ASCO 2021 Recap: Immuno-Oncology

“Practice-Changing” Results Seen for Pembrolizumab in Adjuvant Setting in Renal Cell Carcinoma

Treating patients with a common type of kidney cancer with the checkpoint inhibitor pembrolizumab (Keytruda; Merck) after surgery cut the risk of disease recurrence or death by 32%
over a 2-year period, according to results presented in June during the annual meeting of the American Society of Clinical Oncology (ASCO).

The KEYNOTE-564 interim results, which capped the meeting’s plenary session, were described as “practice-changing” by a scientist asked to comment, although more time is needed to learn whether a clear benefit in disease-free survival (DFS) fully extends to overall survival (OS).¹ Merck funded the study.

Renal cell carcinoma (RCC) kills 175,000 people worldwide each year, and its incidence has been slowly rising, due to an aging population and better detection.² Half of patients who have surgery to remove an initial tumor see their cancer return, so the search has been on for treatment that could prevent cancer from reaching an advanced stage. Until now, adjuvant studies have
inconsistent or negative. However, pembrolizumab’s effectiveness in metastatic RCC raised the possibility that the PD-1 inhibitor could work in the adjuvant setting.³

The phase 3 study is the first with a checkpoint inhibitor in the adjuvant setting to improve DFS in patients with high-risk clear cell RCC who have had surgery to remove a tumor or the entire
kidney. Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and lead author of the study, characterized how long researchers in the
fi eld have searched for an adjuvant treatment for high-risk RCC patients after surgery.

“To my knowledge, the first randomized control trial of adjuvant immunotherapy in RCC [utilized] interferon, and this was presented at the 1992 ASCO meeting. At that time, I wasn’t done with high school,” Choueiri said during the presentation. “Now, 29 years later, we finally—finally—have a positive adjuvant event study in RCC.”

Details of KEYNOTE-564
The study randomized 994 patients 1:1 to receive either pembrolizumab or placebo at least 12 weeks after surgery. The primary end point was DFS, with OS as a secondary end point. Patients at
various risk levels were enrolled: intermediate-high risk, high risk, or no evidence of disease after a primary tumor and soft tissue metastases completely resected at least 1 year from nephrectomy.
Results showed:

• The 24-month DFS rate was 77.3% with pembrolizumab, compared with 68.1% with placebo (HR, 0.68; 95% CI, 0.53-0.87; P = .001). The benefit was consistent across subgroups.
• The estimated preliminary OS rate at 24 months was 96.6% with pembrolizumab, compared with 93.5% with placebo; however, the number of events was small, and Choueiri said the results (HR, 0.54; 95% CI, 0.30-0.96;P= .0164) “should be interpreted with caution.”
• Adverse events (AEs) of grade 3 or higher were more common with pembrolizumab than placebo: 32.4% vs 17.7%. No treatment-related deaths were seen in the pembrolizumab group.

Commentator Rana McKay, MD, associate professor of medicine and urology at the University of California San Diego, and Genitourinary Oncology co-lead at Moores Cancer Center, said
that while it will be important to wait for OS data to mature, she did not hesitate to describe the results as “practice-changing.”

“The data represent a paradigm shift as the first positive phase 3 study of adjuvant immunotherapy in RCC,” McKay said. “DFS prolongation represents clinical benefit, given the magnitude of
benefit and limited toxicity.”

If pembrolizumab after surgery is adopted as the new standard of care for these patients, McKay said, “new questions will arise, including, ‘Will there be broad implementation for all patients?
What about the application for non–clear cell patients? And if recurrence does develop, how does this alter first-line treatment for advanced disease?’”

“Ultimately,” McKay said, “this is a quantum leap forward for our patients and provides additional options for individuals with renal cell carcinoma.”

