not opt to have surgery so other nurses can become spokesperson, if you will, indirectly, just helping to educate others about this clinical trial.

Sandra Duncan, RN, BSN, discusses her transition to clinical research, and what her responsibilities are like supporting the ongoing CheckMate-73L trial. 

The Role of a Nurse Coordinator in the CheckMate-73L Trial

The FDA has approved mobocertinib (Exkivity) for the 

indication of adult patients with locally advanced or metastatic non-small cell lung cancer

 (NSCLC) whose disease harbors an epidermal growth factor receptor (EGFR) exon 20 insertion mutation as detected by an FDA-approved test, either following or beyond platinum-based chemotherapy.

This first-in-class, oral tyrosine kinase inhibitor (TKI) is the first approved oral therapy engineered to target EGFR exon 20 insertion mutations, according to Takeda Pharmaceutical Company Limited, the manufacturer of the small-molecule TKI.

“EGFR Exon20 insertion+ NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi A. Jänne, MD, PhD, Dana Farber Cancer Institute, in a press release. “The approval of EXKIVITY (mobocertinib) marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses.”

The regulatory decision is based on findings from the phase 1/2 trial of Exkivity. In the trial, 114 patients with EGFR Exon20 insertions who had been previously treated with platinum-based therapy received mobocertinib at a 160-mg dosage. Findings revealed an overall response rate (ORR) of 28% through an independent review committee (IRC) and 35% through investigator analysis. The median duration of response (DOR) was 17.5 months. The median overall survival (OS) was 24 months, and the median progression-free survival (PFS) was 7.3 months. DOR, OS, and PFS were all determined by IRC.

Notable adverse events from the study drug included diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Patients and providers should be aware that there is a risk of interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea associated with the drug.

“Patients with EGFR Exon20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed, but also lacking targeted treatment options that can improve response rates,” added Marcia Horn, executive director, Exon 20 Group at ICAN, International Cancer Advocacy Network. “As a patient advocate working with EGFR Exon20 insertion+ NSCLC patients and their families every day for nearly five years, I am thrilled to witness continued progress in the fight against this devastating disease and am grateful for the patients, families, healthcare professionals and scientists across the globe who contributed to the approval of this promising targeted therapy.”

A confirmatory trial will determine continued approval for the indication.

Takeda’s Exkivity (mobocertinib) approved by US FDA as the first oral therapy specifically designed for patients with EGFR Exon20 insertion _NSCLC. Takeda. News release. Accessed September 15, 2021. https://www.businesswire.com/news/home/20210915006101/en/Takeda%E2%80%99s-EXKIVITY%E2%84%A2-mobocertinib-Approved-by-U.S.-FDA-as-the-First-Oral-Therapy-Specifically-Designed-for-Patients-with-EGFR-Exon20-Insertion-NSCLC

The FDA has green lit mobocertinib for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with an EGFR exon 20 insertion mutation. 



FDA Approves Mobocertinib for NSCLC with EGFR Exon 20 Insertion Mutations

Treating patients with resectable pleural mesothelioma with neoadjuvant cisplatin-pemetrexed plus atezolizumab (Tecentriq), followed by maintenance atezolizumab may be safe and effective, according to an updated analysis of the ongoing S1619 trial presented at the 2021 IASLC World Conference on Lung Cancer.

“When we speak about mesothelioma that is potentially surgically resectable, that is the patient population that we sort of consider potentially curable, although we know that recurrences occur,” explained Boris Sepesi, MD, The University of Texas MD Anderson Cancer Center. “The median survival in patients who undergo multimodality therapy that includes surgery range in different studies between 17 and 25 months… The aim of this study was really to test chemotherapy plus immunotherapy in surgically resectable mesothelioma based on the fact that these are occasionally immunogenic tumors that express PDL1 expression, which is associated with worse outcomes.”

The study sought to assess whether adding anti-PD-L1 inhibitors to neoadjuvant cisplatin-pemetrexed, followed by maintenance immunotherapy after surgical resection and adjuvant radiation would enhance T-cell activation against microscopic disease and potentially increase overall survival (OS) in patients with malignant pleural mesothelioma.

Overall, 21 patients successfully completed neoadjuvant therapy, although 7 were unable to proceed to surgical resection. Of those 7, 2 patients reported severe toxicity, 4 experienced disease progression, and 1 death occurred due to non-immune related renal and respiratory failure.

There were 18 patients with stable disease or partial response who were able to receive surgical resection, and 16 patients registered to receive maintenance atezolizumab for 1 year. Thus far, median progression-free survival is 18 months and OS has not been reached.

