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

Articles

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

The introduction of immunotherapy to the treatment paradigms of esophageal and gastric cancers has been an exciting advance, said Namrata (Neena) Vijayvergia, MD, who added that although agents, such as nivolumab (Opdivo), are not yet approved by the FDA in the adjuvant or metastatic settings, they should be considered for use based on National Comprehensive Cancer Network (NCCN) recommendations.

“Experts put out these guidelines for a reason,” said Vijayvergia. “There are phase 3 data supporting [the use of immunotherapy in esophageal and gastric cancers].”

On January 20, 2021, the FDA granted a priority review to a supplemental biologics license application (BLA) for adjuvant nivolumab (Opdivo) in patients with resected esophageal or gastroesophageal junction (GEJ) cancer following neoadjuvant chemoradiation treatment.

Also, on January 20, 2021, the FDA granted a priority review to a supplemental BLA for nivolumab in combination with a fluoropyrimidine- and platinum-containing chemotherapy for use in patients with advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma.

® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Vijayvergia, assistant chief of Gastrointestinal Medical Oncology, assistant professor in the Department of Hematology/Oncology, and medical director of Medical Oncology at Fox Chase Cancer Center Partners, of Fox Chase Cancer Center, discussed the emerging role of immunotherapy in resectable and metastatic esophageal and gastric cancers, as well as key nuances that could complicate these agents’ utility in clinical practice.

®:How do the results of the CheckMate-577 trial support the use of nivolumab as adjuvant treatment for patients with esophageal cancer?

:The CheckMate-577 study was very exciting in terms of adjuvant therapy for patients with esophageal cancer. [The results support the use of] adjuvant therapy with nivolumab [for these patients].

[CheckMate-577] compared nivolumab with placebo in patients who had treatment for their esophagus cancer and, at the time of surgery, did not have a complete pathological response. Giving those patients nivolumab in the adjuvant setting for up to 1 year led to an improvement in progression-free survival [PFS]. The disease-free survival was 22 months for the nivolumab group compared with 11 months for the placebo group. The curves started separating at around 3 months, and at around 6 months, they separated further. The separation continued for a long time, which is a really exciting finding. [Nivolumab] is something that is going to hopefully get [FDA] approval in [the adjuvant] setting soon. Interestingly, this study included patients with squamous and adenocarcinoma, so [adjuvant nivolumab] works for both [patient populations].

Should chemoimmunotherapy be considered for patients with metastatic esophageal cancer?

In [the metastatic] setting, esophageal and gastric cancer are differentiated from each other.

There are new data [regarding] the role of adding immunotherapy with pembrolizumab [Keytruda] to chemotherapy for patients with esophageal cancer. The KEYNOTE-590 trial [enrolled] patients with locally advanced and unresectable metastatic esophageal adenocarcinoma or squamous cell carcinoma. Patients were randomized to receive chemotherapy, which was cisplatin and 5-fluorouracil, with pembrolizumab or placebo. The primary end point was overall survival [OS] and PFS.

Interestingly, in this study, most patients, not just those who had a CPS greater than 10, benefited from the addition of pembrolizumab to chemotherapy with a hazard ratio [HR] of 0.73. Obviously, the extent of benefit improved in patients who had squamous cell carcinomas, as well as those who had PD-L1 [expression] greater than 10%.

What data support the use of immunotherapy in metastatic gastric cancer?

In terms of gastric cancer, we had the CheckMate-649 study that was presented at [the 2020] ESMO [Virtual Congress] that suggested the addition of nivolumab to chemotherapy in patients with a CPS greater than 5 was associated with an improvement in OS and response rate. The OS was 11 months [with chemotherapy alone] vs 14 months [with nivolumab/chemotherapy], favoring the combination arm. The study’s primary end point was to look at patients with a CPS of greater than 5 for PD-L1 [expression], but when [the investigators] looked at the entire population, the benefit was maintained [with nivolumab] in all patients. However, that was not the primary end point. The outcome of the study was that adding nivolumab to oxaliplatin-based chemotherapy was beneficial in patients who have a CPS greater than 5.

Apart from [CheckMate-649], there were 2 other studies that complicated the picture a little bit. There was the ATTRACTION-4 trial, as well as the KEYNOTE-062 trial, which had suggested that the benefit of immunotherapy was not that [significant]. In the KEYNOTE-062 trial, some benefit [was observed] in PFS, but not much in OS, meaning there wasn’t much benefit to adding pembrolizumab to chemotherapy.

