Virtual prehabilitation may improve patients’ physical activity level and exercise capacity before they go in for lung cancer surgery, according to recent research presented at the 2020 World Conference on Lung Cancer.

“Prehabilitation is the practice of enhancing a patient’s functional capacity before surgery, with the aim of improving post-operative outcomes,” explained co-study author Stephanie Wynne, BSc. “In lung cancer surgery, [prehabilitation] is associated with improved functional capacity and quality of life and reduced hospital length of stay, post-operative complications and readmission.”

Wynne explained that lung resection is the most common radical treatment for lung cancer, yet only 10-30% of individuals referred are actual candidates for the procedure, “due to their disease stage and a number of surgical risk factors, including advanced age or performance status, high comorbidities, and reduced cardiopulmonary reserve.” Prehabilitation may help.

While prehabilitation typically occurs in a face-to-face setting, an at-home option is particularly attractive amidst the COVID-19 pandemic.

The study included 20 patients who were undergoing lung surgery at a National Health Service Trust unit in London. They were all given a personalized home-based exercise program, and a diary to monitor compliance. Patients also had written advice and counseling for symptom management and had virtual follow-ups weekly or every other week.

Participants were assessed before and after the interventions on the following outcomes:

Physical activity levels (measured by the Godwin Leisure Time Exercise Questionnaire [GLTEQ])

Mood (measured by the Hospital Anxiety and Depression Scale [HADS])

Exercise capacity (measured by the 1-minute sit-to-stand (STS) test)

The majority (65%) of participants were female, and the average age was 68. At baseline, average MRC Dyspnoea scale score was 2; 45% of patients had 5 or more comorbidities; 70% had a history of smoking and 15% were classified as “vulnerable-mildly frail” per the Rockwood Clinical Frailty Score.

While there was no change in average MRC-Dysponea scale, HADs, or fatigue levels after the intervention, the researchers did see an average improvement of 45.9 points in the GLTEQ scores, and 100% of patients met recommended levels of physical activity. Additionally, the average STS score improved by 5.1 points, which exceeded the minimum clinically significant difference of +3. 

“To conclude, our findings demonstrate that remote, home-based prehab is feasible, [and it] may improve a patients’ pre-surgical physical activity and exercise level,” Wynne said. “This is pertinent given the ongoing uncertainty surrounding COVID-19 and its impact on face-to-face health care delivery.”

While this study showed that at-home prehabilitation may work in patients, the authors note it should be investigated further, especially for elderly or vulnerable patients who may have limited access to technology.

“We’re now designing a triage tool to best support patients based on their therapeutic needs and access to technology,” Wynne said.

Wynne S, Dickinson F. Providing thoracic prehabilitation during COVID-19: review of a virtual model. Presented at: 2020 World Conference on Lung Cancer. January 28-21, 2021.

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A virtual prehabilitaiton program improved patient outcomes before they underwent lung cancer surgery.
 

Virtual Prehabilitation Is Efficacious Before Lung Cancer Surgery

Patients with non-small cell lung cancer (NSCLC) who experience immune-related adverse events (irAEs) may have better survival outcomes than those without irAEs, according to research presented at the 2020 World Conference on Lung Cancer.

Additionally, patients with STK11 mutations tended to have a shorter progression-free survival (PFS) than those who had STK11 wildtype. In patients who presented with KRAS mutations, STK11 mutations also correlated with a lower 12-month overall survival (OS) rate.

The researchers analyzed the outcomes of patients with stage 3b/4 NSCLC who were tested for the STK11 mutation and were treated with immune checkpoint inhibitors between July 2014 and November 2019. In addition to determining the role of STK11 mutations and if occurrence of irAEs predicted immunotherapy response, the authors also wanted to determine the incidence of STK11 mutations and irAEs among Hispanic and non-Hispanic patients.

The study population included 96 patients who were SKT11 wildtype and 31 with an SKT11 mutation, both groups had a median age of 65 at diagnosis. Forty-eight patients experienced an irAE (median age, 70 years) and 77 patients were irAE-negative (median age, 66 years). Overall, there were 30 Hispanic patients involved: 8 harbored the SKT11 mutation, and 14 experienced an irAE.

STK11-Mutant Versus SKT11 Wildtype Outcomes

Median OS was higher in STK11 wildtype patients than it was in STK11-mutant patients (12.1 months versus 8.6 months, respectively; 

= 0.03). Twelve-month OS was also higher with the wildtype group (73% versus 55%; 

=0.03). Patients with an STK11 wildtype did have a slightly higher median PFS (6.3 months versus 5.6 months) and 12-month PFS (45% versus 43%), though those findings were not statistically significant (

When it came to STK11 and KRAS mutations together, patients with STK11 wildtype had a higher rate of 12-month OS than those with the STK11 mutation (70% versus 40%, respectively, 

However, the OS findings were not statistically significant (11.4 months versus 5.3 months; 

=0.13), nor were PFS findings in the KRAS-mutant group. Median PFS in the SKT11 wildtype group was 5.1 months and in the SKT11 group was 3 months.