References

1. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy
adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase III
KEYNOTE-564 study.J Clin Oncol2021;39(Suppl 15):abstr LBA5. doi:10.1200/JCO.2021.39.15_
suppl.LBA5
2. American Cancer Society. Key statistics about kidney cancer. Updated January 12, 2021.
Accessed June 9, 2021. https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html
3. Keytruda + axitinib in first-line treatment of aRCC—initial analysis: superior overall
survival (OS) vs sunitinib. Keytruda. Accessed June 9, 2021. https://www.keytrudahcp.com/
renal-cell-carcinoma/

At 5 Years, More Than 30% of Patients in PACIFIC Had Stable NSCLC, Data Show

Lung cancer remains the leading cause of cancer death in the United States, projected to take 131,000 lives this year.¹ But recent news in lung cancer has been positive—fewer new cases and fewer deaths—due to lower smoking rates, improved screening, and much better therapies.

Results presented at the 2021 American Society of Clinical Oncology annual meeting show the durability of a a practice-changing immunotherapy, as 5-year results for durvalumab (Imfinzi; AstraZeneca) showed that 43% of certain patients with non–small cell lung cancer (NSCLC) were alive after 5 years and 33% of those who received the agent had no advancing disease.²

Those rates are double or triple what would have been expected in the past, according to an investigator for the phase 3 trial, called PACIFIC. The trial evaluated the effectiveness of giving
durvalumab for 1 year to patients with stage III NSCLC whose disease had not progressed after receiving platinum-based chemoradiotherapy.

David Spigel, MD, chief scientific officer at the Sarah Cannon Research Institute and an investigator in the PACIFIC trial, said patients were included regardless of their PD-L1 status, even though durvalumab binds to PD-L1. The monoclonal antibody blocks the interaction with PD-1 and CD80 to deter a tumor’s ability to work around the immune system.

Results from the abstract presented at ASCO showed:

• Overall, 473 patients in PACIFIC were randomized to receive durvalumab and 236 received placebo. The last patient completed treatment in May 2017. As of January 2021, median follow-up was 34.2 months.
• The 60-month overall survival (OS) rates were 42.9% for durvalumab and 33.4% for placebo (stratified HR, 0.72; 95% CI, 0.59-0.89).
• The 60-month progression-free survival (PFS) rates were 33.1% for durvalumab and 19.0% for placebo (stratified HR, 0.55; 95% CI, 0.45-0.68).

Several initiatives are underway to boost lung cancer screening rates to catch cancer earlier. The US Preventive Services Task Force recently recommended that screening should begin for smokers or former smokers at age 50 years instead of 55 years.³

Although most patients present with NSCLC at stage III, multiple ongoing trials are examining the use of durvalumab in earlier stages of NSCLC, and the immunotherapy is also being tested in combination with other therapies in the stage III unresectable setting and in the neoadjuvant early-stage setting.

If screening rates improve and patients are tested at younger ages, more patients can be treated when NSCLC is at a curable stage. In presenting the results, Spigel said the 5-year data establish
“a new benchmark for the standard of care in the unresectable stage III NSCLC setting.”

“Historically,” he said, “only 15% to 30% of these patients survived 5 years.”

When Another Option Is Needed
The practice-changing results from PACIFIC don’t apply to every patient with stage III unresectable NSCLC, according to Helen Ross, MD, a medical oncologist at Banner MD Anderson Cancer
Center in Gilbert, Arizona, who presented results from the phase 2 AFT-16 study.⁴

“Unfortunately, many, if not most, of our unresectable stage III NSCLC patients won’t be eligible for adjuvant checkpoint inhibitor treatment,” she said. “We hypothesize that neoadjuvant atezolizumab
given before chemoradiotherapy might allow more of our eligible patients to receive the potential benefit of a checkpoint inhibitor. And they would be able to continue adjuvant immune checkpoint inhibitor therapy after chemoradiotherapy, if they still had good performance status and no progression of disease.” Ross explained the study schema:

• Patients with unresectable stage IIIA and IIIB NSCLC received 4 cycles of atezolizumab, with restaging after cycles 2 and 4.
• Those who had not progressed went on chemoradiotherapy chest radiation with weekly carboplatin/paclitaxel, and they were also eligible for standard consolidation therapy.
• Those who still had not progressed after restaging were eligible to complete 1 year of atezolizumab.
• Of the population of 64 patients with unresectable stage III disease, data from 62 who received at least 1 dose of atezolizumab were presented.

