Shaping the Future in Lung Cancer

Heather Wakelee, MD

Targeted therapies had yet to demonstrate significant efficacy against lung cancer when Heather A. Wakelee, MD, chose to specialize in thoracic oncology, and checkpoint inhibitors were still years away from introduction.

The year was 2001. Wakelee was an oncology fellow at Stanford University in California, and lung cancer was a risky choice. The only treatment options for metastatic disease were traditional chemotherapies, but Wakelee was hopeful that lung cancer would prove druggable and that she could play a significant role in bringing those agents to patients.

“Shortly after I started, the EGFR discoveries were being made, and then ALK, and then, after that, we finally got back to immune therapies,” said Wakelee, who first went to Stanford as an intern, became a faculty member, and now specializes in the treatment of lung cancer, thymoma, and mesothelioma.

She is the faculty director of the Stanford Cancer Clinical Trials office, lead investigator for the ECOG-ACRIN cancer research group at Stanford, and president-elect of the International Association for the Study of Lung Cancer (IASLC). “It’s been really exciting,” said Wakelee, who also is a cochair of the 17th Annual Winter Lung Cancer Conference^®, which will take place February 7 to 9, 2020, in Miami, Florida.

In an interview with OncologyLive^®, Wakelee discussed her investigative focus, major trends in the treatment of lung cancer, and the upcoming conference. She has been planning the event with cochairs Rogerio C. Lilenbaum, MD, chief medical officer of Smilow Cancer Hospital at Yale NewHaven Health, in New Haven, Connecticut; Mark A. Socinski, MD, executive medical director of AdventHealth Cancer Institute in Orlando, Florida; and Julie R. Brahmer, MD, MSc, director of the Thoracic Oncology Program and director of the Sidney Kimmel Cancer Center at Johns Hopkins Bayview in Baltimore, Maryland.

A Driving Force

Wakelee’s colleagues and collaborators suggest that she has been one of the most important investigators behind the lung cancer treatment revolution of the past 2 decades.

“She has played a significant role in bringing new treatment options to patients. She led one of the first definitive trials to test the idea that targeted therapies could increase cure rates in early-stage disease. That strategy has now been undertaken by many other research groups,” said Suresh S. Ramalingam, MD, a frequent research collaborator who is deputy director of Winship Cancer Institute of Emory University in Atlanta, Georgia. He called Wakelee an ideal choice for helping to design and lead the Winter Lung Cancer Conference® and bring oncologists up-to-date on recent developments in care and best practices.

The program will include presentations on navigating increased options for immunotherapy-based regimens in metastatic disease, use of molecular testing at diagnosis and following progression on targeted therapies, selecting the best therapy for oncogene-driven non—small cell lung cancer (NSCLC), use of consolidation immunotherapy, and current surgical and radiation oncology approaches.

Targeted Agents

“The research on targeted agents in NSCLC is moving very fast. It seems like we’re hearing about another new targeted agent every few months,” Wakelee said. Among those that “everyone is talking about right now,” she said, is the investigational KRAS inhibitor AMG 510, for the treatment of patients with KRAS G12C—mutated NSCLC.

The FDA granted fast-track designation to AMG 510 in September 2019, shortly after an oral presentation of updated data from an ongoing phase I trial. The presentation included data on 23 evaluable patients with KRAS G12C—mutant tumors who had completed the first 6-week CT scan or had early progressive disease. The objective response rate (ORR) was 48%, and the disease control rate was 96%. Among the 13 patients who received the phase II dose of 960 mg, 7 (54%) achieved a partial response (PR) and 6 (46%) achieved stable disease.¹

A similar compound under development is MRTX849, which also targets KRAS G12C. Reporting findings from a phase I/II expansion cohort trial, Mirati Therapeutics said that at the highest dose (600 mg, twice daily), 3 of 5 evaluable patients with NSCLC achieved a PR and the remaining patients experienced stable disease.² Across all dose levels, 3 of 6 patients with NSCLC achieved a PR. KRAS mutations are present in about a quarter of all NSCLC adenocarcinomas, and G12C mutations are present in more than half of those cases.³

“KRAS is an important target both because it’s a huge percentage of adenocarcinomas and because it’s been thought to be fairly undruggable,” Wakelee said. “We still are only seeing data on dozens of patients as opposed to hundreds of patients, and it’s not clear when we’re going to get an approval, but because it’s the first step in that direction, it’s likely going to be relatively soon.”