Patients who experienced an irAE had statistically significant better PFS and OS outcomes.

Average PFS was 9.5 months in those who had an irAE, compared to 4.4 months in those who did not (

=0.005). Twelve-month PFS was also better in those who had an irAE than those who didn’t (60% versus 33%, respectively; 

When it came to OS, average OS was 14.2 months in the irAE-positive group and 7.3 months in the irAE-negative group (

<0.001). Twelve-months OS was also higher in the group who had an irAE, at 85%, compared to those who did not, 60% (

The most common irAEs were hypothyroidism, which was experienced by 35.7% of Hispanic irAE-positive patients and 14.7% of non-Hispanic irAE patients; rash (21.4% and 29.4%); and pneumonitis (7.1% and 5.9%).

The authors note the results indicate that the occurrence of irAEs may be useful in identifying possible responders to therapy. Therefore, they ask providers to monitor and manage those events carefully to maximize whatever benefits may come from therapy while also reducing risks.

They also mentioned that their findings should be further evaluated in larger studies in the future.

Raez Le, Uba R, North A, et al. STK11/LKB1, KRAS mutations and immune-related adverse events as predictors of response to immunotherapy in lung cancer. Presented at: 2021 World Conference on Lung Cancer Singapore, January 28-31, 2021.

Patients with non-small cell lung cancer (NSCLC) who experience immune-related adverse events (irAEs) may have better survival outcomes than those without irAEs.

Mutations, irAEs May Help Predict Immunotherapy Response 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. 

This article was originally published on OncLive as, "

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

Immunotherapy May Highlight Neoadjuvant Treatment's Use in Lung Cancer

Although lung-sparing lung nodule resection in the form of lesser resection is available to some patients with lung cancer, it is critical to tailor surgical interventions based on pathologic assessment results, said Henning Gaissert, MD, who added that utilizing a multimodal approach to treatment can help alleviate some of the burden of treatment selection.

“It is very challenging to [determine] the right surgical approach for each individual patient,” said Gaissert. “[Lung cancer] has changed over time and our sensitivity for what kind of lesions we wish to pursue has changed. We are now more interested in smaller lesions because we see fewer larger lesions. That has changed the outcome for lung cancer resection.”

However, some patients who undergo lesser resections may need to then undergo total lobectomy in order to decrease their risk of recurrence in the future.

“Surgeons need to revisit [patients after lesser resection] to determine whether they selected the best option,” said Gaissert. “Sometimes we may need to go back [to do a lobectomy] after completing an operation that we thought was already done.”

 during a 2020 Institutional Perspectives in Cancer webinar on lung cancer, Gaissert, chief of thoracic surgery at Newton-Wellesley Hospital in the Department of Surgery at Massachusetts General Hospital, discussed the importance of tailoring surgical resection strategies to individual patients with lung cancer, eliciting insight from a multimodality team, and implementing total lobectomy in certain patients to avoid future recurrences.

®: How have improvements in radiographic imaging affected the surgical management of lung nodules?

These strategies have evolved over time because we are better at diagnosing radiographically what is present pathologically. Our radiologists know how to better characterize lesions. These days, we are not only characterizing solid lesions, but we are most often characterizing mixed-attenuation lesions or lesions that are composed of solid and ground-glass opacity. Those are mainly lung adenocarcinomas.

Our sensitivity has changed. With that, we are seeing lesions that are on different parts of the malignancy have different degrees of malignancy. That means that we can consider lesser resections sometimes. That is not always straightforward because having a smaller lesion doesn’t always mean having an earlier[-stage] lesion. One can underestimate and overestimate disease. The decisions have not necessarily become easier, but the spectrum of lesions has changed. Thus, the spectrum of resection types has changed. Therefore, we are using a greater number of lesser resections, which has also provided us with different challenges.

How has the shift toward lesser resection created new challenges for surgeons and pathologists?

The main challenge is that for every individual patient we have to find the right resection. [We have had to determine when] not to apply lesser resections to lesions that have a greater potential to [spread] to the lymph nodes and [how to] not overuse a lobectomy in lesions that could be served with lesser resection. Because many of these decisions need to be made in the operating room, we are presenting pathologists with different challenges since we want to have all of the information that we saw on permanent pathology. In the past, we almost always selected lobectomy for resection. Then, the extent of the resection didn’t matter so much because we couldn’t vary the extent of resection.