However, in patients who had a CPS greater than 10, pembrolizumab alone was very effective. Unfortunately, this was not a primary end point of the study and this was more of a secondary analysis. Hence, we cannot take [pembrolizumab monotherapy] to the frontline [setting], but it is beneficial. In patients who are frail and cannot get chemotherapy [but] have a CPS greater than 10, using single-agent pembrolizumab is absolutely reasonable and should be considered.

What could explain the conflicting results observed in the KEYNOTE-062, ATTRACTION-4, and CheckMate-649 trials?

Trying to understand why one [immunotherapy] worked and one didn’t is a little confusing, but patient selection is very important. Interestingly enough, if we look [at the data] and compare these 3 trials, the KEYNOTE-062 trial compared with the ATTRACTION-4 trial and the CheckMate-649 trial used a cisplatin-based regimen rather than oxaliplatin. [The discrepancy] could be that the chemotherapy backbone was different.

Second, the primary study population in ATTRACTION-4 included all-comers, and only 16% of patients were PD-L1 selected. In CheckMate-649, 60% of patients had a CPS greater than 5, so [the population] was more selected for PD-L1 positivity [compared with ATTRACTION-4]. In the KEYNOTE-062 trial, only 36% of patients had a CPS greater than 10.

Also, the [study] locations [were different]. The ATTRACTION-4 trial was done in Asia, [whereas] the KEYNOTE-062 and CheckMate-649 studies were done worldwide.

There were a lot of differences in these studies and people are attributing [the conflicting results] to the chemotherapy backbone in the KEYNOTE-062 trial vs the nivolumab studies. Also, the higher enrichment of PD-L1 in the CheckMate-649 study [may have contributed] to the overall benefit; 82% of patients had a CPS greater than 1 and 60% had a CPS greater than 5 in that study.

Having seen these data, do you adhere to the NCCN guidelines that recommend immunotherapy?

Absolutely. Even though these agents are not approved by the FDA, they are under review by the FDA. The NCCN guidelines recommend nivolumab as a category 1 indication in the adjuvant setting for [patients with] esophagus cancer. For patients with gastric cancer who are HER2 negative and have a CPS greater than 5, adding nivolumab [to chemotherapy] is recommended. Similarly, adding immunotherapy for patients with esophageal cancer [is recommended].

Could there be any overlap between biomarkers such as PD-L1 and microsatellite instability status that could be used identify a specific population of patients that benefit most from immunotherapy?

Interestingly, the KEYNOTE-062 trial tried to do this testing. In the study, about 5% of patients in the pembrolizumab alone–arm were MSI-high [(MSI-H) vs], about 7% in the chemotherapy-alone arm, and about 8% in the pembrolizumab plus chemotherapy arm. A very interesting finding showed that there was a collection of MSI-H tumors that were enriched for PD-L1. If we look at the benefits of therapy in those patients, there is a clear benefit to pembrolizumab plus chemotherapy vs chemotherapy alone. The HRs were in the range of 0.2 to 0.3, [representing] very significant benefit in that area. Patients with MSI-H disease tend to enrich PD-L1 scoring.

There are some data in early-stage disease that patients with MSI-H disease may not respond very well to chemotherapy. That would even extend into the metastatic setting too, but we will see. At this point in time, I would definitely recommend pembrolizumab with or without chemotherapy for patients who are MSI-H.

Beyond immunotherapy, what other advances appear promising in gastric cancer?

There is also a lot of excitement around HER2-directed therapy. A study that was presented during the [2021 Gastrointestinal Cancers Symposium evaluated] 

-altered gastric cancer. [The data showed that] the addition of an FGFR inhibitor to FOLFOX chemotherapy improved outcomes.

Therefore, not only is immunotherapy buzzing in this space, a lot of targeted therapy options [are emerging]. Data with ZW25 [zanidatamab] were presented during the [2021 Gastrointestinal Cancers Symposium]. At the same time, [fam-trastuzumab deruxtecan-nxki (Enhertu)] was approved for second- and third-line HER2-positive gastric cancer.

testing become a standard marker to test for in practice?

 testing] is available, but we typically didn’t test for it because there were no therapies suggesting benefit until now. We’re still awaiting the phase 3 study to [reveal] more data, but it is something we can all work toward easily to figure how to [best identify 

US Food and Drug Administration accepts for priority review application for Opdivo® (nivolumab) as adjuvant therapy for patients with resected esophageal or gastroesophageal junction cancer. News release. Bristol Myers Squibb. January 20, 2021. Accessed March 12, 2021. http://bit.ly/3qDi6bT.