Indeed, the FDA has moved quickly when data have indicated efficacy against a lung cancer mutation that had shown little or no response to older medications. For example, in August 2019, the agency granted accelerated approval to entrectinib (Rozlytrek) for the treatment of adult and adolescent patients who have no alternative effective therapies for solid tumors that exhibit a NTRK gene fusion.⁴

The indication was based on the results of pooled data from 4 trials, which collectively included 54 patients whose solid tumors harbored NTRK gene fusions. The ORR was 57.4% and the median duration of response (DOR) was 10.4 months.⁵

The entrectinib approval came less than a year after the FDA granted accelerated approval to larotrectinib (Vitrakvi) for adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or cannot be resected without severe morbidity, and have no satisfactory alternative treatments or have progressed following treatment.

Approval was based on data from 3 multicenter, open-label, single-arm clinical trials. Efficacy was evaluated in the first 55 patients, including 12 under age 18 years, with unresectable or metastatic solid tumors harboring an NTRK gene fusion. ORR was 75%, including 22% complete responses (CRs) and 53% PRs. Response duration was 6 months or longer for 73% of patients, 9 months or longer for 63%, and 12 months or longer for 39%.⁶

Updated data from 2 of those trials provided more information about larotrectinib’s performance in patients with lung cancer. Of 7 evaluable patients with metastatic lung adenocarcinoma, there were 4 PRs and 1 CR, and 2 patients had stable disease. Additionally, the median time to response was 1.8 months, and the median DOR was not reached.⁷

Patients whose cancer exhibits a ROS1 alteration also have at least 1 new option that could beat the existing standard of care. “Crizotinib [Xalkori], which was originally approved for ALK and MET, now has an FDA indication for ROS1 gene alterations, but crizotinib has some challenges with toxicity. It also doesn’t really get into the brain very well, which is an issue with ROS1-positive NSCLC, which frequently metastasizes to the brain,” Wakelee said. “And now we have a couple of newer drugs that look like they may be significantly better for ROS1-positive NSCLC.”

When the FDA approved entrectinib for NTRK mutations, it also approved the drug for the treatment of adult patients with ROS1-positive metastatic NSCLC, again on the strength of pooled trial data. Among the patients in the 4 entrectinib trials with locally advanced or metastatic ROS1-positive NSCLC, the ORR was 77.4%, median DOR was 24.6 months, and intracranial ORR was 55.0%.⁴

Another drug that could help patients with ROS1-positive cancer is lorlatinib (Lorbrena), which was cleared in late 2018 for patients with ALK-positive metastatic NSCLC that has progressed on other ALK inhibitors. Although the drug was not indicated for patients with ROS1 mutations, early data suggest it may improve outcomes for a significant percentage of patients.⁸

A phase I dose-escalation study of lorlatinib included 12 patients with ROS1-positive lung cancer, 7 of whom had already received crizotinib.⁹ Objective responses were seen in 6 patients (50%). Progression-free survival (PFS) was 7 months. In the phase II study, 47 patients with ROS1-positive disease were enrolled into an expansion cohort and treated with standard-dose lorlatinib. Among crizotinib-naïve patients, ORR was 61.5% and the median PFS was 21 months. Even in the crizotinib-refractory setting, where chemotherapy is the current standard of care, the ORR was 26.5% and the median PFS was 8.5 months.¹⁰

“Most of these individual mutations only occur in a small percentage of lung cancers, but when you add together all of the different targets we now have and you include KRAS G12C, we are getting pretty close to having a treatable mutation in the majority of adenocarcinomas,” Wakelee said. “Anybody diagnosed with lung adenocarcinoma absolutely should get next-generation sequencing, something that identifies at least the top 15 genes where we actually have drugs. Even if they’re still under clinical trial, most patients are going to be able to get access, but if they are not tested, they will never know that other treatment options exist.”