Now, we start off with a lesser resection and ask our pathologists: Was that good enough? They sometimes feel overwhelmed in giving us that answer. We have [to] individually [select] patients in whom we may stop at a lesser resection, but then [we might have to] tell these patients that they require a greater resection with a lobectomy. That is a different challenge compared with 20 or 30 years ago.

In what ways should surgeons collaborate with pathologists and medical oncologists?

There is the collaboration between surgeons and pathologists. However, another collaboration needed is between medical oncologists and surgeons. For surgeons, the task is quite clear as it relates to their collaboration with oncologists. We cannot underestimate diseases. We have to recognize mediastinal lymph node involvement early. Then, if possible, we should refrain from resection and consult medical oncologists and radiation therapists. The challenge there is identifying all patients who may be candidates for multimodality therapy.

The other collaboration refers to patients who are rightfully undergoing surgical resection first and who are then found to have [extensive disease] into their lymph nodes. Those patients [are eligible] for adjuvant chemotherapy. Although these types of patients are not particularly challenging [to treat], surgeons [need] to identify what malignant potential the small lung nodule has. If we underestimate that, we will falsely select a lesser resection when a lobectomy would be [indicated]. We don’t always get that information from pathologists.

I’m referring to the class of patients that concerns me as a surgeon. These patients have cancers where cancer cells are present outside of the main tumor mass in airways. [This refers to tumor STAS (spread through air spaces)], and STAS is difficult to recognize on frozen sections. Yet, it matters because when we select a lesser resection, the outcome is not as good as with lobectomy. We will face some patients who had a lesser resection who will then be taken for a complete lobectomy. We’d like to avoid these situations, but they are not always avoidable [when] we try to select the most appropriate surgical resection.

What could provide reassurance that a lesser resection is the optimal approach?

I cannot foresee what the pathologists are going to come up with to identify all relevant factors. It could be that we are placing a lot of pressure on our pathologists to submit the specimen and a complete opinion. That is difficult because we are in the operating room waiting for the outcome of the pathologic examination. We give them perhaps a half hour or 45 minutes, but we do not give them an hour to make up their minds.

These challenges and tensions will persist. That means that we, [as surgeons], have strategies to deal with that. We have to prepare our patients that, during the operation, we may want to avoid lobectomy. However, the operation might consist of 2 stages where we have [to perform] a complete lobectomy if we do not have all the information during the [lesser resection]. That is a difficult discussion to have with an individual, but all of my patients who I recommended a second operation to forgive me. A less forgivable situation is if I don’t do the important second operation and the patient then has a higher risk of local recurrence and a higher risk of death.

I encourage surgeons and oncologists to consider a second operation if appropriate.

If there’s not complete confidence that a lesser resection will be sufficient, do you proceed with a lesser resection first or do you move forward with a lobectomy?

That is an excellent question that requires consideration of many individual points. Whenever I answer that question, I try to come up with individual examples.

I recently saw a woman in whom I did a wedge resection for a very small adenocarcinoma 7 or 8 years ago; I still follow her. I identified a very small ground-glass opacity [nodule] that was slowly enlarging and was deep in a contralateral lobe. I did a wedge resection on this patient, aided by placement of fiducial [markers] so that I could identify where that lesion was. Then, I agonized with a pathologist over the appropriateness of leaving the wedge resection.

[Ultimately], I decided to proceed with a lobectomy because the patient could tolerate it. Then, I got the pathology report back and saw other features of very small cancer with poor differentiation and micropapillary disease that I didn’t even consider at the time of [reviewing] the frozen section. That makes [moving beyond wedge resection] not only defensible, but it makes lobectomy the best possible procedure for this patient.

Those are just individual factors. I might have done a wedge resection. Then, I would have had to agonize with this patient over whether to do a lobectomy.

What benefits do a multidisciplinary approach bring to the surgical management of patients?

When we bring excellent radiologists and multidisciplinary colleagues to the table to review these radiographs carefully, we can deliver astonishing results. One result I find [impressive] from our Lung Nodule Clinic is that 40% of patients with lung cancer had lesions that were 10 mm or smaller in diameter. Also, the proportion of patients who underwent resection for benign lesions is quite small.

That happens when you bring people together to review treatment options. [It is important to elicit the help of] well-trained radiologists who can afford to specialize on chest disease alone. As we know, that is not the situation in the United States. I may be speaking to general radiologists who cannot afford to do that.

Then, the purpose of the Lung Nodule Clinic is also very important because we then have more than 1 set of eyes looking at seemingly small problems. [Establishing lung nodule clinics] is important to improve [care] and provide individual patients with the best possible advice.