Participants were evaluable if they had received at least 2 cycles of the triplet neoadjuvant therapy, were chemo-naïve, had mesothelioma, and extended surgical staging. A total of 28 patients were screened between November 2017 and May 2020 with the intention of obtaining 24 eligible patients.

Patients were then administered the triple-combination regimen with the following dosage: 75 mg/m2 cisplatin, 500 mg/m2 pemetrexed, and 1200 mg IV atezolizumab every 3 weeks. As long as patients did not experience disease progression, they continued to resectable surgery. Following surgery, they were to be treated with 1 year of maintenance atezolizumab.

Within this pool of potential participants, 25 received at least 2 cycles of neoadjuvant cisplatin-pemetrexed-atezolizumab.

The median age of participants was 68 years. The majority of participants were Caucasian, and the patient pool was predominantly male. Four patients planned on receiving

extrapleural pneumonectomy (EPP) surgery, while 24 planned on receiving pleurectomy and decortication surgery (P/D).

The primary end point of the trial was to assess the safety and tolerability profiles, as well as better understand the feasibility, of 

neoadjuvant cisplatin-pemetrexed-atezolizumab treatment followed by surgery and maintenance atezolizumab. For the treatment to be considered safe or tolerable, there would be no reported grade 4 or 5 immune-related adverse events (irAEs). To be considered feasible, 75% of patients (18/24) needed to complete at least 1 dose of maintenance therapy.

The final analyses will separately assess patients who received EPP surgery and those who received P/D surgery for their resectable operation. Of the 18 that successfully received resection surgery, 17 received P/D and 1 received EPP. So far, 16 patients have registered to receive maintenance atezolizumab for 1 year. There are still 3 patients undergoing treatment with maintenance atelozimab therapy.

Investigators concluded that the triplet combination appeared to be reasonably tolerated in the patient population. There was only 1 patient who reported grade 4 or 5 AEs. Notably, that patient did experience multiple grade 4 AEs and 1 grade 5 AE. That patient experienced severe acute renal injury, sepsis, pneumonitis, and respiratory failure.

The most common neoadjuvant therapy-related AEs were nausea (n = 20), fatigue (n = 15), neutropenia (n = 11), anemia (n = 12), anorexia (n = 11), and vomiting (n = 7). Researchers also observed cases of hyponatremia (n = 5), creatinine increase (n = 6), constipation (n = 7), dysgeusia (n = 5), and infusion-related reactions (n = 3).

“These are some preliminary survival results which at this point seem rather encouraging although the median follow up is not the same as in some of the previous trials,” said Sepesi. “Some of these results are comparable to, [or] perhaps, slightly better to historical cohorts, but we will have to complete the trial, and complete the adequate follow-up to be able to make any conclusions from this regimen.”

“As always with mesothelioma, this trial highlights the challenging nature of the new adjuvant therapy, because of the heterogeneity of the disease, as well as how patients react as well as the difficult and complex surgical therapy,” he concluded. “However, I think this is a step forward in terms of complex treatment of mesothelioma.”

While Sepesi chose to refrain from speculating on the benefit of adding atezolizumab to the regimen, in a post-presentation discussion, he noted that future research will also need to look at patients based on nodal status (N0 vs N+) since those outcomes are different in surgically managed mesothelioma.

There are still 3 patients undergoing the therapy in this trial.

Tsao A, Qian L, Cetnar J, et al. A trial of neoadjuvant cisplatin-pemetrexed with atezolizumab combination and maintenance for resectable pleural mesothelioma. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021; Virtual. Absract OA13.01

Updates from the ongoing S1619 trial suggest that a triplet combination regimen of neoadjuvant cisplatin, pemetrexed, and atezolizumab is effective and tolerable in the treatment of patients with resectable pleural mesothelioma. 

Neoadjuvant Triplet Regimen Safe, Effective in Patients With Resectable Mesothelioma

Flexible patient-focused approaches may increase clinical trial accessibility and enrollment in international lung cancer clinical trials beyond the COVID-19 pandemic, shared Matthew P. Smeltzer, PhD, at a virtual press briefing during the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer.

Findings, which evaluated international lung cancer clinical trial enrollment before and throughout the pandemic, showed a derived benefit from flexibility in “place” and “time” to increase trial participation.

More specifically, trial sites reported that the most effective strategies to mitigate COVID–19-related challenges included telehealth visits, remote diagnostics, remote patient-reported symptoms, and remote consenting alternatives to address issues associated with trial “place.” To achieve flexibility in “time,” the findings suggested allowing delayed assessments and visits, as well as IRB changes.

“Overall, a more flexible approach, [and] removing unnecessary barriers may improve enrollment and access to clinical trials, even beyond the pandemic,” shared Smeltzer, an associate professor of epidemiology and biostatistics at the University of Memphis.

