Chasing a Cure in Lung Cancer: Kris Urges Pushing Forward in COVID-19 Era

Mark G. Kris, MD

The treatment of patients with metastatic lung cancer today bears scant resemblance to what it was when Mark G. Kris, MD, entered the field 4 decades ago. Back then, patients with disease that had spread to the liver would be sent directly into trials of experimental drugs because there were no therapies for this population. “If you were going to go on a National Cancer Institute trial, any drug that they had would be given to you as the first treatment—any drug, whether it had any relevance to lung cancer or not,” Kris recalled in an interview with OncologyLive®.

The picture is far different now, when therapies for patients with non–small cell lung cancer (NSCLC) include a growing menu of molecularly targeted agents and checkpoint blockade immunotherapies. Rapid declines in death rates due to lung cancer have fueled the most pronounced single-year drop in overall cancer mortality ever observed in the United States (2.2%, 2016-2017).¹

Now, because of coronavirus disease 2019 (COVID-19), the lung cancer landscape is undergoing another transformation, as are all branches of medicine in the United States and globally. Kris, who is the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center (MSK) in New York, New York, learned on the fly how to continue treating patients with cancer when the region became an early epicenter of the pandemic in March. Although elective surgeries and routine medical visits were put on hold, the treatment of patients with lung and other forms of cancer had to march on.

“I think the message is, you can’t stop the delivery of care for people with lung cancers,” said Kris, who works as an attending physi-cian for MSK’s Thoracic Oncology Service after serving more than 20 years as the divi-sion’s chief. “So, our challenge is, how do we continue to provide the same level of care and the right decision-making when there is this unbelievable force pervading everything?”

How best to care for patients during the pandemic will be among the topics discussed during the 15th Annual New York Lung Cancers Symposium® on November 7. The conference, hosted by Physicians’ Education Resource®, LLC (PER®), will be held as a live virtual meeting. Kris is chairing the program along with Roman Perez-Soler, MD, chairman of the Department of Oncology and chief of the Division of Medical Oncology at Montefiore Medical Center and deputy director of the Albert Einstein Cancer Center, both in the Bronx, New York.

The pandemic has made its mark on the agenda at Kris’ impetus. Balazs Halmos, MD, MS, director of thoracic oncology and clinical cancer genomics at Montefiore, is scheduled to discuss the lessons for lung cancer care from the pandemic as the closing lecture. The meeting will likely include a session on how to use teleoncology to provide care effectively and appropriately in the age of COVID-19, Kris said.

The need for such guidance is clear, according to Kris: For all their years of study, doctors, like everyone else, are wrestling with new technology as they figure out how to manage videoconference software during patient visits and consultations with fellow doctors. “Think how much we could have advanced for all the time that every person has said, ‘Can you hear me now? Can you see me now?’ ” Kris said with a laugh. “How many times a day do we say that, you know? And not everybody is technology savvy for an interactive telemedicine session.”

“Institutions were not geared up” for the advent of telemedicine, he added, noting that MSK “went from about 100 telemedicine visits a day to something like 1400 a day by April.”

Although the virtual symposium will not have the same vibe as an in-person meeting, the program will offer opportunities for the open discussions that have become a feature of the gathering. Kris recalled a case study discussion from last year’s symposium about whether to care for a patient with a small tumor with surgery, radiation, or an ablative procedure. Such discussions mirror debates held at the institutional level, he noted.

This year’s agenda also includes several tumor board–style case-based discussions, along with presentations on best practices for the use of immunotherapy in patients with NSCLC and small cell lung cancer and on emerging molecular targeting strategies.

There will be an emphasis on multidisciplinary care. “One overarching change in lung cancer treatment is that there really isn’t a person nowadays who gets treated by just 1 specialist,” Kris said. “Whether or not other modalities are added is very patient specific. However, what isn’t specific is the discussion. There needs to be a discussion about whether there is a role for other treatments.”