Lung-Sparing Nodule Resection Gains Traction in Lung Cancer, But Needs Multidisciplinary Considerations.

Lung-Sparing Nodule Resection Needs Multidisciplinary Approach in Lung Cancer

Molecular testing is a critical component of the treatment selection process in lung cancer, as a host of effective drugs have since been developed to target alterations such as ALK, ROS1, and RET, according to Yujie Zhao, MD, PhD, who added that the integration of RNA-based sequencing into these strategies could potentially provide further benefit to patients.

“It’s paramount for patients to undergo molecular testing; this allows us to discover actionable alterations. We also encourage the use of liquid biopsies,” Zhao emphasized. “[Sometimes we are faced with the] issue of tissue availability; sometimes this can be due to limitations of local expertise. If that is the case, I would encourage [that you] consider sending patients to a tertiary center. There, interventional radiologists, or even thoracic surgeons, could help them obtain tissue for testing. I would also encourage the incorporation of RNA-based sequencing into your approach, as well.”

® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Zhao, an internist oncologist at Mayo Clinic, highlighted progress made with actionable alterations in lung cancer, the importance of molecular testing, and efforts needed to overcome resistance mechanisms to available targeted agents.

Several agents have been developed to target ALK alterations in this disease. Of course, there was crizotinib (Xalkori), and agents like alectinib (Alecensa) and brigatinib (Alunbrig) have since joined the treatment arsenal. How do these agents compare?

Alectinib has been compared head-to-head with crizotinib and this research showed superiority [with alectinib] in terms of progression-free survival and overall survival. Moreover, alectinib was found to have better central nervous system penetration and intracranial activity, which is a huge advantage.

Similar to alectinib, brigatinib has also demonstrated superior efficacy and excellent intracranial activity; this agent was [also found to] outperform crizotinib. The response rate was high with this drug and the responses appeared to be durable.

Lorlatinib (Lorbrena) has also emerged as an option for use following progression on crizotinib. What is the hope for moving this agent into earlier lines of treatment?

This agent shows great activity in later-line settings and has very promising activity in the first-line setting, [as was seen in the phase 3 CROWN trial]. However, the agent has not been FDA approved [for use] in the frontline setting yet.

Shifting to RET fusions, the field has seen a lot of activity over the past year with drugs that have shown impressive activity. Could you discuss selpercatinib (Retevmo) and the data that have been reported from the first-in-human LIBRETTO-001 trial?

LIBRETTO-001 is a phase 1/2 study that evaluated the role of selpercatinib in patients with RET-altered lung and thyroid cancers. This study had multiple arms. In non—small cell lung cancer, the agent was found to work very well. The response rate was around 85% in the treatment-naïve patients and 64% in those who received prior platinum-based chemotherapy. These response rates were excellent.

Pralsetinib (Gavreto) also obtained regulatory approval in September 2020 based on data from the ARROW trial. What is the efficacy of this agent, particularly in those with brain metastases?

Pralsetinib has demonstrated great activity. The overall response rate in patients [previously treated with platinum chemotherapy] was 55%; [it was 66% in treatment-naïve patients]. Three patients, out of 9, had an intracranial complete response to treatment. Although the number of patients was small, the response rates reported were impressive.

With all of these additional actionable targets, what is your approach for molecular testing?

Molecular testing is very important. When it comes to fusions such as ALK, ROS1, and RET, the treatments available are very effective and well tolerated. The responses [elicited with these agents] are also very durable. It's important that we do not miss any patients who could potentially be candidates for these therapies.

Broad panel DNA-based next-generation sequencing (NGS) is commonly used in this space; however, there are some limitations with this approach. In research published by [investigators from the] Memorial Sloan Kettering Cancer Center, 232 patients did not have any actionable alterations, per DNA-based NGS results. However, when RNA sequencing was performed, it was discovered that 33 patients did have actionable fusions. Among these patients, some had MET exon 14 skipping mutations, 10 patients had ROS1 fusions, 4 patients had ALK alterations, 3 had RET fusions or rearrangements, and a few more had NTRK gene fusions. With this said, I would encourage my colleagues to consider both DNA-based NGS and also RNA-based sequencing. This may be more costly and take more time [for the results] to turnaround, but it will provide great value to our patients.

How are you utilizing liquid biopsies in practice?

Liquid biopsies are important because we can have trouble obtaining tissue. Many times, we send out a test, and we are told that the tissue [sample] is insufficient. As such, liquid biopsies, which utilize circulating DNA in the peripheral blood, have been very helpful.

I once had a patient who harbored a RET fusion and we wanted to put her on trial, but we couldn't find her initial biopsy. We ordered a liquid biopsy, which confirmed that she had a RET fusion and as a result, we were able to enroll this patient to a clinical trial. It’s also important to note that liquid biopsies have a quicker turnaround than tissue biopsies.