The study looked at the enrollment data from 173 clinical trial sites and 171 trials, across 45 countries. Data assessment included enrollment numbers from before the pandemic, in 2019, and continued across 2020 and 2021.

Significant disparities in enrollment were observed between 2019 and 2020. The average number of monthly trial enrollment shifted from 3.2 to 2.5 between April 2019 to April 2020. Similar changes were observed in May (3.4 to 1.8), June (3.1 to 1.5), July (3.2 to 1.7), and August (3.0 to 2.0).

The investigation considered results from a data collection survey which evaluated aggregate monthly enrollment for international lung cancer trials between 2019 to 2021, as well as from an action survey, which assessed the impact of COVID-19 on the conduct of clinical trials and identified mitigation strategies used.

“So, where the [changes] are the most discrepant was at the beginning of the pandemic and April to August. But we see, by September to December, the gap starts to close quite a bit,” explained Smeltzer. “And it looks like, relative to 2019, monthly 2020 enrollment started to rebound despite the drastic increase and total COVID-19 cases diagnosed each month across the world.”

Researchers then put together a survey to better understand how the pandemic specifically impacted the trial sites.

The surveys found that the most frequent site challenges included fewer eligible patients (67%), protocol compliance (61%), suspension of trials (60%), research staff availability (48%), and institutional closures (39%).

“Many trials were suspended,” Smeltzer summarized. “And so that was a challenge. Availability of research staff was [also] a major challenge, and institutional closure. These are all challenges that were sort of at the institutional level.”

The surveys also gained insight into the concerns and challenges faced by patients themselves. Sixty-three percent of patients reported that a willingness to visit trial sites was a challenge to participation. An ability to travel accounted for 60%, whereas access to trial site was reported to be a challenge by 52%. Forty percent of patients shared that an exposure-related quarantine impeded on their ability to participate in a trial, while 26% shared that a COVID-19 infection prevented their participation.

In addition, fear of COVID-19 infection (83%), travel restrictions (47%), securing transportation (38%), and lab-radiology access (14%) made up the bulk of concerns patients had in relation to lung cancer clinical trials between 2020 and 2021.

To respond to these challenges and concerns, trial sites implemented a variety of mitigation strategies. Besides the most effective strategies mentioned above, common mitigation strategies included modified monitoring requirements (44%), telehealth visits (43%), labs at non-study facilities (27%), modified required visits (25%), and mail-order medications (24%).

“We asked them ‘What were the most frequent mitigation strategies that they used? What did they do to try to improve the conduct of the trials both in terms of enrollment and compliance?’’’ said Smeltzer. “Modifying monitoring requirements was the No.1 response followed closely by telehealth visits.”

Other popular strategies involved radiology at non-study facilities (20%), altered trial schedules (19%), electronic consent processes (10%), and an altered consent process (7%).

“We think there's some good lessons learned here,” said Smeltzer. He concluded by sharing that the results of this trial provide a good base assessment into the rigor needed to maintain the value and quality of clinical trials while also allowing flexibility to ensure that trials are feasible, accessible, and patient friendly. Furthermore, researchers are optimistic that the results of this assessment will continue to be beneficial beyond the COVID-19 pandemic.

Smeltzer MP, Bunn PA, Clark R, et al. Study of the impacts of COVID-19 on international lung cancer clinical trials. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Virtual. PL02.09

International lung cancer clinical trial sites reported that flexibilities in time and place were effective strategies to mitigate COVID–19-related patient concerns and to increase participation. 

Modified Monitoring Requirements, Telehealth Increase Lung Cancer Clinical Trial Enrollment in COVID-19 Era

Mobocertinib (formerly TAK-788) induced improved patient-reported outcomes (PROs) in patients with previously treated non-small-cell lung cancer (NSCLC) harboring 

 exon 20 insertion mutations, according to a poster presentation of the EXCLAIM extension cohort made available as part of the 2021 World Conference on Lung Cancer.

In patients considered to have difficult-to-treat disease who were treated as part of a phase 1/2 trial (NCT02716116), superior PROs were evidenced by better core NSCLC symptoms within 2 months of treatment initiation which was maintained for the duration of therapy and was consistent with clinical activity.

“Overall health-related quality of life was maintained during therapy, despite the occurrence of adverse events such as rash and gastrointestinal-related symptoms,” Maria Rosario Garcia Campelo, MD, of the University Hospital A Coruña in Spain, said during a presentation of the data.