Table 1. Kris’ Research Sample: Select Contributions^2,4-11

Table 1. Kris’ Research Sample: Select Contributions

Research Achievements

Early in his career at MSK, where he joined the staff in 1983, Kris learned the value of collaboration with other specialists. “I was very lucky because I was allied here with our surgeons. They knew everything about the illness, including where the problems were and those cases where they performed successful surgery but the patient didn’t survive because the cancer grew back,” Kris said. “It was the surgical leadership that dragged all of us into trying to develop adjuvant treatments, because they saw that patients, despite a successful surgery, had metastasis at some point.”

Searching for the underlying causes of cancers and new therapies to treat patients has been a hallmark of Kris’ research. In 1981, he was among the first investigators to report Kaposi sarcoma and Pneumocystis pneumonia among homosexual men in New York City and California, an important observation for subsequent research into HIV and AIDS.^2,3 In the lung cancer field, his research has helped advance chemotherapy, anti-nausea medication strategies, and targeted therapies (TABLE 1^2,4-11).

Notably, Kris and colleagues conducted research that helped pave the way for the approval of gefitinib (Iressa), the first EGFR-targeted therapy for NSCLC, which the FDA authorized for an unselected patient population in 2003.^9,12 Gefitinib was withdrawn from the market 2 years later but reintroduced in 2015 as a first-line treatment for patients with EGFR-mutated metastatic NSCLC.¹³

In 2008, Kris was among investigators from cancer centers throughout the United States who formed the Lung Cancer Mutation Consortium; their findings led to the identification of the major driver mutations in NSCLC such as EGFR, ALK, BRAF, MET, and ERBB2 alterations.¹⁴

To Kris, the unfolding EGFR story in NSCLC reveals the therapeutic implications of learning the molecular and biologic characteristics of cancer. “A better biologic understanding gives you a better chance to match a treatment to the cancer in that person,” he said. “That’s something we’ve struggled to do, instead of giving treatment X to everybody. We’re trying to carry that paradigm forward as much as we can.”

Kris’ efforts to advance the field have placed him in the forefront of lung cancer research for years, noted Paul A. Bunn Jr, MD, a 2014 Giants of Cancer Care® award winner who worked with Kris on the consortium and other projects.

“He was involved in the earliest trials of platinum-based chemotherapy in both small and non–small cell lung cancer,” said Bunn, distinguished professor of medicine and the James Dudley Chair in Lung Cancer Research at the University of Colorado School of Medicine in Aurora. “He’s been interested in all phases—more in treatment of early-stage patients, including use of adjuvant and neoadjuvant chemotherapy. He’s also been involved in determining whether pathologic response to neoadjuvant chemotherapy would be predictive of cure and improve survival. Early data showed that pathologic response will predict disease-free and ultimate survival.”

Melissa L. Johnson, MD, remembers Kris not only for his groundbreaking research but also for his mentorship during her fellowship in medical oncology and hematology at MSK, which included a year as a chief fellow.

“MSK is such a wonderful place,” said Johnson, who is associate director of lung cancer research at Sarah Cannon in Nashville, Tennessee. “So many leaders who are [on the] cutting edge come together there. There’s so much innovation there. To me, Mark Kris rose above them all. He treated everyone the way he’d want to be treated. He had a common-sense approach to his leadership that was refreshing and fair.”

Table 2. Phase 3 Immunotherapy Trials in Adjuvant NSCLC Settings

Table 2. Phase 3 Immunotherapy Trials in Adjuvant NSCLC Settings

Curative Trends

In taking stock of changes in lung cancer care, Kris noted that a significant number of patients who were treated with immune checkpoint inhibitor (ICI) therapy are reaching the 5-year mark without a recurrence. At the 2019 American Society of Clinical Oncology Annual Meeting, Garon et al reported a 5-year OS rate of 23.2% overall and 29.6% for PD-L1–positive disease among patients with newly diagnosed advanced NSCLC who received pembrolizumab (Keytruda), a PD-1 inhibitor, during the KEYNOTE-001 trial (NCT01295827). Historically, the OS rate for this population has been about 5.5%.¹⁵