US Food and Drug Administration accepts for priority review application for Opdivo® (nivolumab) combined with chemotherapy as first-line treatment in metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma. News release. Bristol Myers Squibb. January 20, 2021. Accessed March 12, 2021. http://bit.ly/3a4b6OL.

This article was originally published on OncLive as, "

Immunotherapy Makes Waves in Gastroesophageal and Gastric Cancers

Namrata (Neena) Vijayvergia, MD, discusses the emerging role of immunotherapy in resectable and metastatic esophageal and gastric cancers, as well as key nuances that could complicate these agents’ utility in clinical practice.

Immunotherapy Enters Gastroesophageal and Gastric Cancers

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

Six indications for immune checkpoint inhibitors (ICIs) granted under the FDA’s accelerated approval process that later failed confirmatory clinical trials are being reassessed as the agency continues an industry-wide evaluation of the pathway.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) will hold a special 3-day public hearing on April 27 to 29 to allow expert commentary and patient testimony about the drugs, which are being used to treat triple-negative breast cancer (TNBC), metastatic urothelial carcinoma (mUC), gastric cancers, and hepatocellular carcinoma (HCC), the agency said Thursday. Based on the testimony, ODAC will consider whether the approvals should be withdrawn and whether additional trials should be conducted.1

The hearings will involve 2 indications for atezolizumab (Tecentriq), 3 for pembrolizumab (Keytruda), and 1 for nivolumab (Opdivo). Specifically, these indications will be reviewed:

Atezolizumab―in combination with nab-paclitaxel (Abraxane) for the treatment of patients with PD-L1–positive unresectable locally advanced or metastatic TNBC; and as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy

Pembrolizumab—as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy; for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that express PD-L1 and has progressed after 2 or more prior lines of therapy; and for patients with HCC previously treated with sorafenib (Nexavar)

Nivolumab—as a single agent for patients with HCC who previously received sorafenib

The FDA announced the hearings after a flurry of ICI indications were voluntarily withdrawn by pharmaceutical companies, starting in December 2020, as part of what the FDA described as an industry-wide evaluation of accelerated approvals in oncology “in which confirmatory trials did not confirm clinical benefit.”1

As part of the voluntary withdrawals, Bristol Myers Squibb and Merck said they will discontinue indications for nivolumab and pembrolizumab, respectively, for patients with metastatic small cell lung cancer whose disease has progressed after platinum-based chemotherapy and at least 1 other line of therapy; AstraZeneca will withdraw an indication for durvalumab (Imfinzi) for patients with locally advanced or mUC that has progressed after chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy; and Genentech will halt an indication for atezolizumab for patients with mUC previously treated with platinum-based chemotherapy.

Under the accelerated approval program, drugs are able to gain indications more quickly than through a regular approval timeline based on a surrogate end point. Pharmaceutical companies are then required to conduct a trial that confirms a clinical benefit; if the study is successful, the FDA grants regular approval status.2

The FDA’s Oncology Center of Excellence, which reviews and expedites the development of cancer drugs, requested the April hearings. The center is headed by Richard Pazdur, MD, a 2019 Giants of Cancer Care® award winner for Community Outreach who also is serving as acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.

“We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible,” Pazdur said in a statement.1 “The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies. However, when confirmatory trials do not confirm clinical benefit, a reevaluation must be performed to determine if the approval should be withdrawn.”

The hearings will give oncology experts outside of the FDA and patients with cancer an opportunity to describe their experiences with the drugs, said Pazdur. “After this advisory meeting, our staff will consider the committee’s comments and will make final decisions regarding continuing approval of each indication,” he said.

The accelerated approval pathway, introduced in 1992, has been “an extremely important mechanism to promote development of and access to therapies for serious or life-threatening illnesses,” according to a report by Friends of Cancer Research. Cancer therapies approved through the pathway reached patients a median of 3.4 years earlier than they would have if their status was dependent upon a primary clinical end point such as overall survival for approval, the report noted.3

Since the program began, only 6% of accelerated approvals for oncology drugs have been withdrawn, including the 4 recent ICI indications, the FDA said.1

Other indications for the ICIs under review are not affected by the April hearings or the announced withdrawals.

FDA in brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. FDA. March 11, 2021. Accessed March 11, 2021. 

Accelerated approval program. FDA. Updated October 26, 2020. Accessed March 11, 2021. 