The objective of the current analysis was to evaluate PROs associated with daily oral mobocertinib at 160 mg daily in the discussed patient population. PRO tools used included the European Organisation for Research and Treatment of Cancer Core Quality-of-Life Questionnaire (EORTC QLQ-C30) for cancer-related functions and symptoms, the European Organisation for Research and Treatment of Cancer Core Quality-of-Life Questionnaire lung cancer module (EORTC QLQ-LC13) for lung cancer–specific symptoms, the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) and visual analogue scale (VAS) for general health-related quality of life, and selected items from Patient-Reported Outcomes–Common Terminology Criteria for Adverse Events Questionnaire (PRO-CTCAE) to assess symptomatic toxicity in these patients. Questionnaires were given prior to clinical evaluation or procedures at baseline, at select visits, and at 30 days following the last dose of treatment.

Compliance rates were above 80% for all instruments and were often above 90% for most cycles. At the data cutoff of November 1, 2020, 25 out of 96 patients (26%) remained on treatment with mobocertinib for a median time of treatment of 6.8 months (range, 0.0-18.8). Median patient age was 59 years (range, 27-80), with most patients being women (65%) and never smokers (73%) and the majority having adenocarcinoma histology (99%) and an ECOG performance status of 1 (71%). The median number of prior therapies was 1, with prior platinum-based chemotherapy accounting for 90% of patients, prior immunotherapy in 34%, and prior 

 inhibitors in 31%. Baseline brain metastases were present in 34% of patients.

Clinically meaningful lung cancer symptom improvement by EORTC QLQ-LC13 was defined as a 10-point or greater decrease in symptom score. At a median follow-up of 13.0 months (range, 0.7-18.8), clinically meaningful changes in dyspnea occurred in 54.4% of patients, with a mean change to baseline symptoms of –3.2 (

 = .019). Cough improved in 46.7% of patients with a mean baseline improvement of –9.3 (

 < .001). For chest pain, improvement occurred in 38.9% of patients with a mean baseline improvement of –8.2 (

 < .001). In over 50% of the patients examined, dyspnea, cough, and chest pain were improved or stable throughout the study.

By EORTC QLQ-C30, baseline scores were maintained or improved in most patients treated with mobocertinib, for a least square mean change of –1.8 (95% CI, –4.8 to 1.2; 

 = .235). By PRO-CTCAE, the majority of adverse effects of were not categorized in the 2 highest categories of “severe” or “very severe”, with only diarrhea and dry skin escalating to above 10% of events being in the highest categories (22.2% and 11.1%, respectively). By EQ-5D VAS, patient-reported general health-related quality of life remained largely stable during treatment. 

Previously reported data from the trial demonstrated efficacy of mobocertinib in this patient population, with a confirmed overall response rate of 28% (95% CI, 20%-37%), a median overall survival of 24.0 months (95% CI, 14.6-28.8), and a median progression-free survival was 7.3 months (95% CI, 5.5-9.2). The mechanism of action of mobocertinib is unique in that it selectively targets exon 20 insertion mutations in EGFR

“Exon 20 insertion mutations account for up to 12% of NSCLC tumors with 

 mutations. Most of these patients are treated in the first line with platinum-based chemotherapy, but their disease, unfortunately, progresses very rapidly,” Campelo said. Use of mobocertinib in these patients may fulfill an unmet clinical need.

Garcia Campelo MR, Zhou C, Ramalingam SS, et al. Mobocertinib (TAK-788) in EGFR exon 20 insertion+ metastatic NSCLC: patient-reported outcomes from EXCLAIM extension cohort. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Virtual. Abstract FP09.02.

Selectively targeting the EGFR exon insertion mutations was associated with improved outcomes in patients with previously treated non-small cell lung cancer. 



Patients Report Improved Outcomes Following Mobocertinib Treatment for NSCLC Subtype

The phase 3 CheckMate-73L trial (NCT04026412) is assessing the safety and efficacy of combining immunotherapy and chemotherapy with radiation in patients with stage III non–small cell lung cancer (NSCLC) that is unable or not planned to be removed by surgery.

Nagla Abdel Karim, MD, professor of medicine, medical director, Georgia Cancer, discussed how investigators plan to monitor patient responses and prepare for potential adverse events associated with treating patients with ipilimumab (Yervoy) plus nivolumab, along with chemotherapy.

“We are aware that patients can have inflammation of the esophagus, some difficulty swallowing, some inflammations. We have the nausea, the vomiting, the best supportive care works well to control those side effects,” she explained. “In addition, and if we are adding immunotherapy during that period of time, or later on in the consolidation.. we pay attention to the autoimmune side effects. That’s why we monitor the thyroid function, we monitor if patients get diarrhea, if there are sides of colitis or pneumonitis, if they have inflation of the lungs, if they get a shortness of breath, or just [are] out of breath while doing daily activities, we monitor oxygen level.”

Videos

Nagla Abdel Karim, MD, explains how researchers will address safety and manage potential adverse events in the ongoing phase 3 CheckMate-73L trial.

Lung Cancer