Organizational Leader, Active Clinician

Wakelee has authored or coauthored more than 200 articles, mentored dozens of younger researchers, and built Stanford’s thoracic oncology program into a national powerhouse, yet she also finds time to treat 40 to 50 patients a week and fill leadership roles with both the ECOG-ACRIN cancer research group, for which she serves as thoracic committee cochair, and IASLC.

“She is fantastic at bringing groups of people together, particularly across country borders, and coordinating our efforts to maximize progress in our battle against lung cancer. She is exactly the sort of leader to inspire this international association of physicians and scientists,” said Joel W. Neal, MD, PhD, a Stanford colleague who said he respects Wakelee’s abilities as a mentor and collaborator.

Wakelee grew up in a rural part of northern California. Her father was a banker, and her mother was an elementary school teacher, but Wakelee always knew she wanted to become a doctor. “I was drawn to oncology because the oncologists I met during my training somehow just felt like ‘my people’ and because, unlike many people, I found that I was able to have those very hard conversations with patients who were facing difficult diagnoses without them completely draining me of my energy,” Wakelee said.

She noted that the rapid proliferation of treatment options necessitates a different kind of talk that upsets many patients. “A new diagnosis of cancer is scary, and most patients naturally want to start treatment yesterday,” Wakelee said. “Part of our job as oncologists is being able to have that communication to help them understand why we may need a little bit longer [to do things like next-generation sequencing] to make sure we start with the right treatment option.”

Checkpoint Inhibitors

For patients with advanced cancers that lack any targetable mutation, the right treatment is typically immunotherapy, but the FDA has approved a number of checkpoint inhibitors for use with and without chemotherapy, which affords numerous options.

Frontline use of consolidative immunotherapy began shortly after the publication of the phase III Pacific study results in late 2017 (Table^1,2). That study randomized 713 patients with unresectable stage III NSCLC to either durvalumab or placebo every 2 weeks for up to 12 months after definitive treatment with chemoradiation. Median PFS from randomization was 16.8 months with durvalumab versus 5.6 months with placebo.¹¹ Updated results released at the 2019 American Society of Clinical Oncology Annual Meeting showed that, after a median follow-up of 33.3 months, median OS had yet to be reached in the durvalumab arm versus 29.1 months in the placebo arm. The 36-month OS rate was 57.0% with durvalumab versus 43.5% with placebo.¹³

“The PACIFIC study has been a major practice changer, a really significant paradigm shift in treating a significant group of patients,” Wakelee said. “A lot of the other more recent updates have been variations on the theme.”

The IMpower150 trial found survival benefits for another immunotherapy-chemotherapy combination (without radiation but with bevacizumab [Avastin]). Median OS among the patients in the wild-type population was longer among patients treated with atezolizumab (Tecentriq)/bevacizumab/ carboplatin/paclitaxel than those treated with bevacizumab/carboplatin/paclitaxel: 19.2 months versus 14.7 months (P = .016).

That same trial, which included more than 100 patients with an EGFR or ALK alteration, showed that patients who were no longer benefiting from targeted therapy—or were experiencing intolerable adverse effects while using it—could benef it from the combination of checkpoint inhibitors, bevacizumab, and chemotherapy. Such patients who were treated with the atezolizumab/bevacizumab/chemotherapy combination had longer median PFS than those who received the bevacizumab/ chemotherapy regimen: 9.7 versus 6.1 months (HR, 0.59; 95% CI, 0.37-0.94).¹⁴

The past year also saw more data to support the use of immunotherapy combinations in some patients and more data on long-term survival among patients who respond to checkpoint inhibitors.

Investigators published updated results of the CheckMate 227 trial, which compared chemotherapy with nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with stage IV or recurrent NSCLC. Among the patients with a PD-L1 expression level of 1% or more, median OS was 17.1 months with nivolumab plus ipilimumab and 14.9 months with chemotherapy, and 2-year OS rates were 40.0% and 32.8%, respectively. Among patients with a PD-L1 expression level of less than 1%, median DOR was 17.2 months with nivolumab plus ipilimumab and 12.2 months with chemotherapy.¹⁵