Optimizing the use of accelerated approval. Friends of Cancer Research; 2020. Accessed March 11, 2021. https://bit.ly/38vV28l

FDA Will Reassess 6 Immunotherapy Accelerated Approvals

Six indications for immune checkpoint inhibitors granted under the FDA’s accelerated approval process that later failed confirmatory clinical trials are being reassessed as the agency continues an industry-wide evaluation of the pathway.

FDA to Reassess Accelerated Immunotherapy Approvals

Improving upon the widespread benefit of single-agent and combination immunotherapy by determining optimal patient selection and introducing combinations targeted toward novel pathways, such as TIGIT, has the potential to further the field of advanced non–small cell lung cancer (NSCLC), explained Davey B. Daniel, MD.

“Immunotherapy following chemotherapy is the standard of care, but there are questions that we need to answer,” said Daniel. “Although we have several options for chemotherapy plus immunotherapy, we don’t have a clear winner. We know that we can improve upon immunotherapy alone, and there are a number of interesting trials out there that may help us understand that.”

® Institutional Perspectives in Cancer webinar on lung cancer, Daniel, a medical oncologist at Tennessee Oncology, discussed key immunotherapy trials in advanced NSCLC and explained how the results can be extrapolated to clinical practice.

PACIFIC Trial Continues to Demonstrate Benefit With Single-Agent Durvalumab

Updated data from the phase 3 PACIFIC trial, which were presented during the 2020 ESMO Virtual Congress, showed that durvalumab (Imfinzi) continued to provide meaningful overall survival (OS) and progression-free survival (PFS) benefit at 4 years compared with placebo after concurrent chemoradiotherapy in patients with unresectable stage III NSCLC.

Patients in the PACIFIC trial were randomized 2:1 to receive 10 mg/kg of durvalumab every 2 weeks for up to 12 months (n = 476) or placebo every 2 weeks for up to 12 months (n = 237).

In the intention-to-treat (ITT) population, the median 4-year OS was 47.5 months with durvalumab compared with 29.1 months with placebo (stratified HR, 0.71; 95% CI, 0.57-0.88). The 4-year median PFS was 17.2 months versus 5.6 months, respectively (stratified HR, 0.55; 95% CI, 0.44-0.67).

“Historically, I would have told [patients that only about one-quarter of patients are cured. Now, with 4-year survival of almost 50%, it is really reassuring,” said Daniel.

Notably, all subpopulations, irrespective of sex, age at randomization, smoking status, NSCLC disease stage, tumor histologic type, prior definitive chemotherapy, and best response to prior therapy (complete response was not applicable), favored durvalumab versus placebo with regard to OS and PFS.

Post-hoc analyses revealed that patients with PD-L1 expression between 1% and 24% and 1% or greater would derive an OS survival benefit from durvalumab versus placebo. Patients with PD-L1 expression of less than 1% would not derive an OS benefit from durvalumab but would derive a PFS benefit.

 demonstrated improved OS and PFS with durvalumab versus placebo irrespective of prior chemotherapy (platinum and non-platinum) and radiation.

“We are not going to repeat this type of trial again. The control arm is always going to be immunotherapy [rather than] a placebo, so it is important to glean as much information as possible from these results,” explained Daniel.

Remaining questions regarding the PACIFIC trial include whether some patients should have received surgery, the overall benefit that patients with stage IIIA versus stage IIIB disease can derive from durvalumab, and the role of sensitizing mutations, particularly 

, in this treatment regimen. The ongoing phase 3 LAURA trial (NCT03521154) may provide some insight into the latter question by assessing the effects of osimertinib (Tagrisso) following chemoradiation in patients with unresectable stage III NSCLC, Daniel said.

Novel Chemoimmunotherapy Regimen Emerges From the CheckMate-9LA Study

In May 2020, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) plus 2 cycles of platinum-doublet chemotherapy was approved by the FDA for the up-front treatment of patients with metastatic or recurrent NSCLC who do not harbor 

CheckMate-9LA, the trial for which the regulatory decision was based on, randomized patients 1:1 to receive 360 mg of nivolumab every 3 weeks plus 1 mg/kg of ipilimumab every 6 weeks with chemotherapy every 3 weeks for 2 cycles (n = 361) versus chemotherapy every 3 weeks for 4 cycles with optional pemetrexed maintenance (n = 358).

“CheckMate-9LA was designed to overcome that dip in the survival curve that we saw in many of the prior immunotherapy trials,” said Daniel. “The thought was that the chemotherapy backbone would decrease the tumor volume and prevent hyperprogression while allowing the immunotherapy to [elicit] a long-standing, durable response we all hope for.”