The average age of patients in the study was 63.9 years; 51.6% of the patients were female, 77.4% were white, 61.3% were former smokers, 11.3% were never smokers, and 56.5% had an ECOG
performance stage of 1.

RESULTS. The median PFS was 23.7 months; the 12- and 18-month PFS rates were 66% and 57%, respectively. The 18-month OS rate was 84%, with the median OS not estimable. Adverse events
included one each of grade 3 pneumonitis, pneumonia, and colitis, and one event of grade 4 Guillain-Barre syndrome.

Ross explained that the study team then undertook an exploratory analysis “to look at outcomes, including PFS from the end of chemoradiotherapy, to try to mirror the findings of the PACIFIC trial.”

“Our PFS [rates] at 12 and 18 months from the end of chemoradiotherapy were 78% and 72%, respectively,” she said. “The PACIFIC trial reported PFS at 12 months of 55.9%, and at 18
months of 44.2%.”

Based on these phase 2 findings, Ross said, “We think the neoadjuvant approach merits further study in unresectable stage III NSCLC.”

References

1. Key statistics for lung cancer. American Cancer Society. Updated January 12, 2021. Accessed
June 9, 2021. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html
2. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes with durvalumab after
chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial. J Clin
Oncol 2021;39(Suppl 15):abstr 8511. doi:10.1200/JCO.2021.39.15_suppl.8511
3. Grady D. Yearly lung cancer scans are advised for people 50 and over with shorter smoking
histories. The New York Times. March 9, 2021. Accessed June 9, 2021. https://www.nytimes.
com/2021/03/09/health/lung-cancer-smoking-screenings-black-women-younger-adults.html
4. Ross HJ, Kozono DE, Urbanic JJ, et al. AFT-16: phase II trial of neoadjuvant and adjuvant
atezolizumab and chemoradiation (CRT) for stage III non-small cell lung cancer (NSCLC).
J Clin Oncol. 2021;39(Suppl 15):abstr 8513. doi:10.1200/JCO.2021.39.15_suppl.8513

ASCO Clinical Spotlight: Camille Hertzka Addresses 5-Year PACIFIC Trial Findings, Future Ambitions for Durvalumab

CAMILLE HERTZKA, vice president and head of oncology, US Medical, AstraZeneca, discussed
updated findings of the PACIFIC trial indicating that a third of patients with unresectable non–
small cell lung cancer are stable at 5 years.

Updated findings of the PACIFIC trial showed an overall survival (OS) rate of 43% in patients with unresectable non–small cell lung cancer (NSCLC) after 5 years of treatment with durvalumab,¹ which is a promising trend that will continue to be investigated in future clinical trials, said Camille Hertzka, vice president and head of oncology, US Medical, AstraZeneca. FDA approved durvalumab, sold as Imfinzi, in this setting in February 2018.² This interview has been edited lightly for clarity.

EVIDENCE-BASED ONCOLOGY™ (EBO): As you report 5-year data on PACIFIC, what percentage of stage III NSCLC patients are receiving the regimen of concurrent chemotherapy followed by durvalumab?

HERTZKA: We’ve seen from the very beginning—from the first presentation [of results], and after the FDA approval—a lot of enthusiasm around these data. And now, we see that approximately 70% of patients are currently being treated with the PACIFIC regimen.¹

EBO: Updated results on subgroups will be reported later, but OS data suggest favorable outcomes for several patient groups. Do the subgroup analyses generally hold up?