Kris said he has seen a similar longer-term OS trend in clinical practice and that these patients can be described cured. “[Patients] should say it: ‘I had cancer, it’s gone, it’s 5 years now, it hasn’t come back,’ ” Kris said. “I say that you’re cured, or at least that should definitely be the goal of therapy. But people are afraid to say it. [Doctors are] afraid to tell the patient, ‘You might be cured.’ We don’t want to give people unrealistic hope. But, you know, that’s the fact.”

He is most enthusiastic about potentially curative emerging strategies. “The bottom line is to cure,” Kris said. “Things that have a chance to cure people with advanced lung cancers are to me the most exciting.”

According to Kris, the most dramatic development today in lung cancer treatment relates to the benefit of osimertinib (Tagrisso) in patients with early-stage EGFR-mutant NSCLC reported in interim findings from the phase 3 ADAURA trial (NCT02511106). The study randomized 682 patients with stage IB, II, or IIIA disease who had undergone complete resection with or without chemotherapy to receive either osimertinib at 80 mg daily or placebo. Patients received treatment for 3 years, or until disease recurrence or discontinuation criteria were met. The primary end point was investigator-assessed disease-free survival (DFS) in patients with stage II or IIIA disease.¹⁶

Findings showed an 83% improvement in the median DFS of patients with stage II or IIIA disease who received adjuvant osimertinib versus placebo (HR, 0.17; 96% CI, 0.12-0.23; P < .0001). The median DFS for patients who received osimertinib (n = 233) was not reached (NR; 95% CI, 38.8-not calculable [NC]) compared with 20.4 months (95% CI, 16.6-24.5) for those who received placebo (n = 237). In the overall study population, the median DFS for participants who received osimertinib (n = 339) was NR (95% CI, NC-NC) versus 28 months (95% CI, 22.1-35.8) for those who took the placebo (n = 343), which translated into an HR favoring osimertinib therapy of 0.21 (95% CI, 0.16-0.28; P < .0001).¹⁶

The ADAURA results support the use of molecular testing for every patient with NSCLC who is a candidate for surgery, Kris said. “This is a trial that will truly change how we care for people with EGFR-mutant lung cancer,” he said. “I think all the patients with an EGFR mutation and a successful lung cancer surgery will be offered osimertinib after the conclusion of chemotherapy, if appropriate by their stage, and radiation, if appropriate by their stage.”

Another key development involves use of the PD-L1 inhibitor durvalumab (Imfinzi) for patients with unresectable stage III NSCLC whose disease has not progressed after concurrent platinum-based chemoradiation therapy. The FDA approved the PD-L1 inhibitor for this indication in February 2018 based on the results of the PACIFIC trial (NCT02125461), in which patients received durvalumab at 10mg/kg of body weight or placebo.¹⁷

In the study, the median progression-free survival (PFS) with durvalumab (n = 473) was 16.8 months versus 5.6 months with placebo (n = 236), resulting in a 48% reduction in the risk of disease progression or death (stratified HR, 0.52; 95% CI, 0.42-0.65; P < .001).18 The PFS rates for durvalumab compared with placebo, respectively, were 55.9% versus 35.3% at 12 months and 44.2% versus 27.0% at 18 months.¹⁸

“We went for decades without improving upon giving chemotherapy and radiation for people with locally advanced but not metastatic cancer—people who were not able to have surgery,” Kris said. “We tried all kinds of things. Nothing helped. In fact, some things harmed. Suddenly, by giving a year of durvalumab, more people are cancer-free afterward and more people are cured.”