Findings from the CheckMate-9LA trial, which were presented during the 2020 ASCO Virtual Scientific Program, showed that the median OS was 15.6 months with chemoimmunotherapy versus 10.9 months with chemotherapy alone (HR, 0.66; 95% CI, 0.55-0.80). The 12-months OS rates were 63% and 47%, respectively.

Additionally, the median PFS was 6.7 months with the chemoimmunotherapy combination versus 5.0 months with chemotherapy alone (HR, 0.68; 95% CI, 0.57-0.82). The 12-month PFS rates were 33% and 18%, respectively.

Patients with squamous and nonsquamous histologies benefitted from the chemoimmunotherapy regimen; however, patients with adenocarcinoma derived slightly more benefit, potentially due to the addition of maintenance pemetrexed, said Daniel. Moreover, across all PD-L1–expression subgroups, the chemoimmunotherapy regimen performed better versus chemotherapy alone.

“I care about where the tail continues to plateau in immunotherapy trials. CheckMate-9LA doesn’t have enough [follow up] to compare it with other [immunotherapy trials],” said Daniel. “The decision isn’t clear as to which [chemoimmunotherapy regimen] to choose, but this is another option.”

Anti-TIGIT Therapy Shows Promise in the CITYSCAPE Trial

“We know that immunotherapy alone with a PD-1/PD-L1 agent is attractive, but can we improve those outcomes?” Daniel asked. “The TIGIT pathway is likely [as] important as other checkpoint pathway proteins are. In early preclinical data, there [appears to be] synergistic activity between [TIGIT] and PD-L1 [inhibitors].”

The phase 2 CITYSCAPE trial randomized patients with 

 wild-type NSCLC with a PD-L1 tumor proportion score (TPS) of 1% or greater to 600 mg of intravenous (IV) tiragolumab plus 1200 mg of IV atezolizumab (Tecentriq), both every 3 weeks, or placebo plus atezolizumab.

Initial findings from the study, which were presented during the 2020 ASCO Virtual Scientific Program, showed an overall response rate (ORR) of 37% with tiragolumab/atezolizumab (n = 67) versus 21% with placebo/atezolizumab (n = 68) in the ITT population. Patients with PD-L1 TPS status of 50% or more had an ORR of 66% with tiragolumab versus 24% with placebo. Patients with PD-L1 TPS status between 1% and 49% had ORRs of 16% and 18%, respectively.

The median PFS in the ITT population was 5.55 months in the tiragolumab-containing arm versus 3.88 months with placebo (HR, 0.58; 95% CI, 0.38-0.89). The median PFS was not reached in patients with high PD-L1 expression who received tiragolumab versus 4.11 months with placebo (HR, 0.30; 95% CI, 0.15-0.61).

Notably, in January 2021, the FDA granted a breakthrough therapy designation to tiragolumab plus atezolizumab for the frontline treatment of patients with metastatic NSCLC whose tumors highly express PD-L1 and are 

 Moreover, the confirmatory phase 3 SKYSCRAPER-01 trial (NCT04294810) is evaluating the anti-TIGIT antibody plus atezolizumab versus placebo/atezolizumab in treatment-naïve patients with locally advanced, unresectable or metastatic, PD-L1–selected NSCLC.7

1. Faivre-Finn C, Vincente D, Kurata T, et al. Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. 

 2020;31(suppl 4):S1178-S1179. doi:10.1016/j.annonc.2020.08.2281

2. Faivre-Finn C, Spigel DR, Senan S, et al. Impact of prior chemoradiotherapy-related variables on outcomes with durvalumab in unresectable stage III NSCLC (PACIFIC). 

 2021;151:30-38. doi:10.1016/j.lungcan.2020.11.024

3. U.S. Food and Drug Administration approves Opdivo (nivolumab) + Yervoy (ipilimumab) combined with limited chemotherapy as first-line treatment of metastatic or recurrent non-small cell lung cancer. Published May 26, 2020. Accessed January 19, 2021. https://bit.ly/2yxso7U

4. Reck M, Ciuleanu TE, Cobo Dols M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. 

. 2020;38(suppl 15)9501. doi:10.1200/JCO.2020.38.15_suppl.9501

5. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). 