As for long-term survival, results of a pooled analysis of 2 phase III trials showed a 4-year OS rate of 14% for patients treated with nivolumab compared with 5% for those who got docetaxel. Among patients who had a complete or partial response at 6 months, 58% of those treated with nivolumab were alive 4 years later versus 12% of those treated with docetaxel.¹⁶ A 5-year analysis of pembrolizumab (Keytruda) monotherapy found an OS rate of 23.2% in newly diagnosed patients with advanced or metastatic NSCLC and 15.5% in previously treated patients. These findings compared favorably with historical preimmunotherapy OS rates of about 5%.¹⁷

Table. Phase III PACIFIC Trial: Key Findings (N = 709)^11,12

“All the trial data and all the approvals create a huge number of potential treatment options for many patients, but the evidence we have to date suggests that we should begin by testing for targetable mutations and PD-L1 levels. If a patient has targetable mutations, we begin with targeted therapy. If there are no targetable mutations and PD-L1 levels are high, we start with checkpoint inhibitor monotherapy. If there are no targetable mutations and PD-L1 levels are low, we give the checkpoint inhibitor in combination with chemotherapy,” Wakelee said. “If there are both high levels of PD-L1 and targetable mutations, we ignore the PD-L1 and start on targeted therapy because we know that when someone has EGFR or ALK or ROS1 mutations or others, they are not likely to respond to a checkpoint inhibitor, even if their PD-L1 levels are very high.”

Early Detection

Although new medications are extending lives for patients with advanced lung cancer, the only current hope for curing large numbers lies in earlier detection. Results from the NELSON trial of lung cancer screening indicate that regular CT scans could reduce 10-year mortality in high-risk patients by 26% in men patients and 39% in women patients.

The study enrolled more than 15,000 people in Belgium and the Netherlands who had smoked more than 10 cigarettes a day for more than 30 years or more than 15 cigarettes a day for 25 years. Half of the participants got CT scans at prespecified intervals, and the other half served as controls. The lower mortality in the experimental arm stemmed from early detection. About 50% of the cancers diagnosed in the screening arm were early stage, and 65% to 70% were stages Ia to II. In the control arm, about 70% of cancers were stage III/IV at diagnosis.¹⁸ The results echoed those of the National Lung Screening Trial, which found that CT scans reduced lung cancer deaths by 20% (P = .004) in 53,454 high-risk Americans.¹⁹

“Despite that very clear mortality benefit, in the United States, [just] 4% of people who would be eligible, based on who went on to that study, actually get screened,” Wakelee said. “Some private insurers are not paying, even though it’s in all standard guidelines now. A lot of primary care physicians are not emphasizing it. And patients are not always agreeing to do it; some use it as a justification to continue smoking if they get a clean scan. We need to be getting primary care doctors more aware of this…and smoking cessation counseling needs to be part of the screening.”

The potential survival benefit of early detection should continue to grow, both because improved tests could catch more early cancers in more asymptomatic patients and improved treatments should cure more early cancers.

The big hope on the screening side is the development of liquid biopsies, blood tests designed to find solid tumors. Dozens of private companies and academic research groups are working to develop such tools, and several have begun early-stage testing. Data presented at the European Society for Medical Oncology Congress 2019, for example, showed that 1 test achieved a 76% sensitivity and 99.4% specificity when looking for signs of prespecified high-mortality cancer types in nearly 3600 blood samples. The sensitivity was 32% for patients with stage I cancer; 76%, stage II; 85%, stage III; and 93%, stage IV.²⁰

“We’re not yet at the point that such tests are ready for clinical use, but it’s likely going to be happening within a short number of years. I don’t know if it’s going to be less than 10. I think most likely within 10 that will be a more standard strategy,” said Wakelee, who noted that other ongoing research could make early detection particularly valuable.

“There are a lot of trials being done to test the effects of giving immune checkpoint inhibitors either before surgery or after surgery, alone or in combination with chemotherapy,” Wakelee said. “We have yet to see the sort of survival details from those trials, but we’re seeing some encouraging preliminary data from the neoadjuvant trials.”

For example, presurgical treatment with nivolumab plus ipilimumab resulted in an overall major pathological response rate of 33% in patients with early-stage, resectable NSCLC.²¹

The rapid and ongoing flow of new trial data is incredibly exciting, Wakelee said, but also creates a major challenge: conveying the most important discoveries in such a way that general oncologists can optimize care that ordinary patients with lung cancer receive.