What is some of the work that is being done to address resistance to these agents?

We understand that patients will eventually develop resistance to these targeted therapies.

With this said, we must determine which mechanisms need to be overcome and how we can do that.

For all these therapies, [we know of] 2 types of resistance mechanisms. One would be a mechanism that the cancer cell utilizes to bypass the effect of the drug. For example, there can be an activation of additional pathways in the cancer cells. Another mechanism could be a mutation that arose in the target genes, such as ALK, ROS1, or RET. Those mutations will enable the kinase to avoid the interaction or interfere with the interaction of the drug with the target.

These are the types of alterations that can lead to drug resistance. A few ongoing trials are evaluating new agents that could potentially overcome this challenge.

Need for Molecular Testing in Lung Cancer Is Underscored as Additional Targets Emerge

More Targets Discovered, More Molecular Testing Needed in Lung Cancer

Bristol Myers Squibb announced that it is withdrawing nivolumab (Opdivo) from the US market for the treatment of patients with small cell lung cancer (SCLC) whose disease progressed after chemotherapy and 1 or more prior lines of therapy.

The indication was granted accelerated approval in 2018 after promising response rates and duration of response was seen with nivolumab in patients with SCLC in the phase 1/2 CheckMate-032 trial. However, confirmatory trials (CheckMate-451 and CheckMate-331) showed that the drug did not meet the primary endpoints of overall survival.

“We believe in the power of science to address some of the most challenging diseases of our time, and so we pursue innovations with the goal of transforming patients’ lives,” said Abderrahim Oukessou, M.D., vice president, thoracic cancers development lead, Bristol Myers Squibb, 

“Although we are disappointed by the withdrawal, we appreciate that the FDA shared our commitment to bringing an innovative new therapy to patients with high unmet need when the science pointed in that direction. Similarly, we respect the FDA’s efforts to evaluate accelerated approvals across the industry to ensure the integrity of this important program,” Oukessou said.

Oncology nurses and physicians should discuss new treatment options or best next steps for patients with SCLC who are currently undergoing treatment with nivolumab. 

Results of confirmatory trials showed that the drug did not meet its primary endpoints for patients with small cell lung cancer.
 

Nivolumab's SCLC Approval Is Pulled From US Market

The year 2021 will encompass a bigger focus on neoadjuvant and adjuvant trials, more novel molecular compounds for more select subgroups, and a migration of circulating tumor DNA (ctDNA) into a more minimal residual disease (MRD)—based setting, according to Balazs Halmos, MD.

“2020, despite being a terrible year as a result of COVID-19, actually has been a good year for thoracic oncology,” said Halmos, a professor of medicine at Albert Einstein College of Medicine and director of the Thoracic Head and Neck Program at Montefiore Medical Center. “As for next year, I think it will be hard to replicate what we've seen this year in terms of the great successes, but there are definitely a number of stories that will continue to unfold.”

, Halmos reflected on the most exciting advances of the past year in thoracic oncology, and also gave his predictions for what will unfold in 2021 as it relates to lung cancer treatment.

Let's look at the big picture for lung cancer for next year. What are some trends that you see on the horizon for 2021?

[First in looking at 2020,] kudos to all of the companies for completing their studies, kudos to the clinical investigators for putting patients on studies, and kudos to the patients for participating. But, certainly, the FDA has done a fantastic job in the middle of this pandemic in taking their job very seriously and looking at data quickly, so that patients can receive medications that are more effective, but also safer. [It also includes] oral drugs, [lower-grade] safety profiles, and not necessitating visits to the physician. They are often also changing the schedules of some of the immunotherapies that we're offering to our patients to a more convenient schedule. The FDA has done a great job this year.

One that is the highlight now for 2021, but certainly is in very early stages, is the KRAS story. We will learn a lot more in the coming year or 2 as to what the activity of the different compounds is. How can they be combined with conventional treatments up front, with chemotherapy, or immunotherapy, or [will it be used] as second-line treatment? Is there some benefit of 1 compound versus the other or are there particular molecular combinations—for example, with the KRAS G12C [inhibitor]. There are some of the downstream inhibitors&mdash;for example, the SOX inhibiting compounds&mdash;so there is great excitement in that field. That's a significant subset of patients, so it will be very important to watch.

Another aspect is looking at the smaller, but still very important, molecular subsets. We've seen a lot of exciting data about EGFR exon 20 insertion—positive patients. Those data sets will continue to mature and the FDA might make some calls on some of the leading molecules. We do anticipate some great excitement there. ERBB2 is emerging as a real target now in lung cancer with these excellent antibody-drug conjugates that have shown success in breast, colon, and gastric cancers, and likely will yield great benefits in ERBB2–positive lung cancer patients, as well.