. 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503

6. Roche’s novel anti-TIGIT tiragolumab granted FDA breakthrough therapy designation in combination with Tecentriq for PD-L1-high non-small cell lung cancer. News release. Roche. January 5, 2021. Accessed January 19, 2021. http://bit.ly/2LoNrj2

7. A study of tiragolumab in combination with atezolizumab compared with placebo in combination with atezolizumab in patients with previously untreated locally advanced unresectable or metastatic PD-L1-selected non-small cell lung cancer (SKYSCRAPER-01). ClinicalTrials.gov. Posted March 4, 2020. Updated December 31, 2020. http://bit.ly/2YaVCmx

Immunotherapy Keeps Impressing in Advanced NSCLC, With Improvements on the Horizon

Immunotherapy continues to improve upon the treatment of non-small cell lung cancer, and there are more exciting advancements on the horizon.

Immunotherapy Only Gets Better in NSCLC

Pembrolizumab (Keytruda) combined with ipilimumab (Yervoy) did not improve survival and had higher rates of toxicity compared with pembrolizumab monotherapy as a first-line treatment for patients with metastatic non—small cell lung cancer (NSCLC) who had a PD-L1 tumor proportion score (TPS) of 50% or greater, and did not harbor EGFR or ALK aberrations, according to findings of the phase 3 KEYNOTE-598 trial that were presented at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer.

Results showed that the median overall survival (OS) was 21.4 months for patients who received pembrolizumab/ipilimumab versus 21.9 months for those who received the PD-1 inhibitor alone (HR, 1.08; 95% CI, 0.85-1.37; P = .74). The restricted mean survival time differences were —0.56 at the maximum observation time and –0.52 at 2 years, which met the study’s futility criteria.

Additionally, the median progression-free survival (PFS) was 8.2 months and 8.4 months for the combination and monotherapy arms, respectively (HR, 1.06; 95% CI, 0.86-1.30; P = .72).

Based on the observed efficacy and safety, an external data monitoring committee recommended that the study be stopped due to futility and that patients discontinue treatment from both ipilimumab and placebo, explained lead study author Michael Boyer, MBBS, FRACP,&#8239;PhD.

"This means that pembrolizumab monotherapy remains a standard of care first-line treatment for this group of patients,” said Boyer, clinical professor of medicine at the Chris O’Brien Lifehouse and the Central Clinical School of the University of Sydney, in Sydney, Australia.

In the multicenter, phase 3 KEYNOTE-598 trial (NCT03302234), which was comprised of centers in North America, Europe, and Asia, investigators sought to determine whether the addition of ipilimumab to pembrolizumab could improve efficacy versus single-agent pembrolizumab in patients with metastatic NSCLC whose PD-L1 TPS was at least 50% and did not harbor EGFR or ALK aberrations.

To be eligible for enrollment, patients had stage IV NSCLC, could not have received prior systemic therapy, no known untreated central nervous system metastases, and no more than 1 measurable lesion per RECIST v1.1 criteria.

Patients were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks for up to 35 cycles with ipilimumab at 1 mg/kg every 6 weeks (n = 284) or saline placebo (n = 284) for up to 6 cycles.

Stratification factors included ECOG performance score (0 vs 1), region (East Asia vs not East Asia), and histology (squamous vs nonsquamous). The primary end points were PFS and OS, both of which were assessed by the stratified log-rank test in the intent-to-treat population. Key secondary end points were objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 criteria by blinded independent central review and safety.

The protocol-specified first interim analysis was set to occur when approximately 255 deaths occurred and an estimated 1 year had passed since the last patient was randomized to treatment. Nonbinding futility criteria at this analysis were differences in the restricted mean survival time between the combination and pembrolizumab/placebo of less than or equal to 0.2 at the maximum observation time and less than or equal to 0.1 at 2 years of follow-up.

Additionally, 372 events occurred for PFS and 272 deaths at this time point.

The PFS and OS data in patient subgroups were consistent with the overall trial results, Boyer added. However, he noted that tumor mutational burden has not yet been studied as a subgroup.

Further data showed that the ORR was 45.4% in both arms. The median DOR was 16.1 months and 17.3 months for the ipilimumab/pembrolizumab and placebo/pembrolizumab groups, respectively.

Regarding safety, there were 76.2% of treatment-related adverse events (AEs) in the ipilimumab/pembrolizumab group compared with 68.3% for the pembrolizumab/placebo arm, the most common of which were pruritus (20.6% with pembrolizumab/ipilimumab vs 14.9% with pembrolizumab/placebo), rash (17.4% vs 10.7%, respectively), and hypothyroidism (14.2% vs 11.4%). Immune-mediated AEs occurred in 20.2% of pembrolizumab/ipilimumab-treated patients and 7.8% of pembrolizumab/placebo-treated patients.