“In putting the Winter Lung Cancer Conference® together, the other organizers and I looked for ways to optimize the experience by giving real expert perspective on most of the hot topics in lung cancer,” Wakelee said. “To use immunotherapy as an example, we have a whole session focusing on who should get it and when you should give it to them and when you should stop and when you should restart.

“We also make sure there’s a lot of interactive time, so that with each speaker, with each panel, we make sure that there’s a good amount of time for questions from the audience. And we do have some also case-based presentations to make it a bit more real-world.”

Most of the conference panelists are medical oncologists, but there will also be surgeons and radiation oncologists. Looking forward, Wakelee said she believes that such speakers will become even more common. “We are moving away from just being medical oncologists,” she said. “We already have people from other specialties speaking each year, and I’d guess that trend will only increase. A considerable amount of the most exciting research in lung cancer is testing treatment protocols that combine medical oncology with surgery and/or radiotherapy to achieve more durable remissions or, in the case of early-stage cancers or even oligometastatic cancers, outright cures.”

References

1. Govindan R, Fakih M, Price T, et al. Phase 1 study of safety, tolerability, PK and efficacy of AMG 510, a novel KRAS^G12C inhibitor, evaluated in NSCLC. Presented at: International Association for the Study of Lung Cancer 2019 World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA02.02. bit.ly/2PvwbZv.
2. Mirati Therapeutics presents first clinical data of phase 1/2 trial of MRTX849 at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics [news release]. San Diego, CA: Mirati Therapeutics, Inc; October 28, 2019. ir.mirati.com/news-releases/news-details/2019/Mirati-Therapeutics-Presents-First-Clinical-Data-Of-Phase-12-Trial-Of-MRTX849-At-The-2019-AACR-NCI-EORTC-International-Conference-On-Molecular-Targets-And-Cancer-Therapeutics/default.aspx. Accessed October 30, 2019.
3. Papadopoulos KP, Ou SHI, Christensen J, et al. A phase 1/2 multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation. Poster presented at 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Poster 3161. mirati.com/wp-content/uploads/2019/05/Mirati_ASCO_42x42_052819_PRINT.pdf.
4. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA website. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc. Updated August 16, 2019. Accessed October 30, 2019.
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8. FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. FDA website. www.fda.gov/drugs/fda-approves-lorlatinib-second-or-third-line-treatment-alk-positive-metastatic-nsclc. Updated December 14, 2019. Accessed October 30, 2019.
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15. Hellmann MD, Paz-Ares L, Carbo RB, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer [published online September 28, 2019]. N Eng J Med. doi: 10.1056/NEJMoa1910231.
16. Bristol-Myers Squibb announces long-term survival results from pooled analyses of Opdivo (nivolumab) in previously-treated non-small cell lung cancer patients [press release]. Princeton, NJ: Bristol-Myers Squibb Company; April 2, 2019. news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-announces-long-term-survival-results-pool. Accessed October 30, 2019.
17. Garon EB, Hellmann MD, Costa EC, et al. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: results from KEYNOTE-001.J Clin Oncol. 2019;37(suppl 18; abstr LBA9015). doi: 10.1200/JCO.2019.37.18_suppl.LBA9015.
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19. Aberle DR, Adams AM, Berg, CD, et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. doi: 10.1056/NEJMoa1102873.
20. Oxnard GR, Klein EA; Seiden MV, et al. Multi-cancer detection of early-stage cancers with simultaneous tissue localization using a plasma cfDNA-based targeted methylation assay. Presented at European Society for Medical Oncology Congress 2019; September 27-October 1, 2019; Barcelona, Spain. grail.com/wp-content/uploads/ESMO_2019_Oxnard_CCGA2_Training_Final.pdf
21. Reuben A, Zhang J, Lin JY, et al; NEOSTAR Study Group. T cell repertoire analysis of non-small cell lung cancer patients treated with neoadjuvant nivolumab alone or in combination with ipilimumab (NEOSTAR trial). Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 8532. meetinglibrary.asco.org/record/173517/abstract.