Of course, ERBB2 is a complex target in lung cancer; we have ERRB2 mutations, and different types of ERBB2amplification as well. There's a lot that we need to learn as to which particular patient subsets could be the best candidates for these novel approaches.

Of course, with immunotherapy, we will continue to find new ways to benefit our patients. The TIGIT molecule had brought a lot of excitement. But, there are definitely a lot of other approaches as well that we’re so keen to support. That could include different vaccines that are being developed that can include expanding different lymphocyte subsets now. It can also be a more individualized approach; it's almost like the CAR T-cell therapy approaches that are being investigated in some of these particular subsets. There is a lot of excitement there.

Let's not forget that, ultimately, we want to cure more patients, so bringing all of this to an earlier-stage setting where we have the highest chance for cure will be so important. Some of the adjuvant studies with immunotherapy compounds will start reading out and will be incredibly important to watch out for and quickly integrate if positive results are obtained. We are keeping our fingers crossed for that. And, of course, we are incorporating these novel compounds, especially the immunotherapy combinations into the stage III setting. In PACIFIC, we've seen a major advance, but why not take another step forward? We do want to support those studies as well. We'll be very eager to see the readout of those.

You already highlighted a handful of new molecules. Are there larger, phase 3 studies for next year that you're anticipating?

Definitely the adjuvant studies [are anticipated]. Some of them might have readouts, and some of them completed accrual maybe about 1 year ago. They will take some time to mature, but maybe some inkling will come out. Especially, if the results are very positive, you may get an earlier read vs if the results seem to be fairly similar between the experimental and control groups.

Another one that I'm very eager to see is a compound called canakinumab. This is kind of an anti-inflammatory agent that actually came from left field from the cardiovascular literature, where they found that as much as it did benefit patients post-myocardial infarction to some extent, but it also did reduce lung cancer incidence by almost 50% in those studies—stunning results in a way. There are a number of phase 3 clinical trials that are being completed and are likely to read out very soon. It will be very good to see that because that will be a completely new class of compounds that could impact our practice. I'm very curious about that.

What were the biggest advances in 2020 as it relates to molecular testing?

It's hard not to think about molecular testing, with the ease that we have now with ctDNA as something that you have to continue to bring up. Each practitioner needs to start being familiar with the platforms that can be used so conveniently, so easily, and so powerfully to impact patient care, and now we have very validated settings in lung cancer. We are very ahead of all other fields.

We know that up front, if you have limited amount of tissue, it may be not enough to complete testing. Or, if there's a need to speed up testing, due to a very symptomatic, sick patient, etc., ctDNA can make a huge impact. If you identify an actionable alteration by ctDNA, you can act upon it as if it was detected in tissue. It also is very important in the acquired resistance setting to monitor secondary changes; that can impact second-line and subsequent lines of therapy.

I'm very eager to see now ctDNA moving into kind of the MRD platforms, where we can maybe detect MRD after surgery or definitive chemoradiation and maybe we can use it to monitor immunotherapy responses. We've seen a lot of exciting technologies this year reflecting that, so that's the next wave—the MRD detection with the ctDNA platforms that are being developed, for example, by Signatera. There is also great excitement about early detection as well, with some of these novel technologies.

Halmos Zeroes in on Year Ahead for Lung Cancer Treatment.

Balazs Halmos, MD, discusses new advancements in lung cancer that are projected for 2021.

Expert Gives Lung Cancer Forecast for 2021

The FDA has approved osimertinib (Tagrisso) for use as an adjuvant treatment following tumor resection in patients with non—small cell lung cancer whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

The regulatory decision was based on data from the double-blind, placebo-controlled, phase 3 ADAURA trial (NCT02511106), which showed that osimertinib, when used as an adjuvant therapy, led to a statistically significant improvement in disease-free survival in patients with stage IB/II/IIIA EGFR-mutated NSCLC. The agent resulted in a 79% reduction in the risk of disease recurrence or death (HR, 0.21; 95% CI, 0.16-0.28; P <.0001).

A total of 682 patients with EGFR exon 19 deletions or exon 21 L858R mutations were randomized 1:1 to receive osimertinib at either 80 mg orally once daily or placebo following recovery from surgery and standard adjuvant chemotherapy, if given.

Additional data presented during the 2020 ASCO Virtual Scientific Program showed that the median DFS in the subset of patients with stage II/IIIA disease had not yet been reached in the osimertinib arm versus 20.4 months in the placebo arm (HR, 0.17; 95% CI, 0.12-0.23; P <.0001). Notably, the DFS benefit proved to favor osimertinib across all subgroups analyzed.