AEs of grades 3 to 5 occurred in 35.1% and 19.6% of patients, respectively; and serious AEs were in 27.7% and 13.9% of patients, respectively. AEs led to death in 7 patients on pembrolizumab/ipilimumab versus 0 in the single-agent pembrolizumab arm.

Patients were on a median 5.6 months with ipilimumab versus 8.8 months with placebo; the median number of 3-week cycles was 10 with the combination versus 15 with the pembrolizumab/placebo arm.

1. Boyer M. Pembrolizumab plus ipilimumab vs pembrolizumab plus placebo as 1L therapy for metastatic NSCLC of PD-L1 TPS ≥50%: KEYNOTE-598. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.09

2. Boyer M, Sendur MAN, Rodríguez-Abreu D, et al. Pembrolizumab plus ipilimumab or placebo for metastatic non—small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%: randomized, double-blind phase III KEYNOTE-598 study. J Clin Oncol. Published online January 29, 2021. doi:10.1200/JCO.20.03579

Pembrolizumab/Ipilimumab Combo Does Not Improve Survival, Shows Higher Toxicity in PD-L1+ NSCLC

Pembrolizumab (Keytruda) combined with ipilimumab (Yervoy) did not improve survival and had higher rates of toxicity compared with pembrolizumab monotherapy as a first-line treatment for patients with metastatic non–small cell lung cancer (NSCLC) who had a PD-L1 tumor proportion score (TPS) of 50% or greater, and did not harbor EGFR or ALK aberrations.

Pembrolizumab-Ipilimumab Combo Boosts Toxicity, Not Survival in NSCLC

The radiographic and pathologic responses that have been seen with checkpoint inhibitors in lung cancer bodes well for the use of neoadjuvant therapy. However, the relationship between response and long-term outcomes, specifically with regard to overall survival, will have to be teased out before they become standard practice, explained David Spigel, MD.

“Patients and partners have asked me whether we can use [neoadjuvant immunotherapy] now, and the answer is no. It’s not a standard way to treat lung cancer at this point,” said Spigel. “[However,] at the pace and way end points read out [by way of] pathologic response rates and disease-free survival, we [won’t be] waiting 5 or 10 years for these long-term outcomes. I’m guessing we’ll see some readouts in the next 1 to 3 years.”

® during a 2020 Institutional Perspectives in Cancer webinar on lung cancer, Spigel, chief scientific officer and director of the Lung Cancer Research Program, and principal investigator at Sarah Cannon Research Institute, discussed ongoing research with immunotherapy in early-stage lung cancer.

 Does immunotherapy have potential to be brought into neoadjuvant and adjuvant settings in lung cancer? 

 A lot is happening in early-stage lung cancer, [which was a setting in which] we didn’t have any options. Even adjuvant platinum-based chemotherapy became something that was accepted only about 12 to 15 years ago.

There’s a lot of excitement, certainly about neoadjuvant approaches, but more pointedly [regarding the use of] immunotherapy in that space. Adjuvant immunotherapy is [also] going to find its way forward.

Even in limited-stage small cell lung cancer, a potentially curable setting, there are opportunities for developing other treatments like immunotherapy. 

How has immunotherapy helped to illustrate the value of neoadjuvant therapy? 

We’ve always had neoadjuvant therapy. [Even] when platinum-based adjuvant therapy became more standard, we were doing neoadjuvant therapy. Typically, it was: Could we find a role to downstage disease to make surgery possible or more successful? But neoadjuvant therapy kind of went away, because the pivotal, randomized, registrational trials were in the adjuvant setting. There were some pivotal neoadjuvant studies, but adjuvant therapy just became kind of the accepted way to go, and neoadjuvant therapy was something we kind of thought about on a case-by-case basis, usually for more locally advanced settings, like stage III and obviously in settings like pancoast tumors, which still is the case. 

With immunotherapy, I give a lot of credit to Patrick Forde, MBBCh, and his team at Johns Hopkins Medicine, but certainly [investigators] in New York as well, who started to show the value of neoadjuvant immunotherapy. For a couple of years now, we have seen impressive radiographic and pathologic responses with very brief exposures to checkpoint inhibitors. I’ve seen patients have amazing, even complete responses at the time of surgery. Now, we’re waiting on randomized trials to see if this [should be a] standard [approach].

Is there sufficient evidence to suggest that a patient who achieves a pathologic complete response to neoadjuvant therapy will have a favorable outcome? What research is being done to determine the relationship between response to neoadjuvant and adjuvant therapy and prognosis? 