HERTZKA: Let me start first with the overall benefit that we see in the study. In the primary analysis we reported a couple of years ago, [there was] an improvement in [progression-free survival] as well as OS. During these analyses at [the American Society of Clinical Oncology annual meeting], we presented a 5-year follow up, which is a critically important milestone when you think about lung cancer, and unresectable stage III lung cancer.

We reported that 43% of the patients included in this study who were treated with durvalumab [were] alive 5 years later, which is really significant for this disease. To me, what is [also] extremely important to consider is the number of patients who have not progressed during these years: One-third of patients who were treated with durvalumab were still progression-free at 5 years.

[More specifically], they were treated for a year with durvalumab after chemoradiation, which means that for this one sort of patient, they have been free of treatments and free of progression for 4 years. It’s really significant for patients.

That is a preliminary analysis, where we had power to demonstrate results into the primary end point. If we look at the subgroup analysis, it has been really consistent over time that the benefits were reported and observed across the different subgroups. What we’ve seen from the very beginning was a tendency of having women, patients who are younger, or patients with earlier stage [of having] a slightly better benefit, but it’s very difficult to say if it’s a better benefit or if it’s just prognostic of these patients.

When you look across studies in lung cancer, you will always see that women have a slightly better prognosis than men; you would [also] always see that younger patients would have a better prognosis. So, I think when we look at these subgroups, it’s important to consider what is predictive and what is prognostic. From what we’ve learned, there was nothing that really stood out that was a surprise. And it’s consistent over time; nothing really changed at the 4-year or 5-year mark.

EBO: Do the 5-year data support new screening guidelines that will call for screening patients for lung cancer at earlier ages? What can be done to boost screening rates?

HERTZKA: That’s a really good question. To me, the priority at this stage is that we need to get all patients who should be screened to be screened. That is a first step.

We see so many patients, and especially medically underserved patient populations, who are not doing the screening as they should. We see so many smokers who feel that they don’t want to hear about bad news so they will wait a little bit longer. [This] is associated sometimes with this fear of feeling guilty that they did something.

It’s also important that we raise greater awareness about the importance of screening in general. So, what can we do? Raise awareness, make noise, tell everybody how important it is to do screening because of the impact it can have. And PACIFIC is a way to tell the story of what an impact it can make, because if you’re not treated early, you will have a late-stage disease and the outcome will be totally different. I don’t think the 5-year milestone is the main point.³ I think PACIFIC in general [is the point], plus all the other studies—specifically, [I’d like to] mention ADAURA, which was presented last year with osimertinib in [an] even earlier stage. That is another very important milestone.⁴

The advances we are making in the early stage are going to be even more impactful if more patients are diagnosed earlier. So, we need to do everything [possible] to get to patients who should be screened earlier for lung cancer and beyond lung cancer, I have to say. And [I’d
like to] add that a lot of technologies are being assessed to improve screening rates, to improve detection of early cancer, and that is a very exciting path moving forward.

References

1. Spigel D, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes with durv alumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial. J Clin Oncol. 2021;39(Suppl 15):abstr 8511. doi:10.1200/JCO.2021.39.15_suppl.8511
2. FDA approves durvalumab after chemoradiation in unr esectable stage III NSCLC. News r elease. FDA; February 20, 2018. Accessed June 12, 2021. https://www .fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-after-chemoradiation-unresectable-stage-iii-nsclc
3. Bradley JD, Nishio M, Okamato I, et al. P ACIFIC-2: phase 3 study of concurr ent durvalumab and
platinum-based chemoradiotherapy in patients with unr esectable, stage III NSCLC. J Clin Oncol.
2019;37(Suppl 15):abstr TPS8573. doi:10.1200/JCO.2019.37.15_suppl.TPS8573
4. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor r esection: ADAURA. J Clin Oncol.
2020;38(Suppl 18):abstr LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5