The 2-year DFS rates with osimertinib versus placebo in those with stage IB disease were 87% versus 73% (HR, 0.50; 95% CI, 0.25-0.96), respectively; these rates were 91% versus 56%, respectively, in those with stage II disease (HR, 0.17; 95% CI, 0.08-0.31) and 88% versus 32%, respectively, in those with stage IIIA disease (HR, 0.12; 95% CI, 0.07-0.20).

The OS data are still immature, at just 5% maturity, and the median OS has not yet been reached in either arm (HR, 0.40; 95% CI, 0.18-0.90).

FDA Approves Adjuvant Osimertinib for EGFR+ NSCLC

The FDA has approved osimertinib (Tagrisso) for use as an adjuvant treatment following tumor resection in patients with non–small cell lung cancer whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

Adjuvant Osimertinib Approved for EGFR-Positive Lung Cancer

The coronavirus disease 2019 (COVID-19) pandemic has become another potential complication for patients with lung cancer, said Mark G. Kris, MD, who added that although the pandemic has disrupted patient care, it has yet to stunt scientific collaboration. 

Such a claim is best evidenced by the transition from large in-person medical meetings to virtual platforms, including that of the 15th Annual New York Lung Cancers Symposium. 

“This year’s NY Lung meeting was different. I don’t think anybody would have expected we’d be in the place we are today,” said Kris, who served as the co-chair of the meeting. “[However,] we had broad representation of the entire community of practitioners treating [patients with] lung cancer. One thing you’ll find [at NY Lung], which you may not find in other meetings, is the opportunity to hear how New York doctors are treating patients with lung cancers today [with] case presentations from institutions in the metropolitan area. People are really open about what they did, what they learned, and [they were] anxious to share that.”

, Kris, a medical oncologist, William and Joy Ruane Chair in Thoracic Oncology, Memorial Sloan Kettering Cancer Center (MSK),&#8239;discussed the strengths of this year’s New York Lung Cancers Symposium, the advances that have been made over the past year, and potential routes forward in advancing the field of lung cancer.  

 What were you most excited to hear about at the 15th Annual New York Lung Cancers Symposium? 

 Although we have this overarching concern about COVID-19 and the impact it has had on the lives of our patients and families and all of us, one of the key messages was that COVID-19 is another complication of lung cancer. The culprit here is lung cancer. We had discussions and presentations about some of the most important issues in lung cancer. Of my patients who died from lung cancer this year, all but 1 or 2 died from lung cancer, not from COVID-19. Our problem is lung cancer and the horrible threat it poses to our patients and what we can do to lessen that threat. 

A lot of very good information has come forward this year regarding ways to move forward. We have had new drugs approved and new information about using targeted therapies in the adjuvant setting, which will change the whole process for how we treat patients in the adjuvant setting. [We’ve also seen] the use of newer technologies. We had a special session on how our practices have changed due to the COVID-19 crisis, and also the use of things like cell free DNA, not just for diagnostic purposes, but also to help us monitor care and to help us guide therapy. All of these things [were covered at the meeting]. We had some great international and national speakers, and it’s one of the best groups we’ve ever had. It’s a shame everyone couldn’t be there to meet them in person.

Of the key developments that have been made in 2020, what has the potential to make the greatest impact on the paradigm?

The first is the ADAURA trial, which evaluated osimertinib [Tagrisso] in patients with completely resected lung cancer that harbors an EGFR mutation. People were very impressed by the dramatic benefit in event-free survival for those patients. [Those data] were game changing, not only for those patients with EGFR mutations, but it’s also going to make people think about looking at targeted therapy for patients with earlier stages and not just in [the] surgical [setting].

The next step is going to be [looking at] using targeted therapy in patients with locally advanced disease that are getting concurrent chemotherapy and radiation. Targeted therapies are going to be important in those patients’ care. This discussion with osimertinib in the surgery setting is going to lead to those other discussions. 

What has it been like to be a part of a team that has contributed so much to the field of targeted therapy in lung cancer?

I’ve been very lucky to work at MSK where my colleagues, many of whom [spoke at the meeting] have been involved in the approval of new drugs, such as selpercatinib [Retevmo]. Having more targeted therapies for [patients with] RET or MET mutations is very exciting. It’s really a kind of a dream come true that these drugs are being approved. 

If you had to describe the impact of COVID-19 on the lung cancer space over these past few months, how would you do so?

It’s been a horrible complication. We spend all this time trying to mitigate nausea and neutropenia, and then suddenly, our patients and their families had this put upon them and tremendous stress, and disruption in their care plans. There’s been a struggle to try to maintain their care. [We spend] weeks and months to put these plans together [with patients and their families], and suddenly [their family members or care takers can’t accompany them to the hospital]. 