Plasma-based assays [may be able to] help us understand what’s going on with a patient who was treated for cure in the adjuvant setting. Can we monitor patients’ disease in the blood and see if they’ve cleared a clone or [whether] clones reemerge? A good friend and colleague, Charlie Swanton, [FRCP, BSc, PhD, of Crick Institute], has helped open our eyes to this possibility. Studies are in progress to look at this question.

Particularly for neoadjuvant studies, unlike in breast cancer, the lung cancer field is not as advanced in terms of understanding the impact of a pathologic complete response rate. It’s probably the same—–that the less tumor that’s present at the time of resection bodes well for a good prognosis down the road. We don’t know that as well in lung cancer, although it’s probably true. We need a little bit more work to understand whether the early findings at the time of surgery are a good surrogate for how patients do long term. 

If you’re going to use drugs, like osimertinib [Tagrisso] or atezolizumab [Tecentriq] in early-stage disease, should you ever use those strategies again, if and when a patient has disease recurrence down the road? How, what, and when should you use it? Those are questions we don’t know, and we’ll have to figure out [the answers to].

Where is research headed in the early-stage setting?

We’re all waiting for the early-stage trials with immunotherapy to read out. We’re waiting for some additional work with osimertinib in the stage III unresectable setting. We are waiting for new drugs to prove that new targets are important, like KRAS G12C in the stage IV setting. As new therapies make it into stage IV disease, the obvious question is going to be the value of those therapies in earlier stages of disease.

We have to get effective drugs in stage IV disease into earlier stages of cancer. However, we can’t assume it’s a one-size-fits-all approach, or that it’s going to work. Drugs that improve response rates don’t necessarily improve survival, so we have to solve that. 

Immunotherapy Could Restore the Value of Neoadjuvant Therapy in Lung Cancer.

Immunotherapy May Highlight Neoadjuvant Treatment's Use in Lung Cancer

“This combination of cabozantinib and nivolumab significantly improved key efficacy measures compared to sunitinib — progression-free survival, overall survival and objective response rate – while showing a low rate of treatment discontinuations due to side effects. The therapeutic benefit demonstrated in CheckMate -9ER and quality of life measures explored emphasize the role of this combination for patients with advanced kidney cancer,” said Toni Choueiri, MD, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School.

The approval is based off findings from the phase 3 CheckMate-9ER trial, which analyzed cabozantinib plus nivolumab compared to sunitinib in patients with previously untreated advanced or metastatic RCC. Results, which were published at the European Society of Medical Oncology Virtual Congress, showed that the combination improved overall survival and compared to the sunitinib arm.

CheckMate-9ER findings also showed that the cabozantinib/nivolumab arm doubled average progression-free survival (PFS) over the sunitinib arm, at 16.6 months and 8.3 months, respectively. Objective response rate was also doubled in the cabozantinib/nivolumab arm, 56% versus 27% respectively.

“While significant progress has been made in the treatment landscape for advanced kidney cancer over the last several years, patients still need more therapeutic options to treat this disease as we search for a possible cure,” said Bryan Lewis, President and Co-founder of KidneyCAN.

“As patients are living longer with advanced kidney cancer, focusing on the safety and effectiveness of new treatments has become even more important. The findings for the combination of Cabometyx and Opdivo in the CheckMate -9ER trial make the FDA approval of this combination a notable development for the patient community,” Lewis said.

Adverse events (AEs) with were consistent with what was previously seen with cabozantinib (a TKI inhibitor) and nivolumab (an immunotherapy agent). Common AEs that occurred in 20% or more of patients included: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough and upper respiratory tract infection

The FDA recommends the following dosage: 240 mg every 2 weeks of nivolumab via IV infusion or 480 mg every 4 weeks and 40 mg of cabozantinib orally every day without food until disease progression or unacceptable toxicity.

“With this important FDA approval, the combination is poised to become a standard in newly diagnosed metastatic kidney cancer,” Choueiri said.

The FDA approved cabozantinib (Cabometyx) plus nivolumab (Opdivo) for the frontline treatment of patients with advanced renal cell carcinoma (RCC).
 

FDA Approves Cabozantinib Plus Nivolumab for Frontline Advanced RCC

While the advent of immunotherapies like CAR T-cell therapy and checkpoint blockade have forever changed the cancer landscape, many patients who use these treatment modalities relapse. However, recent research in 

 may pave the way for more lasting remissions.

Regulating the fas protein may be the key in overcoming resistance in patients receiving immunotherapy treatment, such as CAR T-cell therapy.
 

Immuno-Oncology