Kris said that several large clinical trials testing ICIs in postoperative and preoperative settings in NSCLC have been completed and results are awaited. In the adjuvant setting, phase 3 trials evaluating these strategies are ongoing with the following estimated enrollments: pembrolizumab after surgical resection (KEYNOTE-091; PEARLS; NCT02504372), with 1177 participants; durvalumab in completely resected NSCLC (BR31; NCT02273375), 1360; atezolizumab (Tecentriq) after resection and chemotherapy (IMpower010; NCT02486718), 1280; and nivolumab (Opdivo) after surgery and chemotherapy (ANVIL; NCT02595944), 903 (TABLE 2).¹⁹

On the targeted therapy front, Kris said investigators continue to develop drugs directed at genetic mutations in NSCLC. So far this year, the FDA has approved selpercatinib (Retevmo) for patients with RET fusion–positive tumors, capmatinib (Tabrecta) for MET exon 14 skipping mutations, the combination of ramucirumab (Cyramza) plus erlotinib (Tarceva) for EGFR exon 19 deletions or exon 21 (L858R) mutations, and an expanded indication for brigatinib (Alunbrig) in ALK fusion–positive disease.²⁰

“These drugs chip away at [the cancer burden of individual patients], but they’re not yet part of a curative package,” Kris said about targeted therapy in general. “They shrink the cancer; they shrink it well for a period of time, but it doesn’t lead to a cure. Trying to parlay that information to cure is our challenge.”

Kris wishes oncologists had more influence over 1 critical issue in lung cancer care: persuading primary care doctors to screen patients who are considered at high risk of developing lung cancer with low-dose computed tomography. The US Preventive Services Task Force has proposed new criteria that would expand the eligibility criteria and risk threshold for annual screenings to encompass adults aged 50 to 80 years who have a 20 pack-year smoking history, currently smoke, or have quit within the past 15 years.²¹

Despite the potential to save thousands of lives, the uptake of screening is typically estimated at about 10% of eligible patients, Kris noted. “If you don’t screen for breast cancer, it’s like a moral failing,” he said. “If you don’t screen for lung cancer, people don’t consider it a moral failing.”

Furthermore, he wishes he could persuade physicians nationwide to take the step of sending anyone whose scan shows possible signs of lung cancer for a tissue biopsy.

COVID-19 Impact on Patients

As investigators continue to pursue curative strategies, the COVID-19 pandemic is casting a long shadow on clinical care. Kris, who spends about 40% of his time seeing patients, has made the adjustment to conducting telehealth visits, although the proportion reduced as the number of COVID-19 cases in the New York area diminished toward the summer. It was helpful that testing became readily available at the hospital so a patient’s status could be determined before treatment, he said.

Nevertheless, COVID-19 has changed the entire environment of cancer care. “All the concerns that a person has had with fighting lung cancer are there,” Kris said. “Nothing has changed, and now there’s COVID-19 on top of that. And, you know, the average person with lung cancer in the United States is 71 years old, and a huge proportion of them have COPD [chronic obstructive pulmonary disease] or other comorbid illnesses from their smoking. When you look at a list of anybody who’s high risk, these are the people, so it’s very, very frightful.”

What’s also disconcerting, he said, was an unintended consequence of trying to counter the highly contagious nature of COVID-19: for several months, limited visitor policies meant patients at in-person appointments lost the ability to have family or friends physically present not only to support them emotionally but also to help them digest all the information that doctors provide.

“We tell people to put your care team together; have the people who are important to you be at the visit to be your second set of ears, to ask the questions that you might forget,” Kris said. “And for a while, that was gone. That was and continues to be a real hardship for patients,” but he notes that as of early August, restrictions had been relaxed on allowing inpatients and some outpatients to have visitors.

Although patients with lung cancer tend not to be risk-takers, the stress of staying safe during the pandemic also can take its toll. “Our lives are not staying home,” Kris said. “Our lives are going out. They’re seeing our children, our grandchildren, going to the Jersey Shore. That’s what their lives are. This is not life to them. It’s not their life, and that’s the problem. They have this tremendous fear [about COVID-19], and rightly so.”

References

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