To hear what the doctors are saying, to go over a scan report and make sure you understand it [can be difficult alone]. Here in Manhattan, [family members] have no waiting room. They can’t go to Starbucks, they can’t go in the diner on the corner, it’s all gone. It’s just a horrible stress on our patients. Then, of course, there’s the change in our practices and a physician I work with led a session at the meeting about how our practices have changed and how the practice of oncology has changed. 

Where do you hope the field of lung cancer will be in the next few years?

My hope is that we will be able to come up with ways to use all of the different tools that we have now to treat each and every patient. For example, somebody with metastatic lung cancer 5 or 10 years ago [would receive] chemotherapy. Now, [we have to determine whether to give] an antiangiogenic drug with chemotherapy. We also now have the opportunity to give patients a checkpoint inhibitor with an antiangiogenic drug and chemotherapy. 

We also have to make sure we look for [potential] targets for targeted therapy. All this has to come together for that individual patient, and that’s our challenge right now. We have so many opportunities, but [we have to] make sure that each patient has these opportunities. [These considerations have to be made] at every decision point of their illness too; it’s really complicated now. I’m hopeful that some of the discussions that [happened] at the meeting [gave] people some direction. I don’t think we have all the answers, but we [did spark] a discussion about making sure all the options are on the table at all times.

What distinguishes the NY Lung meeting from other medical meetings?

We [have] a whole bunch of case presentations, and even individual cases by some members. We also had different points of view [weighing in on those cases]. [For example], the moderator [would act as the] treating physician and synthesize the presentations and make a decision for that patient and talk about how they came to that decision. That’s kind of a unique way of discussing a lot of issues; [the meeting is] not simply presentations of data from this and that clinical trial; a lot of the meeting is case based.

2020 Ushers in Newfound Adjustments, Applications in Lung Cancer.

The coronavirus disease 2019 (COVID-19) pandemic has become another potential complication for patients with lung cancer, said Mark G. Kris, MD, who added that although the pandemic has disrupted patient care, it has yet to stunt scientific collaboration. 
 

Lung Cancer Advancements Continue, Despite COVID-19

Durvalumab (Imfinzi) continued to show promising results in patients with stage III non-small cell lung cancer (NSCLC) who had previously been treated with concurrent chemoradiation, according to findings from the phase 3 PACIFIC trial.

Researchers and clinicians were also happy to see that the regimen was more tolerable than previously expected, too, explained Beth Sandy, CRNP. Sandy, a nurse practitioner at Penn Medicine, recently discussed the advent of durvalumab for these patients at the 

Sandy emphasized the importance of finding efficacious treatment regimens for this patient population, which currently has a 5-year survival rate of about 20%.

“This is a curative intent stage,” she said. “About 25% of patients [with NSCLC] are diagnosed at stage III.”

The trial included 2 randomized groups of patients with stage III NSCLC who had not progressed after chemoradiation. The first group was given 10mg/kg of durvalumab every 2 weeks for up to a year, while the other group was given a placebo — something that many people may find surprising.

“But you have to remember that at the time [of the trial], there was no standard of care,” Sandy explained. “Some people were doing full-dose chemo consolidation, but there was really no evidence whatsoever of an advantage with that.”

At the 4-year follow up point, study findings, which were published in the 

, showed that the PD-L1 inhibitor produced better outcomes than the placebo.

The median overall survival (OS) rate for the durvalumab arm was 47.5 months, and 29.1 months in the placebo arm. Additionally, at the time of follow-up, 50% of patients were alive on the durvalumab arm, compared to only 36% on the placebo arm.

“We’ll be really excited to see what that 5-year OS is, which is kind of our benchmark that we use in stage III disease to find out if our patients are being cured of their lung cancer,” Sandy said.

Not only was durvalumab boosting survival outcomes, but it also was not as toxic as some presumed it would be. Sandy explained that clinicians were worried about severe pneumonitis as a result of getting and immunotherapy agent directly after receiving radiation.

However, there was no difference in grade 3 pneumonitis between the two arms. Each had 3% of participants experience the toxicity. When it came to all-grade pneumonitis, there was only a slight increase in the durvalumab arm versus the placebo arm, with 33% and 25%, respectively.

“So we weren’t really giving anyone any more harmful pneumonitis by giving them the immunotherapy right after radiation. Maybe a little bit more incidence, but not in severity where patients are having life-threatening pneumonitis,” Sandy said.

Durvalumab showed a promising survival boost in stage III non-small cell lung cancer, and the immunotherapy agent was not as toxic as some thought it would be.
 

Lung Cancer